THEORY AND APPLICATIONS

IN COMPUTATIONAL CHEMISTRY:
THE FIRST DECADE OF THE
SECOND MILLENNIUM

Pavia, Italy 2 7 September 2012

EDITORS
Enrico Clementi
Jean-Marie Andr
J. Andrew McCammon

AIP CONFERENCE PROCEEDINGS 1456

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Clementi THEORY AND APPLICATIONS IN COMPUTATIONAL CHEMISTRY:
Andr McCammon 1456
THE FIRST DECADE OF THE SECOND MILLENNIUM

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 THEORY AND APPLICATIONS
IN COMPUTATIONAL CHEMISTRY:
THE FIRST DECADE OF THE
SECOND MILLENNIUM

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 To learn more about the AIP Conference Proceedings Series,
please visit http://proceedings.aip.org

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 THEORY AND APPLICATIONS
IN COMPUTATIONAL CHEMISTRY:
THE FIRST DECADE OF THE
SECOND MILLENNIUM
Pavia, Italy 2 7 September 2012

EDITORS

Enrico Clementi
International Academy Quantum Molecular Sciences, Como, Italy

Jean-Marie Andr
University of Namur, Namur, Belgium

J. Andrew McCammon
University of California, San Diego, California

SPONSORING ORGANIZATIONS
Universit degli Studi di Pavia
Fujitsu & RIKEN AISC
Comitato TACC

Melville, New York, 2012

AIP | CONFERENCE PROCEEDINGS 1456

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 Editors

Enrico Clementi
International Academy Quantum Molecular Sciences
Via Carloni 38
22100 Como
Italy
E-mail: enrico.clementi@tin.it

Jean-Marie Andr
Department of Chemistry
University of Namur
Rue de Bruxelles 61, B-5000 Namur
Belgium
E-mail: Jean-Marie.Andre@fundp.ac.be

J. Andrew McCammon
Department of Chemistry and Biochemistry
University of California, San Diego
La Jolla, CA 92093-0365
USA
E-mail: jmccammon@mail.ucsd.edu

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Theory and Applications in Computational Chemistry:

The First Decade of the Second Millennium

Enrico Clementi, Chief Editor,
Jean-Marie Andr Co- Editor,
J. Andrew Mc Cammon, Co-Editor.

Theory and Applications of Computational Chemistry

TACC-2012 and K computer day
University of Pavia, 2-7 September, 2012
 AIP Conference Proceedings, Volume 1456
Theory and Applications in Computational Chemistry: The First Decade of the Second
Millennium
International Congress TACC-2012

Table of Contents

Preface: Theory and Applications in Computational Chemistry: The First Decade of the Second
Millennium-Dedication to the Academic Editors of the International Journal of Quantum
Chemistry
Enrico Clementi, Jean-Marie Andr, and J. Andrew McCammon 1

CHAPTERS

Evolution of computational chemistry, the "launch pad" to scientific computational models: The
early days from a personal account, the present status from the TACC-2012 congress, and
eventual future applications from the global simulation approach
Enrico Clementi 5

The next decade of computing

Greg Taylor 55

The 'big picture' of relativistic molecular quantum mechanics

Wenjian Liu 62

AGP: Search for the consistent RPA reference state

Yngve hrn 67

Concepts of chemical bonding from electron propagator theory

J. V. Ortiz 73

Recent advances in spin-free state-specific and state-universal multi-reference coupled cluster

formalisms: A unitary group adapted approach
Rahul Maitra, Debalina Sinha, Sangita Sen, Avijit Shee, and Debashis Mukherjee 81

Explicitly correlated projector Monte Carlo method based on Slater determinants (PMC-SD-F12
method)
Yuhki Ohtsuka and Seiichiro Ten-no 97

SAC-CI methodology applied to molecular spectroscopy and photo-biology

J. Hasegawa, T. Miyahara, H. Nakashima, and H. Nakatsuji 101

Quantum chemistry, band structures and polymers

Jean-Marie Andr 109

v
Beyond NICS
Stefano Pelloni, Guglielmo Monaco, Riccardo Zanasi, and Paolo Lazzeretti 114

Semiclassical instanton theory of nonadiabatic reaction rate constant. I. Formulation

Yoshiaki Teranishi, Hiroki Nakamura, and Sheng H. Lin 119

QM/MM studies of gas-liquid collisional energy transfer

Xiaohu Li and George C. Schatz 131

Design of modified proteins using knowledge-based approaches

Yves Dehouck, Dimitri Gilis, and Marianne Rooman 139

On the fundamental processes in molecular electrical doping of organic semiconductors

Georg Heimel, Ingo Salzmann, and Norbert Koch 148

Computational approaches to target fishing and ligand profiling

Didier Rognan 157

Accelerated molecular dynamics: Theory, implementation and applications

Yi Wang and J. Andrew McCammon 165

Sampling and statistics in biomolecular simulations

Hoon Sim, Karthikeyan Diraviyam, Akansha Saxena, and David Sept 173

Narrowing the gap in understanding protein structure and function through computer
simulations
Hong Guo 180

Minimalist models for biopolymers: Open problems, latest advances and perspectives
Fabio Trovato and Valentina Tozzini 187

Exploring folding pathways of single proteins using mechanical manipulation

Ptur O. Heidarsson and Ciro Cecconi 201

Molecular dynamics techniques in the studies of the bacterial ribosome

Joanna Panecka and Joanna Trylska 207

Molecular dynamics simulation of water in the low temperature region

A. Krallafa, A. Adda, A. Seddiki, and M. Dauchez 215

Structure of crown ethers

A. A. El-Azhary, N. Al-Jallal, A. Al-Kahtani, N. Al-Badri, K. Al-Farhan, and M. Al-Qunaibit 223

Controlling drug efficiency by encapsulation into carbon nanotubes: A theoretical study of the
antitumor Cisplatin and the anti-HIV TIBO molecules
R. Bessrour, Y. Belmiloud, Z. Hosni, and B. Tangour 230

Nanoscale chemical mapping through plasmonic tips on AFM-based cantilevers

M. Patrini, F. De Angelis, R. Proietti Zaccaria, M. Francardi, M. Lazzarino, L. Businaro,
and E. Di Fabrizio 241

vi
On the use of symmetry in SCF calculations. The case of fullerenes and nanotubes
C. M. Zicovich-Wilson, Y. Nol, A. M. Ferrari, R. Orlando, M. De La Pierre, and R. Dovesi 249

Nanotechnology drives a paradigm shift on protein misfolding diseases and amyloidosis

Vittorio Bellotti and Monica Stoppini 257

Quantum Chemical Topology: Knowledgeable atoms in peptides

Paul L. A. Popelier 262

OBITUARY

Remembering Cesare Pisani

Roberto Dovesi 273

Remembering Bjrn O. Roos

Enrico Clementi 274

Remembering Eolo Scrocco

Caterina Ghio, Maurizio Persico, Carlo Petrongolo, and Jacopo Tomasi 275

Author Index 277

vii
 Preface: Theory and Applications in Computational Chemistry:
The First Decade of the Second Millennium

Dedication to the Academic Editors of

the International Journal of Quantum Chemistry

It is a pleasure and an honor to dedicate this AIP proceedings volume to the

Academic Editors of the International Journal of Quantum Chemistry. The theoretical
and computational quantum chemistry community recalls with gratitude their
dedication and leadership; their generous effort has ensured a free international journal
for high level research, excellently monitored by Editors of internationally recognized
competence.
It is a pleasure and an honor to recall Per-Olov-Lwdin, the journal founder and
Editor in Chief, as well the early Honorary Editorial Board members, W. Heitler, R. S.
Mulliken, J. C. Slater, and the subsequent Editors Jean-Louis Calais, and Yngve hrn,
and the associated Editors Osvaldo Goschinski, John Sabin, Michael Zerner and Erkki
Brndas. The Journal for many years has published proceedings from the Sanibel
Symposia as Supplementary issues. The Sanibel Symposia and the International
Journal of Quantum Chemistry have immensely helped to shape theoretical and
computational chemistry.

Enrico Clementi, Jean-Marie Andr, and J. Andrew McCammon

Theory and Applications in Computational Chemistry: The First Decade of the Second Millennium
AIP Conf. Proc. 1456, 1-1 (2012); doi: 10.1063/1.4730640
2012 American Institute of Physics 978-0-7354-1057-2/$30.00

1
CHAPTERS
 Evolution of Computational Chemistry, the "Launch Pad to
Scientific Computational Models: the Early Days from a
Personal Account, the Present Status from the TACC-2012
Congress, and Eventual Future Applications from the
Global Simulation Approach.
Enrico Clementi

Via Carloni 38 , 22100 Como (Italy)

Abstract. This is the introductory chapter to the AIP Proceedings volume Theory and Applications of Computational
Chemistry: The First Decade of the Second Millennium where we discuss the evolution of computational chemistry.
Very early variational computational chemistry developments are reported in Sections 1 to 7, and 11, 12 by recalling some of
the computational chemistry contributions by the author and his collaborators (from late 1950 to mid 1990); perturbation
techniques are not considered in this already extended work.
Present days computational chemistry is partly considered in Sections 8 to 10 where more recent studies by the author and
his collaborators are discussed, including the Hartree-Fock-Heitler-London method; a more general discussion on present day
computational chemistry is presented in Section 14. The following chapters of this AIP volume provide a view of modern
computational chemistry.
Future computational chemistry developments can be extrapolated from the chapters of this AIP volume; further, in Sections
13 and 15 present an overall analysis on computational chemistry, obtained from the Global Simulation approach, by considering
the evolution of scientific knowledge confronted with the opportunities offered by modern computers.
Keywords: quantum chemical models, molecular interaction potentials, molecular dynamics models, fluid dynamics,
graphics, computer architecture, parallelism, global simulations methodology, biological and medical research.
PACS: 03.65.-w, 03.75.Hh, 05.10.Gg, 07.05.Bx, 07.05.Tp, 31.15.A-, 71.15.-m, 74.20.Pq, 83.50.Ha, 87.10.-e

1. EARLY QUANTUM CHEMISTRY

A) An introductory comment. Our knowledge is necessarily constrained by the physical limitations of the human
body, which - in turn- appears to be the product of an evolutionary response to our planet overall environmental
constraints. As a consequence, the rationalization of what we accept as experimental reality is limited and
conditioned both by our human sensorial limits (input) and by the neuronal mechanism, we use to organize our
experience into knowledge (output). The ancient - but ever present - quest for an absolute knowledge appears
more and more as a rather romantic wish, the more we learn on the complexity of the universe around us and on the
physiological limitations of our body.
Knowledge is the ensemble of what we (each one of today seven billion humans) know, individually, thus an
enormous amount of information on either verifiable or assumed events. Therefore, we talk either of an individual
and subjective or of a collective knowledge. The latter includes information -true and false- from the humanity
past and present, including science, but excluding irrelevant events, namely those fully private and personal. In
this work we limit our interest to a few aspects of science. The collective knowledge can be partitioned into two
types: a) a rational and logical organization of verifiable events, albeit clearly limited to our human time-space, b)
other forms of collective knowledge (related for example either to philosophical, or political, or mystical or religious
or artistic, or etc. visions), where events verification and logic are not considered essential. In this work we shall
deal mainly with type a), which is based on verifiable observations, leading logically to axioms, laws, rules and
hypotheses, and to phenomenological concepts and models, in short, the likely best possible logical knowledge for
humans. We hurry to stress that type b) knowledge certainly represents a contributing to our human cultural
evolution, most unlikely in real conflict with type a), as long correctly exposed and critically interpreted. In our
opinion, type b) knowledge needs to accept type a) as its logical base; we recognize, however, the fact that many
people claim type b) to be the foundation for type a).

Theory and Applications in Computational Chemistry: The First Decade of the Second Millennium
AIP Conf. Proc. 1456, 5-54 (2012); doi: 10.1063/1.4730641
2012 American Institute of Physics 978-0-7354-1057-2/$30.00

5
 In this section we recall a few aspects of quantum theory essential in particular to quantum chemistry and, in
general, to computational chemistry and computational sciences.
B) Beginning of quantum mechanics. Nearly one hundred years ago, an energy equation to explain the electronic
motion in the hydrogen atom1 was proposed and successfully tested, marking a triumph for Bohrs atomic theory. As
a consequence of Bohrs model, hope spread in the scientific community that the energy of atoms and molecules
would soon be easily and accurately available from theoretical models and computational verifications. Today we
refer to this renaissance mentality as the "Copenhagen spirit".
As we know, the Bohr central field model2 was soon supplemented by Uhlenbeck and Goudsmith's electron spin
discovery,3 by the exclusion principle of Pauli,4 by the Schrdinger equation,5 the latter soon approximated first with
a simple product of orbitals by W. Hartree and D. Hartree,6 then with an orbital determinantal function, the Hartree-
Fock proposals 7-10 later refined with the inclusion of atomic near degeneracy,11 leading to the general Hartree-
Fock model. We shall use the notation EWD, EHF, EgHF, and Eexact,n..r. for the simple product, Hartree-Fock,
generalized Hartree-Fock and exact-non relativistic energies.
The 1930 determinantal representation of a wave function due to Slater12 remains a standard, even if not unique
representation13 for wave functions built with one-electron functions, the spin-orbitals. As well known, wave
functions constructed as linear combinations of Slater determinants can lead -in principle- to exact non relativistic
wave functions and energies. With the variational principle, initial orbital guessed for the simple product or for the
Hartree-Fock determinant6-10 can be optimized, leading to the well defined energies, EWD, EHF and EgHF percent wise
increasingly accurate, but, unfortunately, not sufficiently so as to reliably reproduce specific atomic or molecular
expectation values.
Electrons are not only negative charged particles with a well defined mass, but also have a spin, a new feature not
present in classical point charge electricity, where the Coulomb interaction law is enunciated to fully represent the
interaction of charged particles. For the wave function of an electronic distribution, subjected to the Pauli principle,
the energy difference (EHF - EWD), called pre-correlation energy,14 accounts for an energy correction to the
Coulomb law (resulting from the orbital deformation comparing HF with WD) and for an exchange energy
correction for electron pairs with opposite spins. The energy difference, Eexact n.r -EHF was designated by Wigner15 as
correlation energy (a correct definition is more specific, since it differentiates the Hartree-Fock correlation
energy from different correlation energies related to different models, as discussed in the following paragraph).
C) Wigner functional. Recall that in the early 1930s, Wigner proposed a general algorithm15 to estimate the value
of the correlation energy, Ec.HF, considered as a perturbation to be added to the Hartree-Fock energy (often below we
shall use the simpler notation Ec, rather than Ec.HF, if there is no ambiguity.) Wigner approximated the correlation
correction with a functional of the electronic density, designated as , of the form:
Ec = ()d = [a1 + a 2 ) /( a 3 + )] d
1/ 3 1/ 3
(1)
with the HF electronic density of the system and a1, a2, a3 fitting constants obtained as a particular solution of the
free electron model, the latter being exactly soluble. Wigner's work, somewhat disregarded at the time by quantum
chemists, results from the hypothesis that at any inter-electronic distance, two electrons interact not only in
accordance with the Coulomb law (accounted in the Hartree-Fock model) but also require a correlation correction,
for example the one approximated by Eq. 1. (For an interacting electron pair we can think that each electron is
surrounded by a spherical volume more and more "impenetrable" to other electrons the shorter the distance between
the two electrons.)
The electronic density functional of Eq. 1 was extended for example by Gombas16-19 in the 1940s in Hungary,
complementing Wigner term, valid essentially for high density, with a second term for low electronic density. The
equivalent of Eq. 1 was reformulated by Clementi20 in the early 1960s in the USA, by correcting the atomic
electron-electron interaction at very short inter-electronic distances with a Coulomb hole correction. In Clementis
formulation the correlation correction is included as integral part of the Hartree-Fock formalism. Thus, the modified
Hartree Fock energy results from the electron nuclear attraction, the kinetic energy, the Coulomb repulsion, the
exchange correction and the Coulomb hole correlation correction, all this constrained by the virial theorem. As one
can see, Clementis model anticipates the Khon-Sham density functional model (see section 4) by about two
decades, and it retains the wave functions formalism as starting point of quantum mechanical concepts. Initial
applications were on atomic systems, obtained on a modified atomic Hartree-Fock code (at the time there was no
Hartree-Fock molecular code for molecules of general geometry to complement the atomic study). The
computational community did not adopt Clementis model, since interested in different approaches, particularly
proposals of configuration interaction expansions. The early designation for Eq. 1 was "statistical approximation" as
used by Wigner; Clementi made use of this designation for several years (till the early 1970s), but then -since

6
Wigner approximation was essentially unknown to chemists- he turned to the designation "Wigner Density
Functional Approximation"21 and/or "Coulomb Hole approximation".
In general, in the above discussions, it is implicitly (or explicitly) assumed that the Hartree-Fock model should be
considered as "the reference" first order solution of atomic and molecular electronic wave functions. Such an
assumption is likely reasonable for atomic systems (even if it is limited only to non relativistic atoms), however, it is
unacceptable for molecular systems, in view of the disastrous HF behavior at molecular dissociation. A more
general definition of correlation energy, is as follows: the energy difference between the exact non-relativistic
energy and the energy obtained from a reference wave function, the latter capable to correctly model a molecule, at
least qualitatively, as a system of nuclei and electrons both at equilibrium and as a system of interacting atoms at
dissociation (for details see Sections 5).
A more logical development of quantum chemistry would have accepted these considerations as essential,
recalling also the clear analysis in the classic C. Coulson and I. Fisher Hjalmars work.22 However, science moves
not only under the pressure of logic but also under the pressure to develop algorithms useful for many and different
technical applications. It appears that the latter pressure is nearly a dominant characteristic of quantum chemistry,
likely because -all in all- chemistry has mainly applied connotation. (Recall that in the university systems, chemistry
teaching as independent departments is a late eighteen century Swedish innovation.21)
D). 1930-1960 computational chemistry. In summary, the quantum chemistry theoretical landscape, neglecting ad
hoc approaches for two (or very few) electron systems, essentially did consist - up to early 1960 - of the Hartree-
Fock model for atoms and -for molecules- either of the single determinant approximations built with approximated
atomic orbitals, the well known Linear Combination of Atomic Orbitals, LCAO approximation pursued particularly
by R. S. Mulliken23 or of a model, called Valence Bond proposed by Heitler and London24 (see section 9), where
molecular wave functions are constructed with the wave functions of the constituent atoms at dissociation. However,
in view of the numerical complexity in the use of these two models (recall that computers did start to appear only in
the late 1940s) semi-empirical approximations were generally adopted, like the Hckel25 model for molecules and
the Zener-Slater approximation for atoms (see section 2). In general, the early spectroscopy research made use of the
Hartree-Fock or of the LCAO approximations and chemical reactions were explained with the Heitler-London
approximation, since the latter can deal with bond breaking. Wigner correction of the Hartree-Fock model was
ignored by quantum chemists, but used in solid state (note that quantum chemists ignored also the Thomas Fermi
atomic models,26-28 since assumed not to be capable to describe a chemical bond).
E) Semi-empirical computational methods. The use of semi-empirical models is nearly unavoidable in order to
tackle problems too large for available ab initio approaches. In our experience this can be exemplified by the very
early Clementi computations on carbon molecules performed while post-doctor in Berkeley with Prof Kenneth S.
Pitzer. At the time (1958) an accurate heat of dissociation for C2 was experimentally not firmly available; Professor
Pitzer suggested to Clementi to consider carbon vapor, to see if computations could shed some light. Two types of
computations were undertaken: one29 on C2 ground and excited states, which adopted the Pariser-Parr model,30 P-P,
at the time nearly an ab initio computation, the other31 more exploratory dealing with Cn molecules, with n3. The
first work yielded correct binding energies and excited states in the correct order, but accepting as valid the 1958
spectroscopic data, today known to be incorrect for C2 (the method adopted made use of semi empirical values,
related to the experimental excitation energy incorrectly available from experimental data of the time). The P-P
model was extended to C.I. type computations by decomposing the Slater determinant made of the LCAO diatomic
function into a set of determinants representing both neutral and ionic components, and selecting only those
components which did yield correct dissociation states32 of carbon fragments. In that work a few matrices had to be
diagonalized and this lead Clementi to discovered a new tool, the computer.
The Cn computations were performed with a computational approach proposed by Mulliken, Rieke and Brown33
much simpler than the P-P model, so much that Clementi could consider all Cn species, with n from 3 to 17. The
Molecular Orbital energies calculation on Cn was analogous to that for hydrocarbons chains with alternating single
and double bonds. From these computations the heat of formation H0 for the Cn linear polymers of carbon atoms
was determined to be equal to the H0 for C3, 186.5 kcal/mol, multiplied by (n-3) times the heat of formation for an
interior carbon atom.31 It was postulated that at high temperatures the linear chain could deform into loops and
rings. The computational results were consistent with mass spectrometric data.34 It was 1959; the work was
presented at the Boulder Colorado Conference, it impressed Prof. Mulliken and Clementi moved to Chicago, the
Mecca of theoretical chemistry.
Thus since the late 1950s we learned that carbon atoms do not form only the C2 and C3 molecules but also
extended linear polymers and rings, as much later confirmed in another discovery for Cn molecules: the C60 (1996),
a triumph for chemistry and for H. Kroto, K. Curl and R. Smaley. The Cn molecules, linear or closed, are families of
unexpected carbon structures. The saga continues, for example, with the nano-materials.35 Slowly we are learning

7
to view molecules differently from the teaching of traditional chemistry, namely not only as a combination of atoms
with vastly different shapes and size, but also with the specific functions typical of machines, thus embryonic
molecular machines (see for example the proposal by G. Prez-Hernndez and collaborators36). The commonly
accepted postulate that a living cell is equivalent to a most sophisticated chemical plant starts to slowly reveal the
details of the chemical plant blueprint, namely the presence of specific molecular machines. If we attribute life to
a cell (the chemical plant) perhaps we should do the same for selected molecules, the machines of molecular
specific functions. This brings a totally new horizon to our understanding of chemistry, particularly organic
chemistry, now much nearer to molecular biology and life sciences. In this view-point, nucleic acids and proteins are
simply a well publicized specific type of molecular machines.
Exciting, but let us recall that today quantum chemistry is a very limited field within computational chemistry, and
that the latter is very limited compared to the overall efforts of modern science, which in turn is only of limited
interest for the billions of people attempting to survive in our planet. Therefore, in this paper we shall connect
computational chemistry not only to selected general aspects of science but also albeit most tentatively- to models
for social human organization.

2. FROM ATOMS TO MOLECULE (1950-1965)

A) Selected aspects of the Hartree-Fock era as seen from the Mullikens laboratory at the University of
Chicago. The main total energy component in an atom is the nuclear-electron attraction, constrained by the nuclear
electronic screening and reduced by the electro-electron repulsion. John Slater37 proposed rules to account for the
atomic nuclear screening experienced by each electron due to the remaining electrons. Recall that on the base of
Bohr atomic theory, Zener38 approximated an atomic orbital with the function Nrn-1exp(-r)Y(,), where N is a
normalization constant, n the electron principal quantum number, r the electron-nucleus distance, a screening
parameter and Y(,) the spherical harmonics of an electron with quantum numbers l and m.
In molecules, in the traditional Linear Combination of Atomic Orbitals, Molecular Orbital23 approximation
(LCAO-MO) the atomic orbitals were initially represented by R.S. Mulliken with "Slater screening constants". In
the 1950-1960 the numerical atomic Hartree-Fock self consistent field procedure was revolutionized by C. C. J.
Roothaan39,40 who proposed a self-consistent approximation capable to yield Hartree-Fock wave functions by
expanding the LCAO molecular orbitals into appropriated basis sets, for example of Slater type orbitals; the
approach is the so called Restricted Analytical Hartree-Fock method, RHF, today universally used. The term
"restricted" points out that the Roothaan wave function has correct total spin and angular momentum; the RHF
assumes that a molecular orbital is doubly occupied even approaching dissociation. Recall that acceptance of
incorrect spin representation leads to a simpler algorithm, the "unrestricted Hartree-Fock" approximation, UHF.
With the early RHF computer codes written at the University of Chicago in the late 1950s, it was possible to
variationally optimize the atomic screening constant values; indeed, is a variational parameter. Mulliken's
collaborators in Chicago, using Roothaan's RHF approximation (and computer codes), compared computations of
diatomic molecules (with atoms from H to F) either retaining Slater screening values or with variationally
optimised41 molecular values; the Slater's screening rule values turn out to be rather close to the variational ones.
The systematic study of screening constants for atomic systems was later resumed by Clementi et al.42,43 at the IBM
Research San Jose Laboratory, as later discussed in this work.
Superior quality wave functions can be obtained by increasing the variational freedom of the LCAO-MO-SCF
wave functions, for example replacing computations with only one Slater type function per orbital (a technique
called single zeta SCF wave functions) with a linear combination of Slater type functions; this originated the
notations "single zeta", "double zeta", "triple zeta" etc., when 1, 2, 3, etc., Slater-type functions44 are used to
represent a given atomic orbital.
In Chicago, Clementi experimented with this new approach and computed a wave function for the ground state
of the hydrogen fluoride molecule and its molecular ion,44 at a number of inter-nuclear distances, with a multiple
zeta expansion including polarization functions (introduced in the 1950s by Linnet45) attempting to get near to the
limit of the RHF energy. The motivation of this work was a study of the HF molecule by B. Ransil with a minimal
basis set on the F atom orbitals and double zeta on the H atomic orbital; the computation yielded an energy gain, but
the population analyses of the molecule yielded a F+H- electronic distribution. Thus the extension of the basis set
had to be performed with notable care, following practical rules proposed to obtain "balanced basis set for the atoms
constituting the molecule".44 Clementi's HF molecule computation44 is the first many-electron molecular
computation approaching the Hartree-Fock energy limit; the computed atomization energy, De(HF), was rather poor
compared to laboratory data, 92 kcal/mol rather than the experimental 141.5 kcal/mol, but better than 59 kcal/mol
obtained with single zeta basis sets (the HF energy limit is 101.23 kcal/mol). The experimental binding energy,

8
De(exp), was decomposed into the computed Hartree-Fock molecular binding energy plus a molecular correlation
energy component, (HF), called the "molecular extra correlation energy", defined as the difference between the
molecular total correlation energy Ec for the molecule and the sum of the atomic correlation energies, a, thus

(HF)= Ec - a. (2a)

De(exp)=De(HF)+(HF) (2b)
The value of (HF) is expected to increase proportionally with the number of valence electrons, since electrons on
one atom in a molecule correlates not only with the other electrons on the same atom but also with all the electrons
in the molecule; it is also expected that (HF) will be nearly transferable from molecule to molecule for a given
chemical bond, since related to interactions of approximate equivalent electronic distributions. This computation
marks the end of the LCAO-MO approximation and the beginning of the Hartree-Fock era for chemistry, but also
the concomitant awareness of the large correlation energy error present in molecular HF computations. An
extended account of Clementi Hartree-Fock contributions in quantum chemistry is available in MOTECC-8946 as
well in the papers referred in two volumes47,48 published by the International Journal of Quantum Chemistry in
honor of Clementi.
The hydrogen fluoride computation was soon confirmed by an essentially equivalent computation obtained by R.
K. Nesbet,49 at the time at MIT in the J. C. Slater laboratory. Today this computation can be given as an easy
exercise to a freshman quantum chemist; at the time it was a major achievement; M. Karplus published in the
Journal of Chemical Physics an extensive comment50 comparing Clementi and Nesbet computations.
A few personal recollections from Robert S. Mulliken's laboratory, the Molecular Structure and Spectra, LMSS
laboratory (on the last floor of the Ryerson Building, Department of Physics, University of Chicago) in the early
sixties. Professor Mulliken ("RSM" as we would call him) writing papers at his desk, with gloves, coat and hat,
during winter time on Sunday mornings (the University heating system used to be cut off on each Friday evening);
Douglas McLean and Magume Yoshimine, at the time doctoral students, debugging sections of a new molecular
code for linear molecules, their feet on the table, eyes semi-closed, no paper in front, recalling and debugging the
molecular code by pure memory; Clementi and Roberto Moccia sharing an office; Dr. Wlodeck Koos and Dr.
Sigeru Huzinaga quietly, nearly privately, discussing science; a wall covered by four large blackboards on which
Professor Clemens C. J Roothaan (called "C2") would write the SCF atomic code, with small, neat, accurate
characters, below a large warning note "do not cancel". The University of Chicago at the time had no computational
facilities; the only computer in the region was at the Wright Air Development Center in Dayton, Ohio. Thus, weekly
air flights at 6.00 am from Midfield airport in Chicago to Dayton U.S. Air Force base, to use a Univac computer,
available to Prof. Mulliken by a special Air Force contract (to develop the atomic and molecular computer codes).
The computer input was a punched paper tape, the magnetic tapes were laminar strips of steel, physically most
heavy; we would start early in the morning and leave the base in the evening, all the time locked -for security
reason- in a vast room, directly connected to the computer. There are many anecdotes about the LMSS people in
Dayton, concerning P. Bagus, S. Fraga, G. Malli, S. Huzinaga, M. Yoshimine, A. Weiss and others from LMSS.
B) Computational chemistry at the IBM-Research Division in San Jose California (1960-1972). For Clementi, a
postdoctoral at the Chicago University in Mullikens Laboratory of Molecular Structure and Spectra (1959-1960),
the hydrogen fluoride computation was simply a beginning. Clementi, however, had to address a practical problem,
namely to find a permanent job at a site with large availability of computer time (a rare commodity in the early
1960s) and full freedom of research (a perennial dream for any scientist). These requirements in 1960 were
tantamount to a decision to stay in the USA; thus Clementi accepted a long-standing offer to join the new IBM
Research Division Laboratory in San Jose, California (his fear of working in an industrial environment had relented
due to much advice from R.S Mulliken). From the very beginning his idea was to assemble a group of researchers in
different but strongly connected areas, with the computer as the main tool.
From Mulliken's and Slater's laboratories, a number of excellent computational quantum chemists like A.D.
McLean, M. Yoshimine, P. Bagus, G. C. Lie, B. Liu, R. K. Nesbet joined Clementi at his newly established
department "Large Scale Scientific Computations", a name chosen to stress the department research activities:
mainly quantum chemistry and solid-state computations, and a small effort in fluid dynamics (both air circulation
modeling and a tentative solution to a biophysical problems, the blood flow circulation in humans), and a pioneering
neural networks simulation. The initial group of scientists, Mulliken-Roothaan-Slater trained, was eventually
incremented with equally qualified new worldwide additions. It was a unique opportunity to make very clear to the
scientific community that a new era for science, chemistry in particular, was beginning; thus it was important to
publish high-level computational results at an unprecedented rate. For example, not a few atomic Hartree-Fock wave
functions for a given paper, but a set of papers51-62 (in collaboration with Roothaan, Yoshimine, McLean, Raimondi,

9
Roetti and others) in a short span of time, each one with dozens and dozens of Hartree-Fock wave functions
immediately followed by an evaluation of the correlation energy error63-68 (in collaboration with Veillard) obtained as
the difference from atomic experimental data corrected with the relativistic contribution, the latter obtained as
perturbation on the Hartree-Fock functions69,70 (in collaboration with Hartmann). In addition, a variety of all-electron
molecular computations were performed within the Hartree-Fock approximation to elucidate the electronic structure
in molecules from linear to small polyatomic molecules, including aromatic molecules, and molecular ions.71-81 ( in
collaboration with Lie, Mc Lean, Bak, Kortzeborn, and Davies).
All this required the programming of computer codes, in particular Hartree-Fock codes for atoms and
molecules82-88 (written in collaborations with Veillard, Roos, Salez, Mehl in San Jose and later with Ortoleva,
Castiglione, Corongiu and Estrin in Italy). The starting points were the RHF codes for atoms and linear molecules,
written in assembly language, FAP, from the Roothaan students in Chicago. Eventually it was strategic to move to a
new language, FORTRAN, and to extend the molecular code applicability from linear molecules to molecules of
general geometry, with inclusion of novel routines to increase computational efficiency. The computer codes were
also fully documented and freely distributed with the corresponding source code82-88 to many universities and
laboratories. Further, the scientific papers were freely distributed in advance of regular publication in the form of
IBM Research Division Technical Reports, to speed up dissemination of computational chemistry.
To maximize the growth of computational chemistry, Clementi obtained from Dr. Art Anderson, at the time
director of the San Jose IBM-Research Laboratory, the permission to offer in San Jose both computer codes and
computer time to young theoretical chemists worldwide, thus starting a Visiting Scientist Program, de facto a post-
doctoral plan in an industrial environment. This Visiting Scientist program partially supported by IBM World
Trade- brought to Clementi's department at IBM San Jose, in the years 1961-1972, exceptional collaborators,
generally young quantum chemists, for example, S. Huzinaga, B. Roos, P. Siegbhan, J. Almolf, U. Agreen, A.
Veillard, J-M. Andr, M-C. Andr, W. P. Reinhardt, W. von Niessen, H. Popkie, H. Kistenmacher, C. Roetti, R. O.
Watts, G. H. Diercksen, W. Kraemer, O. Matsuoka, C. Salez, R. G. Body, A. Rauk among others. The Visiting
Scientist program was soon extended to all IBM San Jose Research departments and then to the entire IBM
Research Division. In the years 1979-1991 the Visiting Scientist program resulted essential" to quickly
establishing Clementis "IBM Center of Scientific and Engineering Computations" first in IBM Poughkeepsie, N.Y.
and later in IBM Kingston, N.Y. Note that Clementis plan to foster computational chemistry was an excellent
advertisement for what the computer industry can offer to scientific and technical applications. For Clementi,
however, quantum chemical computations were only one aspect of a more general vision based on interdisciplinary
approach to science. A number of review papers89-93 summarizes Clementis contributions to quantum chemistry at
the IBM San Jose laboratory.
A few recollections from the IBM-San Jose Research laboratory: A). The IBM elegant, modern glass Research
building was situated in Cottle Rd, south of San Jose, our first location in 1960. B). I recall the many discussion with
my managers to ensure a computer fully used and totally available to the IBM San Jose Research laboratory;
discussions to make the computer available firstly also at night time, then also during weekends, finally also during
Christmas and Easter vacation time. The management steadily did concur in each request. C).The nice IBM
computer hall with the huge size wall to wall computer full of light sensor and indicators, white, blue and red;
looking at the light pattern it was possible to distinguish the section of the molecular code in progress, for example,
integral evaluation or SCF diagonalization. D). A morning presentation at the IBM headquarter in Armonk, N.Y.
(following a direct request from T.J. Watson, IBM chairman) to defend the project for a new and powerful
computer. It happened that the previous night an American astronaut did land on the moon, giving Clementi the
opportunity to state to Mr. Watson and to the IBM Board of Directors that "a supercomputer on Earth is more
important than men in space." E). The many excellent visiting scientist, for example Jean-Marie and Marie-Claude
Andr, working at the ab initio band structure polymer code or computing, ab initio, the DNA bases, respectively;
my excitement to see new fields opening up; Geerd Diercksen distributing each Friday the week-end computer time
to the department people. F).The human atmosphere was most friendly, excited by the work opportunity, by the
exceptional computational facilities, and charmed by the stay in the San Francisco Bay area in the 1960 California.
As expected, there were also occasional different but rare situations, like when the visiting scientist fully ignored to
work in an industrial environment, where a minimum of security had to be enforced.
All department scientists, permanent and visiting, were selected and/or approved personally by Clementi, often
with the advice and assistance from a group of international leaders in computational chemistry; depending on the
interest and preparation few of the visitors turned out to become Clementis direct collaborators, but the majority
was free to perform their own research with the support of visiting post-doctorals.

10
 3. EARLY BASIS SETS FOR ATOMS AND MOLECULES

In the Hartree-Fock model the atomic wave functions can be expressed either as numerical tabulations or as
analytical expansions of appropriated basis sets. There are different types of basis sets in quantum chemical
molecular computations, like the hydrogenic, the oscillatory, the exponential (Slater type) and the Gaussian
functions, generally centered at nuclear positions and used with either Cartesian or Spherical coordinates. A typical
atomic Hartree-Fock code, for example those we have distributed since our early days,82,84 did consider all these
possibilities. We recall that the Gaussian functions, introduced by McWeeny94 and by Boys,95 can be used either as
primitive or as contracted. More flexible formulations for Gaussian functions, the generalized Gaussian Functions,
have been proposed,96 but seldom utilized,97 mainly for lack of easy availability of codes.
The computer program for linear molecules had routines to accurately compute many center integrals with Slater
type functions, thanks to the Mulliken School in Chicago (in particular Roothaans students A. D. McLean, M.
Yoshimine and A. Weiss). Due to the difficulty of integrating many-centre electron-electron interaction integrals
with Slater functions, most of today's molecular quantum chemical computations make use of Gaussian functions,
since the corresponding many-centre integration is very rapid. However, we note, that recently the Slater function
integration problem has been successfully solved98 by the Madrid school of Professor Jaime Fernandez Rico.
Other types of representations have been explored, for example functions in confocal elliptic coordinates,99-101
Hylleraas-type functions,102-107 basis sets with the function origin not at the nuclear position, but floating at selected
inter-nuclear distances108 and finite elements.109-111 We mention in this regard that the finite element algorithm was
most successfully used in atomic computations of closed shell systems by Flores.109,110
Most of these alternatives have enjoyed, in general, rather limited application, particularly for many electron
systems in polyatomic molecules. One of the reasons is the lack of freely available computer codes, due to
mathematical complexity and the lack of scientific recognition to code-writing efforts. We stress that the Hylleraas
approach has the potential to yield accurate energies without the need of enormously long expansions. (The
approach has been advocated, for example by Kutzelnigg et al.112 Recall that a general integral package for
Hylleraas integrals has been developed, distributed and documented for example in MOTECC-90113). Further, note
that the Coulomb soft hole approach,114 represents an indirect example of the use of Hylleraas inter-electronic
distances parameterization.
At its beginning the Hartree-Fock era made use of exponential (Slater) functions; however, in 1960 there were
no "available, readymade" molecular basis sets, a stumbling block to the rapid progress in computational quantum
chemistry. Libraries of basis should be a "mandatory" starting facility in computational chemistry, even if very
accurate computations will nearly always advise "ad hoc optimized" basis sets. Pragmatically, libraries of basis sets
are most useful, particularly today, when a number of computational chemists seems not to be any longer able to
optimize basis sets, by also yesterday, in the 1960s, when computational facilities were scarce, and optimized basis
sets did represent an expensive computer task. Thus is not a surprise that one among the tasks selected by the IBM
San Jose computational chemist team was the computation of basis sets to be made available via general and free
distribution. The very extended computations of Hartree-Fock atomic and ionic wave functions with Slater
functions51-62 aimed not only at exploiting the Hartree-Fock model ability to yield atomic electronic structures, but
also to provide computational chemistry with basis sets to be routinely used.
However, the very slow progress in computational chemistry for efficient algorithms to integrate many-centre
Slater functions, did advise Clementi to switch in the mid 1960s to Gaussian functions, with a notable support by S.
Huzinaga, at the time a visiting scientist in San Jose. As a consequence, the need to start once again to tabulate basis
sets, this time for Gaussian functions, a task facilitated by the availability of new atomic and molecular codes.
Basis sets optimization lead to different types of basis sets generation techniques. We recall in this regard the
innovation by F. van Duijeneveldt, who proposed, implemented and documented115 an algorithm for basis set
determination, used even today, but generally known as "even -tempered basis sets".
In the Hartree-Fock model, a basis set of n functions leads to a list of ~n4 two electron integrals, of these few
are large, some small, and many negligibly small. In our early version of an open ended molecular wave function
code, IBMOL, we did introduce algorithms to eliminate or approximate very small integrals. The need to speed up
the computations for the many small, but not negligible two electron integrals lead to the proposal of the "Adjoined
Basis set" algorithm,116 where a contracted Gaussian function is substituted by a new primitive Gaussian function at
appropriated inter-atomic distances, an alternative to today's use of the electrostatic expansions. Another
algorithm117 is the so called "geometrical basis set" where, for a given l type basis set, one selects an initial value for
the orbital exponent, o, and creates N functions with orbital exponents j obtained with the rule:
j=KCj-1 j= 1,,N (3)

11
Tabulations for geometrical basis sets of Gaussian functions for the atoms He up to Rn are available in Ref. 118.
The largest geometrical basis sets today available bring about Hartree-Fock atomic wave functions somewhat more
accurate than those originally presented in the systematic study by Clementi and Roetti,61,62 however, in general
without reaching the accuracy level of the numerical HF functions published by Froese-Fischer.119 Recently,120 the
ground state atomic and ionic functions up to Z=54, with inclusion of iso-electronic series for 2 to 18 electrons, have
been re-optimized starting from large geometrical basis sets. These new wave functions have total energies notably
close to those published by FroeseFischer119 and Bunge et al.121
In summary, today there are a number of reliable and available basis sets, both exponential (Slater type) and
Gaussian. Different and more flexible types of basis set would be most welcomed, but unlikely to appear, due to the
somewhat uncritical attitude of government supporting agencies, generally aiming at "short range and applied
research." Note that at the united atom (very short inter-nuclear separation) and at dissociation the Slater type
functions are preferable, whereas Gaussian functions are acceptable at intermediate inter-nuclear distances, and as
floating functions: this seems to suggest the simultaneous use of two basis sets (one with Slater and the second with
Gaussian functions). Computationally this path should be very feasible, for example by extending the Madrid school
algorithm, with a new one code capable, however, to avoid redundancy.

4. WIGNERS PROPOSAL and the COULOMB HOLE FUNCTIONAL

A) The Coulomb hole approximation. As mentioned in 1C), shortly after the publications of the atomic Hartree-
Fock model, Wigner15 proposed that for two approaching electrons (particularly with anti-parallel spins) there is, in
addition to the classical Coulomb repulsion, accounted in the Hartree-Fock model, a spin-dependent shielding effect,
which prevents electrons from getting too close. Wigner15 derived the correlation energy expression using
perturbation theory on a Hartree-Fock function and used the exact solution of the free electron model to
parameterize the perturbation energy expression in Eq. 1, an approach later extended and revisited.122-124 Note,
however, that the free electron model does not contain point-like positive charges, the nuclei, which we know are
essential and very specific in modeling atomic and molecular systems. Therefore, there is a somewhat logical
inconsistency in the Wigner proposal in both accounting and excluding positive point charges (the HF model, as
zero order, and free electron model). Note that the Coulomb hole behavior was also explored by Coulson.126
The Wigner proposal leads to an approximated correlation energy correction once a density, HF, is available
from the HF model. We designate this correlation energy as Ec-HF, stressing in this notation its dependency on the
Hartree-Fock density. The general form of Wigner correlation energy denoting a density functional as c ,is:
E C HF = HF c ( HF )d (4)
To decrease the HF Coulomb energy and to account for the correlation effects, one could simply screen the two
interacting electrons, for example replacing 1/r12 with 1/( r12), where is a screening parameter. Wigners idea of a
radius r(i) for electron i with spin up, delimiting a space region impermeable to electron j with spin down, suggested
to Clementi an average cut-off limit, density dependent, for the inter-electron distance, a "Coulomb hole"
functional123 which replaces the standard Coulomb matrix element computation between electrons i and j. In more
detail, in the HF computation of the Coulomb integrals, the integration from 0 to infinity over the radial coordinates
r(i) of electron i and the integration over the radial coordinates r(j) of electron j, are modified at r(i)=r(j), where the
two electrons are sharply kept apart in an interval from ra=(r(i)-/2) to rb=(r(i)+/2), whit a cutoff value given
from a density dependent semi-empirical parameterisation.123-125 Thus, the standard Coulomb interaction matrix
element

f (i) f ' ( j)dr ( j) + f " ( j)dr ( j) dr (i)

r (i )
0 0 r (i )
(5)

is replaced by

f (i) f ' ( j)dr ( j) + f " ( j)dr ( j) dr (i)
ra
0 0 rb
(6)

where f(i), f(j), f(j) are the standard Coulomb integral factor expressions relating the orbital basis set
representation for electrons i and j, respectively.123 The above cut off is hard, thus the expression in Eq. 6 is
designated as the hard Coulomb hole, later modified into a soft Coulomb hole125 by replacing the Coulomb
operator [1/rij] with the operator:
[1 exp( r )]/ r
2
ij ij (7)

12
The value of , a semi-empirical density dependent value, was determined by fitting atomic energies, ionization
potentials and available correlation energies. The alternate route, i.e. to compute the electronic density for the two
electrons, was for a long time disregarded, since it would have introduced additional computations, with a notable
increase in the overall computer time.
The introduction of the Coulomb hole correction into the HF Hamiltonian is an indirect way to stress that the
Coulomb law is inadequate at very short distances. Alternatively stated, the Coulomb hole algorithm focus attention
on the nature of the space used in quantum mechanics. In the wave function representation each electron has its own
space, but in the standard computation the distance between two electrons, each one with its own space, is
performed classically, as if there is only one space for the entire universe (second quantization is more precise and
selective, improving on the Hartree-Fock space concept). The Coulomb hole approximation applies not only to
atoms but also to molecules.
The idea to introduce correlation via modifications of the HF interactions, e.g. with the Coulomb hole,126 was
preceded by Slaters proposal to extend the role of the HF exchange energy.127,128 Clearly, an exact non-relativistic
energy value can be obtained with modification in the HF algorithm either by decreasing the Coulomb energy
(Coulomb hole) or by increasing the exchange energy; Slater's work eventually did lead to the x
approximation129,130 a very simple functional of the electronic density. Thus, density functional approximations
(DFA) are recurring ideas from the mid 1930s to the mid 1960s based on the assumption of ready availability of an
HF type wave function. In the last eighty years computational chemist's attention was predominately focused on
linear expansions (either C.I. or Multi-Configuration-SCF, or CAS-SCF, or multi-reference) and on perturbation
methods (particularly Mller-Plesset type or the Coupled Cluster approach). Much later, in this century, the
Coulomb hole approximation has been often re-discovered by quantum chemists, see for example E. J. Bearends and
co-workers.131
B). Density functional in molecular computations. In the early 1970s a Wigner-type expression was used for
molecular systems by Lie and Clementi71,72 in a systematic study of the potential energy in diatomic homopolar and
hydrides. This work addresses from the start the molecular Hartree-Fock inability to dissociate correctly. The
correlation correction was not added to HF solutions, as suggested by Wigner, but was integrated in a modified HF
algorithm, following early 1960 atomic computations.124 Further, the HF function was replaced with a multi-
configuration-SCF function containing configurations selected to ensure a correct dissociation energy. Clearly, the
parameters of the density functional had to be re-optimized to ensure no double counting of the correlation energy
effects arising a) from density functional and b) from the multi-configuration expansion. This work marks the first
quantum chemistry computation making use of a density functional in a multi-configuration-SCF type algorithm,
about a decade before density functionals would be "discovered" by the quantum chemistry community. The model
was successfully and systematically tested for the hydrides and homo-nuclear molecules of the first and second
period of the atomic table. In the early 1970s a Wigner type density functional, with a modified Eq. 1 incorporated
into the HF model, was used132,133 also to compute the binding energy in C2H2, C2H4 and C2H6.
Chemists have a long tradition in using empirical rules (phenomenological short-cuts to rationalize chemical
phenomena, when lacking rigorous theoretical representations) called "magic formulas" by R. S. Mulliken.134 The
realistic energies obtained by combining HF type techniques with density functionals demonstrated by us both for
atoms and molecules and the availability of more efficient HF molecular codes (with ~N2 dependency on the
number of electron-electron integrals rather than ~N4) did represent notable steps forward for quantum chemical
molecular computations; in 1972 Clementi, with the full support by R. S. Mulliken, summarized these
accomplishments in a paper in the USA Academy of Sciences.135
C) Reminder on selected computations for atomic correlation. The HF model did represent an important ab-
initio landmark in quantum chemistry, but ab-initio computation of the correlation correction remains even today a
non trivial task. For low Z atomic systems, we present Fig. 1, adapted from Ref. 136; in this figure, for the ground
state atoms from Z=1 to Z=54 we graphically display the HF energy, E(HF), decomposed into nuclear-electron,
E(HFn-e), electron-electron, E(HFe-e), and kinetic energy, E(HFkin). We report, in addition, the relativistic energy,
E(rel), which from Z=1 to Z=54 is known to be relatively close to the HF energy; note, however, the very different
energy scale in the two insets.
Today systematic very accurate ab-initio computations for the correlation energy in atoms with more than ~20
electrons are not available. However, in the right inset we report the atomic correlation corrections as obtained by
us137 (solid line) from Z=2 to Z=54, by Chakravorty et al.138 (red dotted line) from Z=2 to Z=18, by Flores109,110
(open circles) the latter limited to closed shells, and by early computations by Clementi et al.111 (green dot-dashed
line) for atoms from Z=2 to Z=54. Early work of Clementi60-64,123 from Z=2 to Z=36 is not reported, since
graphically non distinguishable from the energies of Refs.125 and 127. The computations in Refs. 109, 110 and 138
are ab-initio, the remaining use density functional related to the Coulomb hole; the overall trend of the computed

13
correlation energies presented in the figure reveals that we do not have, presently, a robust, reliable, reasonably
simple model to compute accurately correlated atom structures. Note that in the figure we have considered only
attempts of systematic analyses (many publications are available with only one or very few computational
examples).

FIGURE 1. Left: non-relativistic and relativistic atomic ground state energies (see text). Right: correlation energy obtained from
different approximations (see text).

5. INTERACTING MOLECULES
A). The NH4Cl energy surface. It is essential for computational chemistry to be capable to describe the energy
variations in a chemical reaction from the initial to the final states. In a reaction bonds are formed and broken, and
quantum chemical models must be able to correctly represent both processes. The Heitler-London, HL, approach is
capable of correctly describing dissociation products of a molecule, but this is not the case for the Hartree-Fock
approximations. As a consequence, until the early 1960s, chemical reactions were quantum mechanically
rationalized, mainly within the Valence Bond approximation.
In the early 1960s, R.S. Mulliken was interested in the relative stability of inner and outer products in energy
transfer systems occurring in reactions like N(CH3)3 or N(C2H5)3 with hydrogen iodide,139 as traditional, he analyzed
the reaction with the valence bond approach. At that time, Clementi had just completed the coding of a general
molecular program with Gaussian basis sets (contracted or primitives) and with his collaborators had compiled
general basis sets of Gaussian functions. In 1966, during a sabbatical year from the IBM-San Jose laboratory as a
visiting professor at the University of Chicago, Clementi decided to approach Mulliken's problem, but with a
simpler system, NH3 reacting with HCl and with a novel view point.140-142 His idea was that the Hartree-Fock as a
model deals with electrons and nuclei, thus it is not limited to represent only a single molecule, but can also describe
systems of interacting molecules ("simply" more nuclei and more electrons) provided it would be possible to
correctly reach dissociation. Many reactions deal with ground state molecules both as in the starting and final states.
In other words, a system of molecules can be considered as a single super-molecule, more localized in some part of
the space than in others. The required computational work for the reaction NH3 +HCl was the mapping of the
energy surface for the two interacting sub-systems, NH3 and HCl, yielding NH4Cl; this was a seemingly nearly
impossible computational task at the time. However, the availability of a molecular code,82 weekly weekend flights
from Chicago to New York with the days and nights at the computational facilities of the IBM Research Division
headquarter in Yorktown, made it possible to complete the task in nearly one half year;140-142 later a refinement was
added.143 The result was that for the first time, a chemical reaction was simulated ab-initio on a computer,
considering all the electrons, using the HF model.
Back in San Jose the computed energies of the NH3 + HCl surface were graphically displayed on a computer
screen, the same was done for the electronic density. The New York Times (October 10, 1968) and Time Magazine
(November, 1968) reported in detail the accomplishment with pictures of the reaction graphical display; the
computational approach was called by the scientific community "super-molecule" approach. Clementi's papers,140-142
however, was one step ahead and in his publication discussed how the computation would have been, if obtained not
only within the Hartree-Fock model but also in the Multi-Configuration-SCF approximation, "the" supposedly
answer to future quantum mechanical computations. The Hartree-Fock era was reaching its end, being replaced by
the post-Hartree-Fock era.

14
In Fig. 2 we display one frame from a film reporting the electronic density evolution during the reaction, reported
also by the New York Times (top left insert), the 1967 computed energy surface141 (top right inset), the computed
energy curves of the NH3.HCl complex for constant N-Cl distances with variable H bridge positions140 (bottom right
inset) and the 1996 computation of the reaction in vacuo (the higher energy curve in the bottom left inset) and in
solution143 (the lower energy curve in the same inset).
We note, however, that in the real world we seldom merge one single molecule of ammonia with one molecule of
hydrogen chloride. Many molecules are made to collide in an atmosphere of air (nitrogen and oxygen) generally
with some degree of humidity (water). Thus, several years later, the study of the reaction NH3+HCl was
reconsidered, simulating the solvent with a continuum characterized by a dielectric constant.143 This time the
computation yielded two energy minima, one for an inner complex and the other for the outer complex. This second
computation represents a rather unique tour de force in the computation of a molecular reaction. Indeed, it compares
a variety of models: HF and Mller-Plesset (MP2) obtained with the MOLECOLE program,144 CASSCF obtained
with the MOLCAS program,145 DFT obtained with the MOLECOLE-DFT program,143 Coupled Clusters obtained
with the ACES II program,146 four components Dirac-Fock obtained with the MOREL program,147 and computations
with simulation of the solvent with an extended version of the MOLECOLE-DFT program.143

FIGURE 2. Top left inset: display of a frame from the graphical representation of the NH3+ HCl reaction (The New York
Times).Top right inset: Computed energy surface of the reaction.141 Bottom left inset: Computed dissociation path in vacuo for
different N-Cl distances140 Bottom right inset: Computed dissociation path in vacuo (full line) and in solution (dotted line).143

B). Interaction potentials. In IBM San Jose, the excitement was high since it was clear that computational
chemistry was becoming more and more relevant to chemistry. We note that the computation required in total about
13 days on the IBM -7094 computer, at the time a very powerful computer; ten years later this computation was the
model for many studies on interacting molecules; today it is a most common type of computation. Thus
"supercomputers" are often the necessary condition for the experimentation of novel methodological applications.
In this period, there was also the first all-electron ab-initio computational encounter with molecules of biological
relevance: the four DNA bases148 study (with J-M Andr and M-C Andr) and the cytosine-guanine base pair
potential energy study149 (in collaboration with von Niessen and Mehl). These papers were the first all electrons, ab
initio papers in quantum chemistry related to DNA bases, demonstrating the feasibility of the Hartree-Fock
computations in the emerging field of quantum biology and also demonstrating that the era of semi-empirical
Hckel level computations for biological relevant systems was at the end.

15
 The possibility of computing the interaction between molecules opened new horizons to computational
chemistry, namely the possibility of molecular dynamics with ab initio interaction potentials. Below, we simply
mention a few studies, among many, which by now have been often reconsidered with computational facilities
thousand fold faster. We recall, as an example, our pioneering study on the Ziegler-Natta reaction between ethylene
with a titanium compound,150,151 (with the collaboration of Novaro, Ruiz-Vizcaya, Blainstein-Barojas and others) the
first ab-initio publication in the field of computational catalyses, carried out at the Donegani Research Institute in
Novara, Italy, with the collaboration of Professor Octavio Novaro at UNAM, in Mexico City.
The early water-water interaction potentials leading to liquid water simulations152-158 (work performed partly in
San Jose, California, partly in Novara, Italy, with Kistenmacher, Koos, Lie, Matsuoka, Popkie, and Romano)
opened computational chemistry to studies of solutions, like the interaction of water with ions,159--164 (work
performed with Barsotti, Corongiu, Fromm, Kozak, Kress, Schwatz and Watts) and with molecules like amino
acids165-169 (work performed with Bolis, Carozzo, Corongiu, Petrongolo, Ranghino and Romano), with proteins170-176
(work performed with Aida, Bolis, Corongiu, Ferro, Fornili, Hartmann, Jonsson, Parak, Ragazzi, Romano,
Salvaderi, Schmidt, Venanzi and Weinstein), phospholipids, membranes channels177-179 (work performed with Chin,
Fornili, Kim, Vercauteren and Welti), DNA components and oligomers180-191 (work performed with Scordamaglia,
Cavallone, Corongiu and Lelj), and water diffusing in ferrierite192 (with Leherte, Lie, Swamy, Derouane and
Andr).. The correlation energy correction was accounted via approximations, using either our Coulomb hole
approach or modifications of the Wigner functional expression. A goal of these studies was to systematically set up
interaction potentials (force fields) for molecules of relevance in biological processes related to molecular genetics,
more specifically the force fields among water, as solvent, and ions, amino acid, and DNA (either components or the
full macromolecule in different forms, like A, B and Z). The agreement of our computations with a vast number of
laboratory data, particularly diffraction experiments, was our gratification and an invitation to progress to larger
and larger systems.

6. RECALLING EARLY MOLECULAR DYNAMICS COMPUTATIONS

Clementi and coworkers list of quantum mechanical computations - in the early 1970- is rather extended; and some
of these studies are partially recalled into two monographs.193,194 Later, additional studies did include more refined
interaction potentials particularly for liquid water195-197 (with Carravetta, Corongiu, Lie, Nieser, Kneller and
Bhattacharia) leading to the conclusion that the pair-vise approximation is definitively inadequate. Three-body
interactions potentials, inclusion of molecular vibration effects, polarizations forces are corrections clearly needed
to obtain full reliability in molecular interaction energy computations when one aims at errors of a fraction of a
Kcal/mol. Thus it was evident that non-availability of reliable intermolecular potentials would limit the predictability
limits of molecular dynamics. At the same time, in the mid seventy, it was clear to Clementi and collaborators that
availability of quantum mechanical derived interaction potentials is, sooner or later, the fundamental requirement to
move from quantum mechanics to reliable stochastic dynamical models. It was equally evident that reliable ab-initio
quantum chemical interaction potentials represented a notably complex and a rather difficult achievement. Indeed,
we do witness even today since 1970 in the computational chemistry community the nearly exclusive use of semi-
empirical pair-wise interactions potentials. Modern screening and sampling techniques, however, are making much
progress, as shown in chapters of this volume.
In the early 1970s one could assume that a next step toward computations of larger chemical system could
eventually arrive with the use of new and more powerful computers, even if this all in all- would only delay a more
permanent solution. Clearly, sooner or later it would become obvious that there is a physical limit to the complexity
of a chemical system above which one had to switch to some different computational models. The computational
complexity should not be measured only with the number of the electrons of the system (quantum chemistry), but
eventually with the number of atoms at first (molecular dynamics), and, later, with the number of molecules (micro-
dynamics and Navier Stokes equations). In other words we had either to abandon or drastically extend standard
quantum mechanical computations, plagued by unphysical constraints like zero temperature, time independence,
acceptance of vacuum without boundary and environment considerations, and acceptance of equilibrium conditions.
Metropolis Monte Carlo and Newton equations or, even better, Langevin dynamics and Navier-Stokes equations
appeared as appealing targets, even if rather unexplored by computational chemists. It was important to keep an
open and critical mind for extending the computational studies to the very new important areas for science and for
the society- of quantum biology and medicine, which clearly required more realist approximations than the old

16
semi-empirical approximations used at the time. However, we recognize that trails generally precede roads and
highways; the pioneering work by Profs. Alberte and Bernard Pullmann remains a basic landmark.198, 199
The possibility to use quantum chemical methods in pursuing molecular dynamics reaction mechanisms was
explored in 1977 in a pioneer study concerning the enthalpy of an enzyme reaction, specifically the reaction in
papain,176 a cystein proteinase, which owes its catalytic action to the presence in his active site of the residues Cys-
25 and His-159 with an ion pair ImH+S-, an hydrogen bond between the imidazole ring and the side chain of Asn-
175.
Recall that at that time there were only embryonic molecular dynamics computer codes, not the variety of
packages today available. Clementi and collaborators proposed that the atomic and electronic motions in an enzyme
were to be assigned to two different types of motions each one with its own time scales, each one considered
essentially independent to a first approximation from the other, somewhat like the nuclear motions and the electronic
molecular motions. The atomic motions are rather slow- and were designated macro-deformations occurring in
the entire enzyme, on the contrary the electronic motions, like charge transfers, are fast and were designated micro-
deformations. The energy variations of the macro-deformations were analyzed with the computer code Refine,200
the micro-deformations with our molecular code IBMOL.
Refine was a computer code used to refine the atomic coordinates of protein and enzymes obtained from X ray
crystallography; it considered molecular motions like stretching, bending, torsional terms and non-bonded
interactions using fully empirical inter-atomic potentials. In our work176 -whenever possible- these interactions were
substituted with the available ab initio potentials (discussed in the previous Section), parameterized to be utilized
with the Refine code. A simple minimization procedure, which moves the atoms one at the time for many cycles,
was utilized to obtain energy minima.
For the micro-deformation, analyzed with the IBMOL code,86 the adopted Gaussian basis set was a 7s,5p for the
C, N, and O atoms, 3s for H and 9s,6p for the S atom. The micro-deformations considered a sub-system of the
enzyme formed by the side chain of Cys-25, the residue His-159 part of Ala-160 and the side chain of Asn-175; the
quantum mechanical computation followed the hydrogen transfer process. Comparison of the computed energy path
with experimental data was encouraging, showing how the reaction enthalpy is stabilized by the macro-
deformations.
The above approach to studies in macro-molecular systems was soon transformed and replaced with the
coding of an early (by now old ) Molecular Dynamics computer program, which also replaced our Metropolis Monte
Carlo code,155 used for studies of liquid water and solvation problems, as discussed in Section 11. In 1979 Clementi
and Doctor Corongiu left the Research Institute Donegani in Novara, Italy, to join the IBM-Data System Division in
Poughkeepsie, New York State, USA, welcomed by Dr. Art G. Anderson, this time President of the IBM-Data
System Division and no longer Director of the IBM Research Division Laboratory in San Jose, California.

7. DECOMPOSITION of the CORRELATION ENERGY

The Hartree-Fock era made clear two points: First, ab initio computations can be used to explore and approximately
predict basic aspects of molecular chemistry, both for isolated or interacting molecules. Secondly, the Hartree-Fock
is inadequate for quantitatively predictions. Thus, the beginning of the post-Hartree-Fock era, namely the quest
either for fully correlated wave functions, or at least correlated for the valence electrons as to yield correct binding
energies.
The correlation energy has been often considered as an error to be accounted for with a single algorithmic
approach (e.g., C.I., MC-CI; MR-CI, Coupled Clusters, etc., etc.); we, however, are of the opinion that there are
several distinct "errors" under the common label of "correlation energy error". A pragmatic strategy suggests to deal
separately with each error. Therefore, we feel it is necessary to provide a decomposition of "the different correlation
effects" 114,125 hidden under Lwdin definition201 Ec=Eexact -EHF.
For a given reference wave function of a model M with energy EM, we define the correlation energy Ec,M as the
difference between the exact non-relativistic energy Eexact,nr and EM, namely:
Ec,M = Eexact,nr - EM (8)
A reference wave function must, at least qualitatively, yield energies in agreement with laboratory data, and, in
molecular computations, it must be nearly equally reliable at different inter-nuclear distances, from united atom to
dissociation. However, recall that a more physically correct definition should consider an exact relativistic total
energy.202,203
It is rather obvious that the Hartree Fock model will be in error whenever it assumes an incorrect electronic
configuration; this specific error occurs when two or more configurations yield the same or nearly the same energy.
We know, since long ago, that in case of near-degeneracy the HF model can be corrected adopting the generalized

17
Hartree-Fock model, following Hartree at al.11 and Clementi and Veillard.67,68 These algorithms were later
generalized; we recall, for example, the Complete Multi Configuration proposal204 and its well know successor, the
CAS-SCF205 approximation. Recall that the Heitler-London model makes use of atomic configurations representing
the separated atoms; again, whenever the atomic configurations are near-degenerate there can be an associated
molecular correlation error.
It makes sense, therefore, to deal with the near-degeneracy correction separately from the remaining correlation
effects; thus we decompose the total correlation into two parts, one related to near-degeneracy and the second to the
remainder (the same conclusion was reached independently by Sinanoglu206,207). Thus, we write:
Ec,M = Ec,nd,M +Ec,d,M (9)
where Ec,nd,M accounts for near-degeneracy effects, the so-called non-dynamical correlation (retaining Sinanoglu
designation), and Ec,d,M is the dynamical correlation remainder. In the following, we generally drop the subscript M,
unless needed, to simplify the notation.
From Hartree at al.11 and Clementi and Veillard.67,68,204 we know that the electronic configurations (ns)r(np)s with n
the principal quantum number is nearly degenerate to (ns)r-1(np)s+1 and to (ns)r-2(np)s+2 configurations (for example
the 3P states 1s22s22p2 and 1s22s02p4are near degenerate). Note that the near degeneracy of the atom is transferred to
molecules composed with that atom.
In a second partitioning the correlation energy is subdivided into two components (see Eqs. 2a and 2b): one,
aa, is the sum of the atomic correlation corrections, a, of each individual atom, "a", at dissociation and the second,
M = (Ec,M-aa), is the molecular extra-correlation energy, namely the variation from aa due to the difference
of electronic coupling at dissociation and in the molecule. Note that, in near-degeneracy analysis, we consider
configurations differing in the quantum number l but with the same quantum number n; therefore, we talk of nlnl
near-degeneracy. The near-degeneracy concept can be extended 208 to include nlnl near-energy excitations, with
the constraint n = n+1, particularly to introduce configurations with different symmetry. For example, for the
ground state configuration of the carbon atom, 3P, is 1s22s22p2, the configuration 1s22s02p4 is of nlnl type,
whereas the configuration 1s22s23d2 (energetically less important) is of nln'l type. Thus near-degeneracy leads to
a partitioning of the full CI set of configurations.
To summarize, we have partitioned the total molecular correlation energy relative to a model M, EC,M, into the
sum of atomic correlations, aa,M, and molecular extra correlation, M; these are, in turn, sub-partitioned into
dynamical and non-dynamical components, yielding aa,d,M and ,d,M for the dynamical correlation and aa,nd,M and
nd,M for the non-dynamical correlation. We write:
Ec,M = a[a,d,M+a,nd,M] + d,M + nd,M (10a)
Since the correlation errors are model dependent, we differentiate the correlation correction as follows:
Ec.HF = aa,nd,HF + aa,d,HF + nd,HF + d,HF (10b)

Ec,HL = aa,nd,HL + aa,d,HL + nd,HL + d,HL (10c)

Ec,HF-HL = aa,d,HF-HL + d,HF-HL (10d)

Comparing Eq. 10d with Eqs. 10b and 10c, note that Ec,HF-HL does not include the non-dynamical terms, being these
accounted for - by construction - in the HF-HL method.

8. MOLECULAR COMPUTATIONS: from the HF and HL to the HF-HL METHODS

As well known, the two original quantum mechanical methods are the Hartree-Fock and the Heitler-London
methods. A basic problem with the molecular Hartree-Fock methods is the nave assumption that the variational
method in the RHF approach can provide qualitative agreement with experimental data, even when molecular bonds
are broken. It was not sufficiently realized that the RHF approach lacks constraints introduced by construction.
From the Lie and Clementi71,72 systematic study of the potential energy in diatomic homopolar and hydrides we
learned on one hand that that it is possible, but rather difficult, to systematically ensure correct dissociation with a
reasonably short Multi Configuration expansion, and on the other hand that it is relatively simple to parameterize a
Wigner-type or a Coulomb hole density functional to account for the inner shell correlation correction, once the
dissociation problem is settled.
Recall that the computed dissociation energies reported in literature are most often no more than rationalized
dissociation energies, using Matsen terminology.209 Indeed, seldom the computation at the equilibrium inter-nuclear
distance is extended to the dissociation distance, due to convergence or other computational problems; as a

18
consequence the dissociation energy is often obtained using independent atomic data, obtained with different models
(and generally different basis sets); thus Matsen did introduce the "rationalized dissociation energy" concept.
These considerations did lead -in the early 2000- to a revision of the Lie and Clementi study, and to the proposal of
the Hartree-Fock-Heitler-London,210 HF-HL, approach. A main point is that the HL component of the HF-HL wave
function ensures correct dissociation by construction and avoids the search for an expansion of determinants71,72
capable to ensure correct dissociation either into separated atoms or molecular fragments (in polyatomic molecules);
a second main feature of the HF-HL approach is the use of non orthogonal orbitals. In the HF-HL model the energy
of the system is the sum of the HF energy, plus contributions from the HL energy, from the near degeneracy, from
the dynamical correlation energy of the valence electrons, and from the inner electron correlation correction.
A personal digression. Since early 2000 Clementi, is retired in Como, Italy with Prof. G. Corongiu (his
collaborator since 1974, presently teaching at the University of Insubria in Como). For computations he depended a)
on the help (in programming and in performing computations) by Prof. Corongiu, b) on a small computer he has
purchased, and c) indirectly on the limited computational facilities available to Prof. Corongiu. In the early 2000
Clementi was well aware that the development of a new methods, like the planned HF-HL project, would require
availability of optimal computational facilities and of a full team of collaborators; eventually the former were found,
thanks to a generous offer of computer time by late Prof. B. Roos, in Lund, Sweden, even if Prof. Corongiu did not
take advantage of this opportunity. It might be mentioned that Prof. G. Corongiu collaboration to the HF-HL project,
was a compromise since she somewhat skeptical about the new computational approach and frightened by the
expected amount of work it would require. Thus, we present the HF-HL model as a research project de facto
unfinished, which, however, has successfully passed feasibility and verifications tests.
The first phase of the HF-HL task (writing ex novo a HF-HL computer code for very small molecules, a Full-CI
HF and a Full-CI HL for H2 and re-computing the Lie and Clementi71,72 set of test cases) is documented in a set of
papers;210-214 later these computations were extended215 with a few molecules iso-electronic with N2 and a few
molecules obtained by adding one atom to a molecule, like H to OH, or C to NH, yielding H2O and HCN,
respectively, or considering the merging of two molecules like two CH molecules into C2H2.
These computational extensions are introductory studies to an eventual extension of the HF-HL model and code
to large molecules, merging of atoms or molecular fragments to create larger molecules. Recall that since the early
1960 Clementi was interested in the computation of complex molecules obtained by merging smaller one,
considered as fragments.83,85 (This approach follows the laboratory chemical tradition; as we all know, the standard
approach in laboratory organic chemistry syntheses is not to obtain a new chemical starting systematically from the
component atoms, as done in computations!)
Below we report on the HF-HL method. In Clementis opinion the present use of variational CI type techniques
with orthogonal orbital is limited by the need of an enormous number of determinants; indeed, millions216 or
billions217 of determinants have been used in CI computations even of small molecules (a problem shared in Multi
Configuration, CASS-SCF, Multi Reference C.I , etc. models). With the HF-HL model the number of determinants
in diatomic molecules computations (with component atoms of first and second period) has been reduced to a few
hundred or at most to a few thousand, with the consequent realistic possibility to analyze the wave function details,
extracting models and rules. However, there is a large cost in this model, due to the presently cumbersome
parameters optimization211 (we use essentially the same algorithms introduced last century, without exploring
gradient or other techniques).
We are of the opinion that parallel super-computers, for example those by IBM or those very recently unveiled by
Fujitsu (the K supercomputer), have finally reached the needed performance, to routinely perform demanding
computations like HF-HL type computations. Recall that the technological advances for example the IBM Blue
Waters Project and presently the Japan's K computer will eventually become "standard" in future computational
chemistry. Equivalently, last century, Clementi did consider the IBM computers of the early 1960 (the time when he
was tackling the NH3 + HCl energy surface) as very large and expensive tools for the time, but destined to
eventually become everyday tools in science and technology. Once more we are reminded that computational
chemistry remains fully dependent on advances in computer technology, graphics and communication devices. The
chapter by G. Taylor in the AIP proceeding volume and the K supercomputer day for the TACC-2012 congress
are most instructive in this regard.

19
 9. COMPARING HARTREE-FOCK AND HEITLER-LONDON BINDING ENERGIES
TO EXPERIMENTAL DATA
A). The Hartree-Fock HeitlerLondon model. In the following we compare binding energies from computational
quantum chemical methods; we consider the molecular Hartree-Fock and the Heitler-London models, which
represent the traditional views of a bond in chemistry, while a third, the Hartree-Fock-Heitler-London method, HF-
HL, is a pragmatic solution which merges the two models often presented in literature as opposing each other; with
our work, however, we have demonstrated their complementarities. The binding energy below reported can be
assumed to be near to the best value one can obtain with these methods. For the hydrides and homopolar diatomic
molecules the details on the adopted basis sets are given in Ref. 211-214.
We recall, using standard notation, the HF and HL wave functions:
HF=det(1,,i,...,n) (11)

HL= [A N 1' (1).... 'n ( n ) SM (1, 2 ,..., n )] (12a)

=kdet(1k,..,ik,,mk) (12b)

where, i refers to the i-th HF molecular spin-orbital; AN denotes the anti-symmetry spin operator and the
normalization constant, SM refers to the spin eigen-functions; i' is the i-th atomic orbital and ik is the i-th atomic
spin-orbital for the k-th determinant in the HL function. In the following we shall use the notation of Eq. 12. The HL
wave function in Eq, 12a or 12b is constructed with all possible degenerate spin functions.218
The HF-HL model is constituted by an ordered set of approximations of increasing accuracy. The HF-HL
hierarchy of solutions (the ordered set of HF-HL steps) accounts i) for the correct dissociation obtained by
construction, ii) for the non-dynamical correlation energy at dissociation and curve crossing, iii) for the ab-initio
computation of the molecular extra correlation energy and iv) for the dynamical correlation energy of the inner shell
electrons via the Coulomb hole density functional.
In the initial step of the HF-HL model, the wave function, HF-HL, is obtained by variationally determining the
linear combination
HF-HL = c1HF+c2HL (13)
Eq. 13 is referred to as the "simple HF-HL model, without inclusion of near-degenerate configurations", sometimes
indicated with the notation HF-HL(1,1), namely one HF and one HL function. One can apply density functional
corrections to Eq.13, an improvement on today DFT computations, but we prefer to compute ab initio the binding
energy, and apply density functional only thereafter, when we correlate the core electrons.
When at dissociation, the atoms in the molecule are in a state with near-degeneracy and/or when there is avoided
crossing, then HF (optionally) and HL (as a rule) are replaced with short MC expansions, tatHF(t) and
pbpHL(p). The corresponding HF-HL wave function, 'HF-HL, is obtained by variationally determining the linear
combination
'HF-HL= tatHF(t) + pbpHL(p) (14)
Eq. 14 is called the "simple HF-HL wave function with near-degeneracy" and the corresponding notations are HF-
HL(t,p) and EHF-HL(t,p). In the following computations, t=1, a choice resulting from analyses of the computations for
the H2 molecule. 210
In a third HF-HL step, we add to pbpHL(p) of Eq. 14 a number of ionic structures designated ibiHL(i): this
addition yields the so called HF-HL ionic model, denoted HF-HL(i) with energy EHF-HL(i) :
HF-HL(i) = tatHF(t)+pbpHL(p)+ibiHL(i) (15)
The wave functions for the ionic contributions are MC expansions; if we replace the MC expansion with a CI
expansion we use the notation HF-HL-CI. The inclusion of ionic structures brings about the dynamical correlation for
the valence electrons.
In general, we include in Eq. 14 the atomic nlnl near-degenerate configurations (structures). Atomic nlnl
near degenerate excitations can be included to represent the atomic polarization, particularly important in van der
Waals binding. The inclusion of nlnl excitations in the last ab-initio step of the HF-HL model yields:
*HF-HL(i) =rar*HF(r)+sbs*HL(s)+ibiHL(i) (16)
with EHF-HL(i)* its energy. This extension allows us to include orbitals with different symmetry. Inclusion of selected
nlnl excited MC-HF (designated *HF) and MC-HL (designated *HL) non-orthogonal configurations represents
the final refinement in the computation of the binding energy via the HF-HL model. At this stage of the computation

20
we add the Coulomb hole, Ch, functional correction, yielding HF-HL(Ch) and EHF-HL(Ch),211-214 a scaling of the
computed energies to recover the correlation energy correction for the inner shell electrons and for the valence-inner
shell interactions.
B). Examples of Hartree-Fock-HeitlerLondon computations. To illustrate the use of Eqs. 13 to 16, we consider
in some detail the C2 and H2O molecules, the first to exemplify the effect of near degeneracy correlation, Eq. 14, the
second the use of Eqs. 13 to 15. As known,219,220 the C2 ground state has 1 g+ symmetry, with two near excited

states, a 3 u and a 3 g , with excitation energies of 0.10 and 0.96 eV, respectively. In Fig. 3 we plot the computed
energies -at the different accuracy levels- for these three states. For each one of the three states the top inset reports
the HF, the HL and the simple HF-HL computed energies given by Eqs. 11, 12 and 13, respectively (thus without
near degeneracy contribution).

FIGURE 3. Ground and low excited state for the C2 molecule computed with the HF, HL and the HF-HL model at different
accuracy levels (top, without near degeneracy, middle with near degeneracy, bottom HF-HL with Ch).

The middle insert reports the HF, the HL and the HF-HL with inclusion of near degeneracy (thus the non-
dynamical correlation energy is accounted for) in the HL model and in the HL component of the HF-HL
computation. Finally, the bottom insets reports the computed energies using Eq. 13, and the HF and HF-HL energies
corrected with the Coulomb hole functional.
The HF component in Eq. 15 has essentially no contribution, and therefore the HL component essentially
corresponds to the full HF-HL function. This is an observation which characterizes the HF-HL method: at the level
of Eq. 13 the HF component is essential, but its contribution tends to vanish the more extended becomes the HL
expansion. This observation tell us that the HF and HL models are zero order approximations in a strict local
sense, not for the entire energy surface from united atom to dissociation, but only either near equilibrium or near
dissociation.
In Fig. 4 the 3 u and 3 g excitation energies for C2 are directly compared to the ground state energies. In this
figure we compare once more the computational results reported in Fig. 3; in the left inset we display the HF-HL
computations, obtained without and with near degeneracy, showing the incorrect excitation order resulting from
neglect of near degeneracy. In the right inset we display again the HF-HL computations with near degeneracy and

21
the energy shift obtained with the Coulomb hole functional. The computed binding energies of the 1 g+ , 3 u and
3
g states from HF-HL without inclusion of near-degeneracy are 41.90, 83.72 and 100.61 kcal/mol, respectively,
to be compared to the HF values of 18.27, 72.94 and 87.34 kcal/mol and the experimental values219 of 147.85,
143.51 and 126.91 kcal/mol. Inclusion of near degeneracy brings the binding energy to 127.10, 124.06 and 107.30
kcal/mol. Thus, the incorrect excitation energy trend obtained with the HF and the HF-HL(1,1) computations has
been corrected simply by the inclusion of near-degeneracy effects. The (HF-HL)-Ch computations for the three
states 1 g+ , 3 u and the 3 g yield, at equilibrium, the final total energies of -75.92379, -75.92009 and -75.89203
hartree (see Fig. 4).

FIGURE 4. Details on the HF-HL computation for the ground and excited state for the C2 molecule.

The computed excitation energies of the 3 u and 3 g states amount to 0.10 eV and 0.82 eV to be compared to the
experimental value219 of 0.10 eV and 0.96 eV. This computation points out the importance of near degeneracy (non
dynamical correlation energy) for molecules containing the C atoms, like CH, C2H2 and molecules containing Be as
well B atoms.
TABLE 1. Binding energies (kcal/mol) for LiH and C2
ground and selected excited states.

case state Eb(EXP) Eb(HF) Eb(HF-HL)

LiH (X) 58.00 34.27 57.68
(A) 24.82 ---- 24.10
C2 147.85 18.27 147.44
143.51 72.94 145.12
126.91 87.34 127.53

The good agreement between computed HF-HL and experimental electronic excitation energies is in line with the
previous result for an excited state in LiH,212 as shown in Table 1.
Let us now discuss the HF-HL computations for the H2O molecule from equilibrium to dissociation into an
oxygen (3P) and two hydrogen (2S) atoms. The basis sets for the oxygen and hydrogen atoms are [17,13,5,4/9,7,5,4]
and [10,5,4/6,5,4], respectively; with these basis sets the HF energies for the O (3P) and H (2S) atoms are
-74.809384 and -0.499999 Eh, respectively. The computed binding energy, at the experimental equilibrium
geometry, from HF, HL, HF-HL (Eq. 13), and HF-HL(i) (Eq. 15) are 161.84, 164.24, 178.35 and 206.56 kcal/mol,
respectively, with a total of 113 determinants for the HF-HL(i). The HL wave function is a linear combination of 7
covalent and 45 ionic configurations (structures), which are built with the [O H- H+], [O+ H-H], [O2+ H- H-], [O- H
H+] and [O2- H+ H+] structures. After addition of one p orbital of nlnl type on the hydrogen atoms, the HL wave
function consists of a linear combination of 13 covalent and 99 ionic configurations, leading to 428 determinants.
The *HF-HL(i) function consists therefore of 429 determinants; it yields a binding energy of 231.35 kcal/mol (work
in progress) to be compared to the experimental energy of 232.77 0.24 kcal/mol26. Note that Ref. 26 reports a Full

22
CI/cc-pVTZ basis set computation for H2O requiring 1.7x109 determinants and yielding a binding energy of 216.29
kcal/mol, whereas CBS extrapolations26 yielded a correlated wave function with the correct binding energy. Work is
in progress for the computation of the potential energy curve for the process H2O (1A1) OH (2)+ H(2S).
Following the above detailed exposition of the HF-HL model computations for C2 and H2O we now compare the
three models, the HF, HL and HF-HL, by presenting systematic test-applications on the hydrides212,213 and
homopolar211 molecules of the first and second rows of the periodic table reported in Tables 2 and 3. In Table 4, we
report computations on a few additional molecules to provide both an example of evolution of chemical bonds in 14
electron diatomic molecules215 and we add preliminary computations on the molecules HCN and C2H2 considering
the energy path to dissociation into molecular fragments.

TABLE 2. Diatomic homopolar and hydrides: total energies (Eh) at equilibrium and at dissociation, either from experiments,
-ET(Re) and -ET(R), or from HF-HL computations with Coulomb hole functional for the inner shell electrons, -ET(HF-HL)(Re)
and -ET(HF-HL)(R).

case -ET(Re) -ET(R) -ET(HF-HL)(Re) -ET(HF-HL)(R)

H2 [1g+] 1.1744757 1.00000 1.17448 1.00000
Li2 [1g+] 14.99543 14.95612 14.99253 14.95596
Be2[1g+] 29.33860 29.33477 29.33761 29.33427
B2 [3g-] 49.41695 49.30780 49.41007 49.30423
C2 [1g+] 75.92560 75.69000 75.92379 75.68883
C2 [3] 75.92193 75.69000 75.92009 75.68883
C2 [3g-] 75.89032 75.69000 75.89203 75.68883
N2 [1g+] 109.54260 109.17860 109.54025 109.17717
O2 [3g-] 150.32700 150.13480 150.32046 150.13415
F2 [1g+] 199.53050 199.46830 199.53180 199.46827
LiH[1+] 8.070491 7.978062 8.07236 7.97798
BeH[3+] 15.24679 15.167363 15.24611 15.16716
BH [1+] 25.28792 25.15393 25.29208 25.15382
CH [2] 38.47868 38.34499 38.47601 38.34429
NH [3-] 55.21756 55.08925 55.21857 55.08846
OH [2] 75.73726 75.56720 75.73765 75.56685
HF [1+] 100.45962 100.23370 100.45867 100.23412

In Table 2, we report the experimental total energies at equilibrium, ET(Re), and at dissociation, ET(R), and
the corresponding values obtained from computations with the HF-HL model using the soft Coulomb hole
functional for the inner shell electrons. The accurate molecular non-relativistic energies ET(R) in Table 2 make use
of the reasonably accurate correlation energy for atoms published by Chakravorty et al.138 the total non-relativistic
energies ET(Re) at equilibrium are obtained by adding the experimental219 binding energy to ET(R).26
For hydrides molecules, the HF, HL, HF-HL(1,1), and HF-HL(i) computations yield 70%, 60%, 80% and 91% of
the experimental binding, respectively. For H2, one needs at least the symmetry contribution, which can be
obtained with Eq. 16; the same comment holds for Li2, where the error results from a small inclusion of core
correlation, again to be corrected with Eq. 16. Note that also the Be2 binding is not reproduced correctly; Be2 being
nearly a van der Waals molecule demands a HF-HL(i)* computation. This analysis confirms the importance of the
improvements obtained with Eq. 16 and with the inclusion of inner core correlation correction to obtain more correct
binding.
Recall that the basis sets utilized can be improved and that we have neglected to include the spin orbit correction
with corresponding electronic configurations; further in the HF-HL(i) computations the correlation energy inner
shell-valence electron contribution to the binding energy is not accounted for. The computed binding energies EbHF-
HL(Ch) reported in the Table 3 are satisfactory, particularly considering the neglect of Eq.16.
In Table 3, we compare the experimental219 binding energy, Eb(exp), with the ab initio computed values obtained
from HF, HL, HF-HL (Eq. 13), and HF-HL(i) (Eq. 15) models. We see that the computed binding energies from the
HF-HL model (Eq. 13) are in qualitative agreement with the laboratory data, and never inferior to those given by the
HF and HL models, which at time fail to yield qualitative agreement. The HF computations fail at dissociation,
whereas the HL and the HF-HL models, by construction, dissociate correctly.
For the homopolar diatomic molecules the HF, HL, HF-HL(1,1), and HF-HL(i) computations yield 35%, 32%,
48% and 84% of the experimental binding, respectively. In Table 4, we consider two groups of molecules. In the

23
first group we list diatomic molecules with 14 electrons to study the evolution of the bond with a given number of
electrons but with different nuclei. In the second group we consider polyatomic molecules dissociating into
fragments215 obtained by different dissociation channels:
a) HCNHC(4) + N(4S) b) HCNCN(2) + H(2S)
c) C2H22CH( ) 2
d) C2H2C2H(2) + H(2S)

TABLE 3. Binding energy (kcal/mol) experimental, Eb(exp), from HF and HL computations, Eb(HF) and Eb(HL), compared to
HF-HL results Eb(HF-HL) from Eqs. 13, Eq. 15 and EbHF-HL(Ch).

case Eb(exp) Eb (HF) Eb(HL) Eb(HF-HL) Eb(HF-HL ionic) EbHF-HL(Ch)

H2 109.48 83.83 94.28 94.50 95.42 109.48
Li2 24.67 3.83 8.68 8.69 25.48 22.95
Be2 2.40 -7.54 -19.23 -7.53 0.50 2.09
B2 68.49 20.53 -15.59 23.05 62.95 66.41
C2 147.85 18.27 -0.92 41.90 138.40 147.44
N2 228.40 120.15 121.96 159.96 215.25 227.83
O2 120.60 30.18 1.51 62.26 110.12 116.91
F2 39.00 -29.24 -17.59 11.46 35.70 39.86
LiH 58.00 34.27 43.11 43.66 46.59 59.22
BeH 49.83 40.20 -29.25 40.50 45.73 49.55
BH 84.10 63.35 72.18 77.78 78.10 86.77
CH 83.90 57.14 65.82 70.03 78.39 82.65
NH 80.50 48.59 57.30 60.29 71.50 81.57
OH 106.60 70.16 72.26 79.62 106.90 107.18
HF 141.50 101.23 92.17 108.36 136.12 140.91

Note that the inner shell-valence correlation energy contribution is not included in the Eb(HF-HL-CI) data of Table 4,
and that the basis set can be improved, thus the data are only preliminary.

TABLE 4. Binding energy (kcal/mol) from experiments, Eb(exp),

and from computations with HF-HL from Eq. 14 and HF-HL-CI.
See text below for the notation a, b, c, and d.

case Eb(exp) Eb(HF-HL) Eb(HF-HL-CI)

N2 228 159.96 198.68
BF 183 159.15 164.87
CO 259 241.22 246.51
NO+ 250 216.65 223.34
case Eb(exp) Eb(HF-HL) Eb(HF-HL-CI)
HCNa 223 197.34 214.94
HCNb 130 106.88 123.41
C2H2c 228 224.59 230.17
C2H2d 124-131 122.91 127.44

In Table 5 we report the number of determinants used in HF-HL(1,1), HF-HL (t,p) and HF-HL(ionic). The
expansions are notably shorter than those needed in CI or CASSCF computations with the same basis set. In
addition, the HF-HL method even in its first step does not fail to qualitatively predict "molecular binding", thus it is
a reference wave function. The present draw-back is the high computational time which will become "reasonable"
with the new parallel supercomputers.
These Tables prove that neither the HF nor the HL model con reliably and systematically yield at least
qualitatively correct binding energies, which on the contrary can be obtained from the HF-HL model even in its
simplest representation (Eq. 13). Further, accurate energies are obtained from the last step of the HF-HL model
(Eqs. 15 and16) with linear combinations of configurations requiring a limited number of determinants (up to a few

24
thousands) not the millions or billions needed by the usual CI-type computations. Finally, the computation make use
of basis sets which can be further optimized.
In summary we consider the HF-HL method as a natural conclusion of more than half century studies on HF and
HL traditional proposals; in addition, we point out that the HF-HL model preserves many concepts developed for
nearly a century to explain chemical binding. Further, this work clearly points out that the use of non orthogonal
orbitals reduces very drastically the highly extended expansions typical of CI, Full CI, CASSCF, etc. with the
orbitals constrained to be orthogonal.

TABLE 5. Number of determinants in the HF-HL expansions of Eqs. 13 to 15.

case Eq. 13 Eq. 14 Eq. 15 case Eq. 13 Eq. 14 Eq. 15

H2 3 - 5 LiH 3 - 5
Li2 3 - 5 BeH 2 8 10
Be2 3 133 436 BH 3 13 15
B2 3 511 527 CH 6 21 31
C2 13 535 781 NH 10 - 39
N2 91 - 183 OH 6 - 8
O2 25 - 39 HF 3 - 8
F2 3 - 5
BF 3 24 138 CN 60 581 656
CN- 133 346 445 CO 30 320 758
NO+ 90 - 182 HCN 40 768 1233
C2 H 2 48 1504 4324 H2O 39 - 429

Below we report on a study with orthogonal orbitals for the H2 molecule, yielding very accurate energies for ground
and excited states, but requiring over 10000 determinants in the CI expansion. We shall see that the expansion
length can be significantly reduced to a very small number of determinants smaller than those reported in Table 5,
by replacing the AO and MO with the new Chemical Orbitals.221 In conclusion, there are good reasons for the
adoption of non-orthogonal orbitals as well for the adoptions of new types of orbitals as discussed in the following
Section.

10. BACK TO THE HYDROGEN MOLECULE

A). Mapping the Excited States. In order to make more concrete our discussion on the evolution of variational
quantum chemical models, we consider H2, the simplest two electron-system molecule. Historically, this system is
the traditional and classical test case for quantum chemistry. The computations reported below were performed by
Clementi and Corongiu also to celebrate the Year for Chemistry, securing accurate and systematic determination
of all the most important excited states for at least one molecule, even if very simple, using standard models, full CI
both of HF and HL type wave functions, with the two standard types of basis sets, with either Slater or the Gaussian
functions. (Tabulation of the computed energies at the selected inter-nuclear distances for the 120 states are available
by request to Prof. G. Corongiu, giorgina.corongiu@uninsubria.it). Then we shall present a new way to solve the
problem with non orthogonal orbitals of new type,221 i.e., with a composite characterization both atomic and
molecular.
We recall that the first quantum mechanical computation for the H2 ground state energy is due to Heitler and
London,24 with a computed binding energy of 0.1176 Eh at the computed equilibrium distance of 1.51 a0, to be
compared to the experimental219 atomization energy De(exp) of 0.17446 Eh at the equilibrium distance of 1.40 a0.
The HL proposal proved that the probabilistic distribution of electrons in a molecule can be approximated,
somewhat grossly, as the product of atomic orbitals (the one electron functions of the separated atoms in the
molecule). With an optimized basis set the Heitler-London computed energy E(tot)HL is -1.15059 Eh to be compared
with the Hartree-Fock total energy222 E(tot)HF= -1.133629 Eh, the latter leading to 77% of the experimental
atomization energy. Koos223 computation reports a very accurate total energy of -1.174475686 Eh. In the past, very
accurate solutions for the H2 atomization energy were obtained with algorithms de facto restricted only to diatomic
molecules, requiring confocal elliptic coordinates, proposed originally by James and Coolidge,99 later optimally
applied by Koos and Roothaan100 and by Wolniewicz.101

25
 Quoting Herzberg,220 the building-up principle to construct molecular wave functions rests on the observation
that the number of electronic states in a molecule is of the same order as for atoms. This leads to Herzberg220 and
Mulliken224 orbital correlation diagrams, which make use of both AO and MO one-electron functions to describe the
electronic distribution from infinite separation to the united atom, subject to the symmetry and spin constrains
expressed by the Wigner and Witmer rules.32 For long, a variational linear combination of determinants was used to
obtain wave functions for the H2 molecule (see the bibliography by McLean, Weiss and Yoshimine225).

FIGURE 5 . and excited states for H2: from the lowest state of a given symmetry to the H2+ ground state.

Recently, we have obtained equivalent accuracy as reached by Koos and Roothaan and by Wolniewicz using
extended but standard basis sets of Slater and Gaussian functions with full configuration interaction (FCI) of
Hartree-Fock type functions (FCI-HF) or of Heitler London type functions (FCI-HL).226-229 Our FCI expansions for
H2 are very extended, with ~12,000 determinants for Slater type functions and ~16,000 for Gaussian type functions.
Note in addition that these computations were not limited to the ground state and a few low excited states of H2, as
generally done in the past literature, but have systematically considered the lowest 140 states of the 20 low
manifolds ( 1,3 g+ , 1,3 +u , 1,3 u , 1,3 u , 1,3
g , 1,3
g , 1,3 u , 1,3 u and 1,3
g ) covering the equilibrium

energy range from the H2 to H +2 ground states. The states 1,3 g+ , 1,3 +u , 1,3 u , 1,3 u are given in Fig. 5; in Fig 6

we report four insets with the singlet and triplet 1,3 u and 1,3 g states, but only one set of energy potentials
1,31,3
representing both the singlet and triplet states for the u and u ,g , due to energy degeneracy.
g , 1,3

Clementi and Corongiu have focused more sharply than previously a) on the energy at "very short" inter-molecular
distances (from1.0 to 0.01 a0) revealing a smooth electronic energy decrease reaching the united atom energy, b) on
the role of the united atom configuration, c) on the relevance of Hund rules for high excitations, and d) on the origin
of the binding energy between atoms. In addition, the large dependency of the correlation energy on the adopted

26
model (either Hartree-Fock or Heitler-London) has been evidenced and tabulated for different states at different
inter-nuclear distances for the two models. Further, the same basis sets (one constructed with Slater and a second
with Gaussian functions) are used to compute the full set of the 140 potential energy curves departing from the
traditional use of different basis sets for different states. These computations call for new studies at much shorter
distances (aiming at to 0.0001 a0) but performed with a relativistic Full CI code, and considering also different H
isotopes. In Clementis opinion a more mature computational quantum chemistry status than the present one, should
allow rather easily the systematic computations for ground and excited states (here exemplified for H2) at least for
the diatomic molecules from low to high Z atoms. Hopefully this will be one of the achievements in this century.

FIGURE 6. , , excited states for H2: from the lowest state of a given symmetry to the H2+ ground state.
B). The chemical orbital concept. The notable contribution to the molecular energy surface of the united atom
configuration is one among the novel results from the H2 computations; this finding has lead Clementi and Corongiu
to the concept of Chemical Orbitals.221 With the Herzberg orbital correlation diagram220 and with the Wigner and
Witmer rules32 in mind, one can define, for a diatomic molecule AB, a new type of wave function formed with
Chemical Orbitals, designate COs, rather than the traditional Molecular or Atomic orbitals, MO or AO,
respectively. Let us consider a diatomic molecule, AB, with ZA=p and ZB=q. We construct a wave function
representing the n=p+q electrons of the system from the united atom, ua, to full dissociation into atoms A (with p
electrons) and B (with q electrons) using chemical orbitals, CO. We define a CO as a one-electron function,
constructed as a linear combination of three old fashion functions, tailored atomic and molecular orbitals,
specifically 1) an AO-type function particularly efficient at the united atom, designated as i(ua), where the index i
refers to the electron i and (i+1) of the set (1, , i, i+1,, p+q ) for the AB system, 2) one MO-type function
particularly efficient near equilibrium both for the i and (i+1) electron pair, designated as i, and 3) two AO-type
functions, one particularly efficient at dissociation for electron i on atom A, designated j(A), and the second AO-
type function particularly efficient at dissociation for electron (i+1) on atom B, designated k(B).
In the Chemical Orbital model, the electrons i and (i+1) correspond grosso modo to an electron-pair in a
traditional orbital (with occupation either 1 or 2); the Chemical Orbitals are described by two non-orthogonal
orbitals designated ui and u(i+1), leading to the Chemical spin Orbitals Ui=ui and Ui+1=u(i+1), with (i=1, , n),
defined as

Ui(s)=ui(s)=[c1i(ua)+c2i(s)+c3j(A)]i (17a)

Ui+1(s)=ui+1(s)=[ c1i(ua)+c2j(s)+c3k(B)]i+1 (17b)

27
with c variational coefficients and s the symmetry specification (, , , etc.) The two CO, (ui) and (ui+1), are
normalised and non-orthogonal. With a set of U1,..., Un spin orbitals we construct the CO wave-function:
CO = AN[ u 1 (1) u 2 ( 2)  u n ( n ) SM (1,2,  , n )] (18)
where A is the anti-symmetriser operator, N is the normalisation constant and the spin eigen-functions with
SM 218

the required values of S and M. By construction Eq. 18 leads to correct dissociation and to the correct united atom.
The correlation correction in the CO wave functions is obtained via a short variational configuration
interaction expansion of CO functions, CO = rdrCO(r). For the H2 molecule,221 with only one configuration and a
minimal basis set, the Chemical Orbital binding energy is computed as 96.05 kcal/mol to be compared with 80.45
and 72.76 obtained with minimal basis set HL and HF computations, respectively. With a large basis sets221 and only
one configuration, the Chemical Orbital binding energy is 100.07 kcal/mol to be compared with 94.44 and 83.83
kcal/mol obtained from the HL and HF models, respectively. With seven configurations the Chemical Orbital model
yields a binding of 109.01 kcal/mol, thus near to the exact value of 109.48 kcal/mol.

FIGURE 7. Comparison of the H2 ground state electronic wave functions.189

It has been shown221 that the wave function constructed with Chemical spin-Orbitals, Eq. 18, is strongly related
to the HF-HL wave function of Eq. 15; stated differently, the HF-HL model is simply a laborious step-by-step build
up, which approximates iciCO(i) . To evidence the formal relations of CO to HF, HL, HF-HL and -at the same
time- to rationalise the importance of ionic structures even in homopolar molecules, we have decomposed CO into a
set of determinantal wave functions;221 indeed, this process yields a combination of HF and HL type wave functions
CO=rcrHF(r)+scsHL(s)+tctHL(t) (19)

where the rcrHF(r) are HF type functions for the entire molecule including the united atom, scsHL(s) are covalent
HL functions, and tctHL(t) are ionic HL functions.
This finding explains the presence and the relevance of the ionic structures in homopolar molecules, and shows
that the HF, HL and HF-HL functions are implicit into the CO, the "parent" wave function. In conclusion, the CO is
a compact representation from where one can extract the HF-HL wave function, and its components, HF and HL, as
indicated in Fig. 7.
We can compare the probability density of HF, HL, HF-HL and CO electronic functions.221,230 In Fig. 7, we plot
the electronic functions, (0.,0.,z1; 0.,0.,z2), for H2 computed at the inter-nuclear separation of 1.4 a0. In the figure
we indicate with full black dots the nuclear positions for nucleus A and nucleus B and with a red dot the inter-
nuclear midpoint position; electron 1 is held fixed at z1=0. The function for electron 2 is plotted from z2 = -3. to z2
=3. a0. Note the difference between the HL and the HF-HL(1,1) functions in correspondence of one of the maxima
of the HF function, a difference enhanced in the CO wave function. Fig. 7 summarizes a trend of conceptual
evolution in theoretical-computational chemistry lasting eighty years.
We conclude this section summarizing our contribution to theoretical formulations in quantum chemistry. After a
starting period when semi empirical computations used hand computations, we selected the Hartree-Foch method
to prove that ab initio methods in theoretical chemistry can answer chemical problems not only in single molecules
but also in molecule to molecule interactions and in atomic systems. This allowed a needed quantitative assessment
of the correlation energy error. Temporarily, the latter was approximated -first by us -with the adoption of density
functionals. At the same time -with Veillard- we attempted to improve the CI approach, clearly inadequate for large
systems, with a new multi configuration approach, which eventually did lead to B. Roos CASS-SCF model. Then,
we presented proposals to gradually decrease the correlation error, once it was clear that it can be reasonably

28
partitioned. With G. Lie we corrected the bad behaviour of the HF model at dissociation by using a short expansion
of selected configurations, however, still too large and not easily determinable. Later, this time with G. Corongiu,
we combined the HL with the HL method ensuring a zero order wave function qualitatively correct from short
distances to dissociation. Note that up today no other model has this basic quality. To move toward a quantitative
accuracy we propose the above reported tested set of approximations of the HF-HL method, which leads to accurate
binding energies from short inter-nuclear distances to dissociation with relatively short multi configuration
expansion of non orthogonal orbitals. To simplify the computation the inner shell electrons are presently correlated
with density functionals. Further, we have shown that the wave unction for extremely short inter-nuclear distanced
can be correctly obtained with the Chemical Orbital approach (which also helps from short distances up to
equilibrium). The HF-HL method can be adapted for parallel supercomputers with a granularity at the single
determinant level. Eventual extension to large molecules can be a fragment type approaches, being rather clear that
the present way to compute large molecules -starting from the constituting atoms- has non learned the lesson offered
since long by synthetic chemists.
As we all know, today the relativistic correction can be added relatively easily, an important step to provide a
united picture for theoretical chemistry. More attention could be give to the use of present basis sets, too rigid to
conform to the molecular electronic density flexibility: either finite elements, or generalized Gaussian functions, or
tensorial representations are some of the possible avenues.
In general our attitude is that no chemical method is both general and valid forever; we progress only with step
by step improvements, as long as formally and computationally tested.

11. FROM MOLECULAR DYNAMICS TO MICRO-DYNAMICS

In this section we recall our approach to systems considered at the time of our computations as large systems; water
was often one component of the system in consideration. To discuss liquid water it is reasonable to first know the
geometry of one single molecule. Today, the system of one oxygen and two hydrogen atoms forming a ten electron
molecule is a relatively simple problem, especially if tackled by semi-empirical computational quantum chemistry,
like density functional computations. In the early 1970s, we started first at the Hartree-Fock level, which yielded a
molecule with an HOH angle slightly too wide relative to experimental data.152 More accurate CI type computations
improved the computed geometry and the computed molecular binding. Then, we enlarged the system by
considering clusters of molecules of water -from few to many- a computation improved several times153,231,232 (work

FIGURE 8. Structure of most stable conformations of water clusters.232

29
 with Kim, Dupuis, Lie, Estrin, Paglieri and Corongiu). In Fig. 9 we report optimized geometries for small water
clusters. To obtain the water-water interaction potential, we considered the energies of a dimer sampled at different
geometries and fitted to an analytical expression for two rigid water molecules. We recall early intermolecular
interaction potentials154,233-235 (work with Popkie, Kistenmacher, Lie and Watts) leading to the so-called MCY
potential,156 (with Matsuoka and Yoshimine) later improved by relaxing the water "rigidity" and allowing
vibrational flexibility, yielding the MCYL two body flexible potential235 (with Lie) later again refined with three236
(with Corongiu) and four body237 (with Detrich and Corongiu) potentials. New potentials were tested, like the
NCC196 (with Niesar, Corongiu, Kneller, and Bhattacharya) and the NCC-flex for liquid water238,240 room and low
temperatures (with Corongiu) and for ice241 (with Corongiu and Sciortino). These potentials introduced polarization
forces between water molecules either without or with vibrational flexibility. Indeed, we are of the opinion that the
two body approximation requires extensions at least to three and eventually four body corrections with vibrational
flexibility and mutual polarization. The use of atomic potentials brings about a large computational cost fully
needed, however, if one looks for clearly defined theoretical models, rather than for phenomenological
representations; today, the latter are generally adopted, due to the excellent reproduction of selected experimental
data.
In water clusters, the geometrical characterization of a single water molecule is grosso modo maintained. One
lesson was learned: atoms form molecules more readily than generally assumed. For example Be2 has little biding
energy, but Be3 is more stable and Be4 even more. Non-traditional clusters of molecule are often surprisingly stable.
We often simplify by limiting our consideration to van der Waals forces, an insufficiently explored area. But what
happens when we consider up to hundreds or many thousands of water molecules? Clearly, the cluster approach is
computationally unfeasible. Thus, we opted for a change of model and moved into Metropolis Monte Carlo and
Molecular Dynamics. In the former, we consider N molecules within a volume V at a temperature T and millions of
geometrical configurations randomly generated. Recall, however, that the new frontiers opened by the early Monte
Carlo and Molecular Dynamics studies were constrained by the assumption of equilibrium conditions, a strong
limitation, if we truly wish to consider biological phenomena. In addition, with molecular dynamics, we generally
do not simulate sufficiently large systems, for example, up to the size of biological cells. There are, however,
interesting attempts in this direction, for example in Refs. 242 and 243 (there is also an unverified proposal244).
Below we recall our approach to large systems, where water molecules are the main component of the system.
Clearly, the cluster approach is computationally unfeasible for hundreds or more water molecule simulations. Thus,

FIGURE 9. Pair correlation functions gOO, gOH and gHH (left insets), H(s) of X-ray scattering) and H(s) and neutron scattering in
the liquid phase (right insets).

30
one needs a change of the model and a move to Metropolis Monte Carlo and Molecular Dynamics In molecular
dynamics for each particle, Newton's equations of motion are solved, and thus we compute trajectories, considering
motions in a small range of temperatures.
The standard laboratory fingerprints for static and structural properties of liquid water are the X-ray and the
neutron beam spectra. In Fig. 9, we compare Clementi and Corongiu simulations196 (with the expanded polarization
model) and experiments245,246 for the pair correlation functions gOO, gOH, gHH, H(s) of X-ray scattering and H(s) of
neutron scattering in the liquid phase. In the figure, the experimental246 neutron scattering sample contains either
99.75% or 0.01% of deuterated hydrogen.
These computations bring the conclusions that (a) many body corrections to the two body potential are very
important for dynamical and structural properties, (b) energetic, structural and dynamical data are necessary to
assess the quality of inter-molecular potentials, (c) eventually, ab-initio quantum mechanical potentials are to be
used to rationalize the empirical potentials, (d) available ab-initio potentials can be further improved due to the
availability of modern parallel computers.
With molecular dynamics, one generally simulates relatively small systems, with at most a few million atoms. We
have asked ourselves whether we can extend the use of molecular dynamics to simulate those systems generally
studied with Navier-Stokes equations, known to provide the most efficient and general set of models for complex
dynamical systems. We have provided an initial answer to the above question by performing molecular dynamics
computations in open non-equilibrium systems, with boundary conditions typical of fluid dynamics simulations. For
example, we considered (see Fig 10) a flow past a barrier, either a plate or a cylinder,247 (with Hannon and Lie) and
displayed the corresponding velocity field, from simulations with about 105 particles for events lasting from a few
pico- to a few nano-seconds, restricted to a scale of a few hundred . We report that such systems scale amazingly
well with results of experimental systems at a few cm2 in size and a lifetime of seconds. For example the simulated
Reynolds number for the wakes past the cylinder computation is about 35 compared with a laboratory value of
2510.
Equally gratifying are the results recalled in Fig. 11 were we report on Benard-type flow obtained by considering
110,000 argon atoms248 (with Given). This somewhat astonishing accomplishment -considering the year of the
computation- can be appreciated by comparing our simulation with the classical Benard patterns observed in
laboratory at a trillion larger scale. In the figure, we report (top inset) the steady state flow showing transient cell
formation, (middle inset) two Benard cells in a steady state, and the temperature and density profiles (bottom inset)
proving the steady state of the simulated flow. This simulation, however, cannot be considered conclusive, since the
boundary conditions, particularly the vertical, imposed on the system might be re-considered to ensure, more easily,
a stable Benard pattern.

FIGURE 10. Flow past a barrier: a plate (top) a cylinder (bottom).

At the same time, computations with Langevin Dynamics were successfully carried out, for example to simulate the
structure of BPTI249 (with Bhattacharya and Xue), a test case which proved that Langevin Dynamics can yield
equivalent information as Molecular Dynamics with a computational time a few hundred times smaller.
We conclude this Section by mentioning one more model250 (with Panda and Sonnad), the Cellular Automata,
CA, model, which hopefully might lead to practical applications. The CA model is a discrete space-time

31
mathematical model of physical systems. A CA simulation assumes a regular lattice, each side of which can have a
finite number of states usually represented by Boolean algebra. The CA evolves in time in discrete steps using
deterministic or non-deterministic local rules or updating. The average behavior of a collection of sites of a cellular
automaton is found to describe the behaviour of physical systems obtained by using models with smooth continuous
variables. The CA model was first introduced by von Neumam251 and Ulam then reconsidered by Hardy et al.252 and
subsequently by Frish et al.253 With this model, we have simulated an obstructed flow250 previously obtaining the
same flow characterizations as those reported in Fig. 11.
The flow past a barrier, the Benard Cell and the Cellular Automata studies dealt with micro-dynamics systems.
We stress that both the Benard and the obstructed flow simulated patterns are in substantial agreement with
laboratory data, and do not depend on the availability of quantum mechanical intermolecular potentials, since the
obtained structures are primarily the result of algorithms based on the conservation of mass and momentum and of
specific boundary conditions at times with temperature gradients. This observation might be critical for future
simulations of very large biological systems, for example simulation of biological cell structures. For such systems
we have preliminarily and tentatively considered two avenues: one makes use of open non-equilibrium molecular
dynamics with boundary conditions, while the other is an untested proposal to extend traditional molecular
dynamics with heavy use of "black box algorithms" introduced to reduce computational complexity.244 This
approach might be combined with Ladik et al.254 suggestion for the numerical solution of systems of partial
differential equations in biochemical cellular simulations.
Studies of hydro-dynamic phenomena at the microscopic scale such as channel flows, flows past a plate or a
cylinder and Raileigh-Benard convection are typical micro-dynamical studies. These are ideally performed on
parallel supercomputers (see the next Section). Computations of chemically reactive flow fields can be tackled with
a partial differential equation for each conserved quantity (mass, momentum, energy, species, etc.) solved
numerically. Multi-grid methods255 are a promising approach for the solution of systems of equations arising from
discretisation of partial differential equations. It is highly probable that future computational simulations on complex
biological systems will more and more consider multi-grid techniques, particularly efficient in parallel
supercomputers.
Modern molecular dynamics codes and computations are very much advanced relative to the early 1970-1990
computer codes and applications reported in this Section, as clearly evident from chapters in this AIP proceeding
volume. The basic problems, however, remain in the output reliability, in the amount of needed computer time, in
the size and complexity of the system analyzed; supercomputers availability can certainly help.

FIGURE 11. Benard transient cells, two steady state cells, temperature and density profiles.

The AIP proceeding paper Accelerated Molecular Dynamics: Theory, Implementation and Applications by Yi
Wang and J. Andrew McCammon most instructively indicates some of the avenues considered in recent studies.
Other significant papers of the AIP proceedings are recalled in Section 15.

32
 12. EARLY PARALLEL COMPUTER ARCHITECTURE

Some quantum chemists approach the computer hardware simply as a commodity, which for a given price offers
specified features. However, quantum chemists generally have optimal qualification to improve the computer
hardware and software. For example, we know that the present quantum chemistry computer codes are generally
born in chemistry departments. A few might recall that in the early 1960s the numerical accuracy of intrinsic
functions was influenced by critical efforts by C.C.J. Roothaan. Further, it was and it remains in the tradition of
chemical research not only to use but also to assemble scientific instruments needed to carry out a research task.
In the early 1980s the IBM Poughkeepsie, New York, the computational chemistry team headed by Clementi was
in the rather peculiar situation to lack top computational facilities to fulfill its research goals, since the best IBM
computers of the time were not as powerful as those offered by competitors like the Japanese industry or the CRAY
corporation. At that time, a few computer science departments were experimenting with a new type of hardware, the
parallel computers.256 For us, the successful coupling in 1982 of a FPS-164 array processor (AP) from Floating Point
Systems to an IBM-4341 prompted the decision to design, assemble and use a parallel supercomputer; our
management was fully behind this "experiment".
The idea was to set up a master-slave system, initially an IBM-4381 with the VM/SP operating system as master and
an array of processors FPS-164 as slave-nodes (AP): three FPS-164s by July 1983, six by December 1983 and ten
by May 1984. The system was a loosely coupled array of processors, thus its name LCAP, sketched in Fig. 12. The

FIGURE 12. Sketch of the Kingston LACP-1 parallel computer.

hardware, software and the early applications in computational chemistry were most successful: by early 1985, a
copy of the system was also installed at the IBM European Center for Scientific and Engineering in Rome, Italy, a
second at the Production Super-computer Facility at the Cornell University Campus, Ithaca, New York, and a third
at the space centre in Moscow. The first computer LCAP-1 was followed by LCAP-2, an MVS-based parallel
system with the more powerful FPS-264 as nodes. The initial goal, namely to reach or bypass the Cray
supercomputer performance, was achieved. For example, the elapsed time ratio LCAP-1 to CRAY-XPM was 0.91,
0.81 and 1.08 with applications from our quantum molecular, molecular dynamics and Monte Carlo codes,
respectively; with LCAP-2 the corresponding ratios were 0.26, 0.25 and 0.38, respectively. Since the above
applications are coarse grain, for medium and small grain parallel applications it was necessary to increase the data
transfer from processor to processor and from processor to mainframe. This was achieved with a fast bus built by
FPS and a large shared memory(commissioned at Yale University and at Scientific Computing Associates257) were
connected to the mainframes and to all the APs. The basic model was inspired by recalling a previous uncompleted
and embryonic study of a brain model258 and on pragmatic considerations on standard telephone networks. The
LCAP-3 was a twenty FPS-264 systems with a two cluster configuration and with an IBM-3090 as a link between
the two clusters.

33
This "experiment" had full priority in Clementi planning from 1983 to 1986. There were many quantum chemists
visitors, learning how to transfer computer codes from sequential to parallel, thus contributing to the upgrading of
the computer programs used in chemistry.
The codes we parallelized were molecular Hartree-Fock259 (with Corongiu, Detrich, Chin and Domingo,) Monte
Carlo and molecular dynamics260 (with Corongiu, Detrich, Khanmohammadbaigi, Chin and Domingo), protein
folding261 (with Chin, Laaksonnen, Nguye, Gibson, Pincus and Sheraga), fluid dynamics262 (with Wojcik, Corongiu,
Detrich, Mansour and Lie) and graphics263 (with Luken, Liang, Caltabiano, Bacon, Warren and Beausoleil), the first
parallel computer codes in quantum chemistry and in molecular dynamics, and fluid dynamics. Since we were
interested in learning more about the performance of our system, we offered LCAP time to scientific institutions, for
example, to map the trajectories of the asteroids in the solar system, or to benchmark kernels from CERN high
energy codes, or to exploit parallelism in codes like seismic, crystal growth, circuit simulations, etc. We refer for
further details on parallelism with LCAP to a review paper264 and conference proceedings.265-267
In general, a computation is an ordered sequence of mathematical and/or logical operations, each one defining a
point in the SVP space, which is characterized by three versors (operational modes): sequential, S, vector, V, and
parallel, P. To a specific computer simulation there correspond a path in the SVP space; to a specific operation there
corresponds a specific point on the operation path, with a start and an end operation, as shown in Fig. 13.
Traditionally, a computer is designed either for sequential operations, or for sequential and vector or for
sequential, vector and parallel; each mode is rigidly hardware predefined. Ideally, however, a computer should be
designed to optimally execute any computational paths in the SVP space, namely it should be capable to
dynamically select an optimal architecture for any path. This implies a somewhat new computer conception, i.e. a
computer with dynamical optimization of architecture modes; for example it could preferentially select channels
(open and/or close channels for communications to selected nodes), change memory for optimal size and speed, etc.
A computational task, for example a subroutine, could be prefaced by specific information needed to select an
optimal architectural mode in the dynamical architecture computer. More studies on biological brain mechanisms
might help the design of an eventual dynamical architecture computer, perhaps even in this century.

FIGURE 13. The SVP space of a computational path.

Today, most supercomputers have adopted parallel architecture, essential to implement larger and larger
simulations. Quantum chemists are actively present also in devising new molecular compounds for future generation
computers components; nano-technology and quasi-crystal material have opened new horizons. Recall that there is a
great need for new technologies, for example, to lower the computer electrical energy consumption
We conclude this section mentioning two very large parallel computer producers, IBM, with the IBM Blue Gene/P
systems, and Fujitsu268 with the newly announced K computer. The K computer is a general-purpose parallel
computer which does not use GPU or other accelerators; it currently combines 68,500 SPARC64 VIIIfx CPUs, each
one with 8 cores, for a total of more than 540,000 cores. LINPACK performance is 8.162 petaflops (efficiency is
93%); the system it is still under refinements. When the K computer will be completely configured (in 2012) it is
expected to achieve a LINPACK performance of 10 petaflops. This year the K computer won the top world position
on TOP500 on June 20th 2011. The IBM Blue Gene/P system at Forschungszentrum Juelich, with over 825 teraflops
is the number 5 world fastest computer, the most powerful supercomputer in Europe.270,271

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 13. THE GLOBAL SIMULATION
A). Introduction. This paper deals with the evolution of computational chemistry, which we analyze from two
different viewpoints. In the first (see Sections 1 to 12) we start by recalling Bohr's discovery, and we continue by
considering the developments in the field, exemplified with the research by Clementi and his collaborators from the
late 1950 to the 1990 and in the last ten years. For more general developments, particularly in the last 10 years, there
are excellent analyses in the following chapters of this volume (see also Section15). An alternative viewpoint is to
discuss the impact of computers on science in general and computational chemistry in particular. Below we start by
considering how humans acquire concepts and then develop knowledge and how the advent of computers is
changing human knowledge. This approach leads most naturally to considerations on the role of computational
models in our society: We shall present our point of view sine ira et studio and we start with our definition of the
term knowledge.
B). Acquisition of knowledge. Humans understanding of what we call "reality" (both inside and outside us) is
constrained first by the limited sensorial input mechanisms of our body, and then by the elaborations within a
special machine (a purposively somewhat vague statement referring to our "nervous system"); these physiological
processes constrain our understanding of what is real", and, consequently, of our knowledge. We must stress that
human knowledge is a tool evolved to foster human survival, and it relates first to our-self, then our immediate
surroundings, and finally to the over-all environment, both near and far, in time and in space.
Recollections of the inputs of events can be transmitted either orally, or in writing or in a variety of different ways,
but our knowledge remains always only a "human knowledge. We assume as an axiomatic evidence the
existence of a time scale and of a three dimensional "space"; all the events we experience are tagged within our
brain, which is also a "time-space" event recollection depository. Most events in the time-space, particularly
mechanical events, are considered reliable since verifiable; further, we assume that these events are linked by the
cause-effect postulate (based on our daily experience). Events, both verifiable and not (i.e. emotional, imaginary,
fantastic, irrational,) originate concepts, either proper, if derived from verified events or improper, if derived from
non verifiable events. Science is that part of knowledge which attempts to systematize and logically connect proper
concepts (thus events verifiable and measurable) both to make predictions, needed for our survival and to test the
correctness of our rationalization. Improper concepts are excluded from science but are an important part -as we all
know- of non-scientific knowledge.
In general, there is a tendency to make a prudent and provisional use of acquired new knowledge, particularly
when this knowledge has either important human implications or needs laborious reasoning. For example we note
that the availability of computers, by now a two generation old commodity, has impacted our society much less than
auspicated by some, considering the implicit enormous advantages from the use of this new tool and the status of
our society which is very far from optimal.
C). Knowledge and power. The differentiation between proper and improper concepts is basic to human evolution.
Since the very early human development, a few people did emerge as natural leaders, often having realized that
superior knowledge can enhance their individual living conditions. Obviously, improved living conditions increase
chances of survival, a privileged situation which -to be kept- often requires also use of power, either personal, or
more collective, for example of a cast or a minority. As a result, privileges did become a commodity
maintained by few via the use of superior knowledge and power. Thus, since long ago competition -or even
conflicts- to demand and/or defend freedom of thinking (i.e. free access to privileges obtained via knowledge-
sharing) characterizes most societies. Recall that this conflict has very deep roots in the survival instinct, found not
only in all mammals and but also -to a different degree- in all living systems. Even today the confusion between
proper and improper concepts is cause of social tensions, misunderstandings, violence and even wars.
With time, long ago, in every society a compromising equilibrium did emerge: that part of knowledge mostly
related to the understanding and prediction of natural events (mostly proper concepts) called physics (needed for
the development of medicine, agriculture, commerce, transportation, defense, and, in general, for the many practical
aspects of urban living) was left to a few, today called scientists and engineers, whereas that part (called meta-
physics) related to regulation of primordial instincts and concerned with the interaction of a human with other
humans (or with any living system) was concentrated in a few centers of power, either dynastic or religious, or of a
minority, sometime as extended as to appear popular. Thus improper concepts were often at the base for economic-
political power In general, the majority of people was allowed to share that fraction of knowledge needed to carry
out their assigned (directly or indirectly) work. Remarkably, this division of knowledge (and hence of power) holds
even today, after thousands of years. Thus physics and engineering are characterized by mathematics, logic and
rational deductions from verifiable observations, whereas politics, economy, social relation, and religion, are partly
based on improper concepts, with adaptation to local traditions and evolving use of power. We are told that our

35
individual brain is too limited to deal with all aspects of knowledge, thus the need of these social subdivisions (and
the implied abuses and conflicts) is ethically justified. The old paradigm can be summarized as limited prosperity
via submission to local authority; considering the deep ignorance of the old time in science and technology, likely
we should look backward with some sympathy and understanding to the social achievements of our ancestors.
However, to survive we must evolve since events are evolving.
Recently we have radically new tools, more and more widespread, the computers and the electronic information
technology; for the first time in the human history we have the opportunity to individually learn many aspects of
knowledge. The reason is that we are no longer compelled to know, attend to, and recall the details of many sub-
tasks now left to the computer and other machines. Consequently, for the first time we have the opportunity to finally
attempt to critically visualize and rationalize the entire structure of our society. The new paradigm is reasonable
global prosperity in a new multi-ethnical society based on science, technology and a redefined concept of freedom.
Today with Internet each one of us has easy access to more information than those once present in the famous
Alexandria library.
Recall that the computer is different from most previous tools. Indeed, human tools, generally, were (and are)
designed to enhance our human physical limitations; but, for the first time in the human evolution- a reliable and
commercially available tool exist, specifically designed to enhance our brain capabilities, with its larger and larger
memory storage and with its ability to connect informational data faster and faster. Recall, however, that the
computer is only a tool, thus an instrument indifferent to ethically positive or negative uses. In our opinion the
diffusion and use of this two generation old tool is still insufficient, also because directly or indirectly opposed by
people afraid to lose cast privileges.
It seems clear that the computer, since its start in the late 1940s, a) is a powerful tool capable to enhance our
brain capabilities, b) that has grown enormously (but far from its limits) in its applicability and potentialities, c) is
used by more and more people internationally. In our opinion the commercial availability of relatively inexpensive
computers (the simplest one have a price comparable to a small fraction of the cost of a tool used by hundreds
million of people, i.e., the car) is an event as important for the human development as it was for example the
discovery of the weal, or the discovery of printed communication. Most unfortunately, today this tool is often used
in rather obvious and some time trivial activities, neglecting true challenges, like expanding more effectively
science, reaching peaceful coexistence, helping towords more widespread health, education and individual freedom.
The above negative situation is due to several factors, like a) the worldwide limited educational level, including a
widespread ignorance of science and technology still sometime present in the upper level of political and social
management even in develop Countries, b) the ever present resistance (and even opposition) to free and independent
thinking (to save cast privileges), c) the inability of the computer market and industry to invest on new computer
hardware and application software particularly directed to the education of young people, from elementary school
students to college, and d) the still notable computer cost considering underdeveloped Countries. There are many
additional technical factors to account for the slow penetration of computer culture in our society; an example is the
present inability to use vocal commands as human-computes interface, a research field once intensively considered
but today practically abandoned, in favor of a somewhat childish touch technology. (In this contest we recall that
at the Clementis IBM Kingston center there was a pilot study to use voice recognition aimed at standard
FORTRAN computer coding.) Extrapolating from the history of human evolution, it is evident that voice
communication to computers is an essential step to secure a more evenly educated society with fuller penetration of
computer use.
D). Over-specialization and widespread ignorance. Presently, we accept the view that most Countries are in an
era of overall global and fast evolution, not only in science but also in the political, economic and cultural aspects
of life, and that all in all - we are in a phase of progress and prosperity even if with occasional critical periods.
We claim that in the developed Countries there is abundance of food, widespread education, reasonable medical
assistance, and, often, reasonable political freedom. Unfortunately, this is not the case for everybody, particularly in
Countries where there are wars, or widespread popular violence, or Countries which are still emerging from poverty
(financial and educational) or for pockets of emarginated people, present even in the so-called developed Countries.
Consistently with the prevailing drive to material affluence, more and more we accept as positive, reasonable and
even necessary the present subdivision of human roles, of their functions, and we accept a social model leading to
deeper and deeper labor specialization. As a consequence of this view, there is more and more widespread
ignorance in many areas of knowledge justified and accepted to ensure over-specialization, which appears as a
necessary condition to reach general prosperity. However, recent social events, particularly in the Western
Countries, point out that the usual alternation of positive and negative economic cycles (assumed as inherent
characterization of our economic system) can become un-controlled. There are indications that our global economy
has entered into a critical period. It is, therefore, reasonable to assume that, likely, we have accepted as valid some

36
social-economica model partially incorrect and no longer tenable. We are of the opinion that, firstly, our widespread
institutionalized ignorance is one of the factor leading to this social deterioration and, secondly, that we have
neglected the large opportunities connected with a full exploitation of computational modeling.
E). Different social models. We could note that today accepted mental attitude is very different from the
intellectual models pursued for example in the golden period of the Hellenic civilization, or in the renaissance period
of the fifteen-sixteen century in Europe, started in Italy. With some idealization and notable oversimplifications, we
could say that these old models did allow a limited political freedom and prosperity (to part of the population),
coupled to high intellectual curiosity and high prosperity for a few of the high social classes, often striving to
individually reach a balanced overall knowledge. Thus, for example, a scientist was often also a philosopher or an
artist and artisans had the competence to create finite products starting nearly from the row materials. This model
eventually collapsed, since it could not cope with problems related to the population growth and migrations, to the
emerging of new nations and the steady concentration of power and capitals in a few hands. After wars and social
turbulence, and a period of renewed scientific and technological growth we witness, in the eighteen century, the
advent of the industrialized Countries.
The scientific organizations and the academic world have -de facto- accepted, subscribed and contributed to the
above mentality of deeper and deeper specialization. As a result today scientists are under the pressure of
specialization leaving the solution of broad social problems to specialized experts. Ironically, the scientific
research is finding the existence of complex networks of interactions and inter-dependences, questioning the
uncritical drive toward over-specialization, and the reliance on specialized experts, one of the causes for the
present depressed economy. Thus, we scientists find ourselves in a somewhat contradictory position; some of us,
consistently with a tradition of free thinkers, attempt to apply our typical scientific logic also to the social problems
of our time, using our tools, including computers and predictive models, other concentrate their talents only on
narrow specialization fields.
One reasonable way to correct some of these negative trends might be a return to a more balanced distribution of
knowledge, with stress on interdisciplinary research, with intense use of predictive modeling, using computers with
more imagination, fully realizing finally-- that the computer is the tool designed to compensate some of our brain
limitations, allowing, for example, to produce massive computer models used to alternative ways to organize our
society.
F). The Global Simulation Approach. Below we outline a general concept, called the Global Simulation Approach
(see Ref 113,118) proposed to characterize science and technology, stressing the interdependence among the many
fields from basic physics to models relevant to the structure of our society.
Today scientific knowledge is not the result of a single homogeneous development, but rather the superposition
of a variety of discoveries gathered in centuries of evolution in many countries. Note that a more critical
interdisciplinary mentality should make scientific knowledge more evenly interconnected, and this might, hopefully,
brings about international cooperation and a global increase in prosperity.
In the Global Simulation model, we distinguish two main modes, two main frames: a "logical-rational frame"
and a phenomenological-pragmatic frame". The "logical-rational frame" is best exemplified by the scientific
methodology expressed via mathematics- typical of physical sciences, particularly by models concerned with the
motions and interactions of physical objects and their nature. For us chemists the objects in consideration are,
typically, electrons and nuclei, and atomic combinations in simple molecules, up to complex ensembles of macro-
molecules of biological interest. Today, larger real systems are mainly dealt by phenomenological and pragmatic
fields, like earth and environmental sciences, biology, physiology and medicine. Very specialized and even more
complex systems are dealt in economic and social sciences, but with models less and less connected to physical laws
and rational scientific knowledge, and biased by improper concepts of traditional wisdom and -de facto- often
conservation of cast privileges.
Human concepts are interconnected and consequently also the scientific models are inter-connected into a
hierarchical set of models. Each model deals with a specific area of knowledge and is concerned with well defined
classes of objects, like elementary particles, or atoms, or molecules or the different components of living objects,
both plants and animals. Among the latter "objects" we recall a particular ensemble of objects, the "people, namely
ensemble of humans organized into different and specific types of societies". Note that no entomologist would
describe ants or bees without a description of their habitat, but, on the contrary our cultural tradition still describes
the anatomy and the physiology of men and women, largely ignoring its evolution and the human habitat, namely
the different structures of society. Thus, most of today economical models are not integrated into the scientific
method but are still based on traditional, sometime ancient concepts of management and subdivision of wealth and
power. Stated differently, on one hand the fast progress of science and technology permeates our life, but on the

37
other hand, we uncritically accept social models for the distribution of power and wealth inherited from a remote
past.
G). Details of the Global Simulation Model. The Global Simulation model is schematically presented in Figs. 14
ad 15. In the Global simulation we consider an ordered set of models such that the output of a model is the input of
the following model.
We sketch, very schematically, only a few fields, mainly related to traditional computational chemistry,
described, for example, in the previous Sections of this work. Alternatively one could start with computational
physics. Fig. 14 is subdivided into two parts, one relates to the traditional "scientific method", the second part, at
the bottom of the figure, provides only a generic title "empirical modeling", sketched in more detail in Fig. 15. All
in all, the objects of the models starting at the top of figure 14 grow in size -top to bottom- from particle physics, to
atoms and molecules, to biological systems and living cells. Fig. 14 provides connections among "scientific models"
all derived from theoretical physics, stressing those dealing with theoretical and computational chemistry. Fig. 15
sketches fields which deals with patterns, shapes, morphology, in general "qualitative and morphological
characterizations" of reality, generally leading to a phenomenological knowledge. Thus in Fig. 15, starting from the
bottom, we considers the inorganic world (earth sciences, where we include all sciences dealing with non-living
objects), and the sciences of the living systems, botany and zoology, related to vegetal and animal life. Zoology
deals also with humans, starting with the human institutions, then narrowing to the human body (with medicine and
its many related sub-fields like histology, etc) and finally ending with the living cell. Eventually, the research
fields indicated at the bottom of Fig.14 will merge with those at the top of Fig. 15 into the general scientific method.
Today empirical topics will be assisted tomorrow by an organized set of computational models, following the
scientific methodology of Fig.14.
There are a few general techniques, adopted in merging of scientific with phenomenological modeling, for
example, Artificial Intelligence (A.I), Neuron Networks (N.N), and Factor analyses, Multi-scale analysis, Structure-
Activity Relations, and Similarity Relations, all relevant to drug design, to chemical pharmacology, and to the new
areas of bio-informatics and computational medicine, topic explicitly considered in the chapters of this volume.
The overall structure given in Fig. 14 is self explaining: the Scientific Method is based on invariant axioms
(conservation of mass, of momentum, etc.), which lead either to emerging new methodologies, like rules of
collisions (and Cellular Automata), or to the more traditional laws of motion; the latter can be either statistical or
deterministic. The notation HF, MB, VB, DFA, DFT and DFA-EF stands for Hartree- Fock, Many Body, Valence
Bond, Density Functional Approximations, Density Functional Theory (without or with external field). Concerning
relativistic theories, we should repeat below the name "Dirac" the entire set of methods and fields placed in Fig. 14
below the name "Schrdinger" (as it was presented in the original drawing of the figure118). Indeed, it is a regretful
limitation of today computational sciences the use of non-relativistic models for problems which would benefit from
the use of relativistic concepts. As shown in articles in this volume, the main reason for this behavior is not only
widespread ignorance, but real computational limitations, including lack of easily available computer codes.
We present in Figs. 14 and 15 not only models and fields, but also their connections; each field has developed its
vocabulary, its rules and its methodology; at each model to model interface there is a superposition of
methodologies, concepts and hypothesis. Logical conflicts - temporary or seemingly more permanent- are expected
to occur at these interfaces. As often done in such situations we have the tendency to "invent fuzzy concepts, often
introducing unverifiable hypotheses coming from improper concepts.
The concept of "life is an example of conceptual fuzziness. In Figure 14, "living matter" is encountered in the
fields placed at the bottom of the figure, when, proceeding from atoms and macro-molecules we reach "cellular
organization", which includes "living cells". In Fig. 15 living cells are reached staring from the bottom of the
figure moving to the top. To our knowledge, today no model provides a fully acceptable scientific explanation of the
exact mechanisms for "life creation", since, presently, we have not scientifically created a detailed molecular
model explaining life. Note that well known chemical concepts (like for example catalytic and auto-catalytic
processes, and dissipative and adaptive systems) are available, but presently not satisfactorily extended to give a
satisfactory definition of the concept of "life", which remains an example of "a fuzzy concept". Hopefully, the
recent proposal that molecules can have specific functionality, like machines, and the fact that cells have selectively
impermeable boundaries (i.e. the membranes, delimiting a cell content from that of the environment), the probability
that a novel and most complex machine (the living cell) can results from the interaction of many simpler machines
(the cellular macromolecules with special functionality), added to the chemical concepts of auto-catalyses,
dissipation, and bifurcation might nearly suffice for eventually removing much of the fuzziness presently
surrounding the concept of life.
In Figs. 14 and 15 we attempt to graphycally show aspects of the inter-dependence of our knowledge.
Unfortunately, often we consider inter-disciplinary research as merely a "mainly intellectual", even "snobbish",

38
viewpoint. Evidently, cause-effect relationship between population explosion, lack of sufficient energy sources,
violent conflicts and wars, uneven distribution of those goods which are essential for survival, environmental
disasters and related inadequate planning, crisis of the financial system particularly in the Western world,
insufficient and unbalanced education, etc., etc. are not considered with sufficient critical attention and objectivity,
which clearly calls for interdisciplinary scientific modelling. The need to propose, develop, criticize, improve basic
computational models appears not to be properly appreciated even in the most economically advanced Countries.

FIGURE 14. Research fields and corresponding inter-connections for today computational chemistry.

FIGURE 15. A few computational areas of the ensemble of "Empirical Models".

H). Eventual computational extensions. Figure 15 complements Fig. 14, a rough indicative sketch with no claim
to be complete. To ensure logical uniformity in the scientific knowledge, we must link the knowledge implied in the
scientific fields of Fig. 14 with those more phenomenological of Fig. 15. Today computers and the super-computers,
the basic tools for the creation and exploitation of very complex computational models, are often misused by nearly
disregarding essential tasks of our society. Let me give an analogy: the discovery of the wheel is certainly a
landmark in the evolution of human technical; only in time we learned to use simultaneously more than one wheel (a
progress equivalent to parallelism in computer technology). But many centuries have passed before we learned to
use the wheel for train transportation, or to regulate the transmission of motion in clocks and automated industrial
plants. The present limited applications of computers is not surprising, since the early computers were extremely
less powerful than the present one. Perhaps, it is now time for each scientist, particularly those in the computational
scientific community, to accept some blame for the present "far from optimal" use, applications and distribution of

39
computational facilities (and for the -de facto- unquestioned acceptance of today non-scientific socio-economical
models).
Fig.15 contains a part traditionally accepted as scientific areas and a second one composed of two macro-areas
economical models and social structure and family structure, traditionally considered outside the domain of
science. Human history can be summarized by considering the variations of social-economical models adopted by
different societies in different times. Note that these models are supposed to provide the answer to the ever exiting
fear of poverty; further, these models have been controlled by minorities detaining power. Economical models differ
in the methodology to increase capital, either creating new sources with new knowledge or by exploiting different
countries or different social classes. The idea that knowledge can eliminate individual poverty without producing
social damage has not penetrated our society.
Clearly, modeling a single man independently from his habitat, community and evolution is inadequate. Recall,
for comparison, that the understanding of the properties of liquid water implies understanding of water clusters, of a
single molecule of water, and of hydrogen and oxygen atoms. Considering an ensemble of humans, one must recall
that each individual human is born and raised within a local structure, the family, which characterizes at first, a local
community, then a geographical region and eventually a full Country. Today we continue to we live using traditional
and ancient local social models, despite the fact that any society, de facto, willing or unwilling, is fast evolving with
time. The human evolution originally was slow, each step lasting centuries, but then it speeded up to a few (or one)
generations; today is very fast, only a fraction of one generation. Old models must be updated, using the best of our
technology; science and computer modeling must have a larger role.
Generally, we scientists explore many aspects of the real world with critical mind. When -as often it is the
case- we are unsatisfied by "traditional explanations" we propose new models; surprisingly, however, we accept
passively models and decision on social directions even if based on "questionably old traditional thinking".
Presently, however, the evolution speed of our society is such that we can no longer passively- await for decisions
based on traditional common good sense; if we know, or think to know, how to improve society, using the
scientific method including modern computational models", then, likely, we have a social obligation to take steps.
The computational community has not only the needed technical preparation, but also an opportunity and a
responsibility. For example, but this is only my opinion, computer experts, could (should) collectively collaborate
at the construction of a vast computer models to simulate different society organizations, which -for the billions of
humans on the planet- simulates a) the needed resourced for adequate food, education and health for each individual
(and this requires the use of disciplines and models from Fig.14 ( including earth sciences and environmental
control) and from Fig.15), and b) reasonable social alternatives in order to make these commodities de facto
available as soon as possible (clearly, recognizing the need for co-existence of existing different economic, political
and social models).
As there is a basic axiomatic foundation in traditional physical sciences, corresponding to verifiable events,
equivalently there is an axiomatic base for social models. The verifiable event is the existence of about seven billion
humans; the axiomatic base is the rights to survive for the human species with the corollary the right to life for
any human as soon as born; this implies for each human equal opportunities for adequate food, education and
health care (the corollary logically questions the acceptance of death penalty and war). After centuries, finally, we
have progresses to condemn genocide, but recall that we still practice indirect genocide, whenever we do not allow
sufficient food, education and medical-care particularly to the very young.
The proposal for constructing vast computer social-economical model clearly will require input from science
and technology. However, any vast computational social model, to become reality, likely presupposes the
existence of a world society notably more widely educated than the present one, a subject tentatively dealt in the
next Section, where we recall an attempt to revive with modern computational models the encyclopedic spirit of the
XIIX century.

14. THE GLOBAL SIMULATION LIBRARY

A). An early attempt. "Renormalization" of the definition of an object is a standard procedure which allows the
transition from one model to a next model, restating both the definition and characterization of the same object in
the two (or more) connected models; renormalization is used both in the rational and in the phenomenological
knowledge frames. However, there are renormalizations, which we find particularly difficult, like the one previously
discussed concerning the characterization of living cells present both in scientific models (Fig. 14) as well in
empirical models (Fig. 15). A vast computational model -as auspicated in the conclusion of the previous Section-
will need inputs from many different areas, both from the scientific and technical community as well as from the

40
political and economical community. Below, we recall a very early experience in setting up a broad
computational model, even if limited to only relatively few scientific areas.
One of Clementis aims both at IBM San Jose and at IBM Kingston, in the period 1960-1990, was to offer to
the computational chemist community not only documented computer codes covering large areas of the field of
computational chemistry, but also to interconnect the different models. A notable difficulty encountered was to
devise algorithms to ensure that the output from a code furnishes easily and immediately usable data for the input of
a connected code, namely to solve renormalization problems. MOTECC-89118 made available the first connected set
of codes, the MOTECC-89 library.
Different models presented in Figs. 14 and 15 were organized as subroutines of a master program, where the output
from one subroutine is structured as to easily become the input for the following code. A number of areas, however,
were not connected, since the project was never fully concluded. In Fig. 16, we report our IBM-Kingston 1989
computer library, a very preliminary attempt to realize a global simulation library.16,118 At the top in the figure, we
have indicated a few general facilities; the lower section of the figure specifies the program the implementations
(details are available in Chapter 1 of MOTECC-89118). The above codes were called either with traditional input or
via inter-connecting algorithms, like a preliminary interconnecting computer graphic package, discussed in Chapter
24 of MOTECC-90.113

FIGURE 16. Global Simulation Library of connected codes from MOTECC-89.

The realization of a global simulation computer library, one of the goals in Clementis 1980-1990 research in
IBM-Kingston, and the writing of the MOTECC volumes required a strong organizational effort with ample
financial support, which we experienced and enjoyed in the 1980 when we were part of a large enterprise, the IBM
Corporation. We hope that eventually this type of effort will be somewhere duplicated, extended and improved,
since it represents a unique "launch pad" toward worldwide technical and scientific progress. In this contest, we

41
recall also the preparation and distribution of a 45 minutes educational audio-video (with voice commentary in
English, French, Italian and Chinese) Unity of Science linking quantum chemical computations to molecular
dynamics and to fluid dynamics.
The MOTECC-89,-90 and -91 volumes (with the computer codes and related documentation available essentially
for free) have been requested by hundreds of users during the Clementi time in Kingston, N.Y.; when Clementi and
Corongiu moved to the CRS4 research center in Sardinia, Italy, the previous MOTECC title (Modern Techniques
in Computational Chemistry) had to be abandoned, due to a legal request from IBM; it was replaced with the title
METECC (Methods and Techniques in Computational Chemistry) leading to the METECC-94 and -95 volumes.
Later on, Prof. Jean-Marie Andr kindly accepted, for a few years, to distribute both the volumes and the computer
codes.
B). A tentative proposal. Communication and computers technology are ways to increase knowledge and
eventually, to improve society. Recall that the discovery of the printing press by Gutenberg had, as a consequence,
the Protestant Reform, and many more people finally could read and freely interpret the Bible; we know, however,
that also wars were among the results of the Reform. Today, television, mobile telephones, Internet and computer
are diffusing to millions of rather poor people knowledge of the privileges existing for few; as to be expected, we
witness violent movements particularly in emerging countries. There is an urgent need to create alternatives to the
use of violence, in obtaining social changes. Parenthetically, in this AIP Proceedings volume in the chapter by
Bessrour, Belmiloud, Hosi, and Tangour there is an appendix presenting a most interesting documentation on
aspects of the Arab Spring concerning how the power of knowledge and communications is influencing social
changes.
The presently institutionalized diffuse ignorance, implicit in our over-specialized society, has lead to the
acceptance of questionable widespread methods and operations, particularly in financial matters, which have
affected negatively large sections of the society. In addition there are many problems we can no longer disregard,
like,for example, population control, shortage of energy and water, climate variations, requests from emerging
Countries, globalization, economic competition, and wars. Vast computational socio-economical modelling, new
computer-assisted educational tools, can bring about solutions for needed social changes by creating a more
knowledgeable, thus, hopefully, a more equitable society.
Consequently, we wonder on the advisability to start an international collaboration (a pragmatic project) leading to
the assembly of vast new libraries of computer programs for e-learning (extended from computational models on
elementary particles up to the inclusion of social sciences) directed to obtain two goals. One is the preparation of
libraries for e-learning with wide diffusion, addressing different age educational levels, improving worldwide
educational standards, especially in emerging countries, pointing out the vast differences in opportunities, Country
to Country and ways to improve. The second goal is to rewrite today economy and socials models, to allow, also via
simulations, optimization of models of human conditions, namely, a better society. This proposal necessarily will
require time for its realization and it will have to be carried out by successive steps. Computer-libraries for e-
learning will allow virtual experimentation via simulations of different socio-economic models rejecting the
traditional use of real life experimentation, with violence and with probability of concomitant failures. Either we
learn to model and rationally optimize our social evolution also via computer simulations, or we shall continue to
witness violence in revolutionary experimentations.
Concerning the first goal we suggest to assemble educational libraries computer aided, to be available in all
elementary schools, in all high schools, by all college students, and also by any researcher and professionals; here
all means people of all countries, rich and poor, leading to a broad international cultural base. This vast effort
should eventually foster an internationally uniform distribution of knowledge, as homogeneous as possible. The
traditional education in our school systems can be partially replaced by a more personal and individual learning via
e-learning, a computer assisted self-education, with educational programs freely available and worldwide
distributed. A low entry level could be developed for elementary schools; an intermediate level should be coded for
high schools and one more advanced, but always interdisciplinary, for university students. The code library
(complemented with an obvious must, like modern graphics, and carefully chosen mathematical bases) should be
made internationally available nearly for free, translated in many languages, directed particularly to young people in
poor emerging countries. Education is an expensive item for any government; more self e-learning can become a
pragmatic solution to cut cost and divert professionals from schools to urgently needed technical and research
activities.
The construction of a computational chemistry library at different specialization levels is both an obvious
preliminary step, even if very limited and an opportunity for the present computational chemistry community. Recall
that today computer lecture series (e-earning) to teach sciences, in general, and chemistry, in particular, are already
available. The difficulty and the challenge is to make these knowledge-tools available to poor and young people in

42
under-developed countries, where even the availability of pencils and paper is often a luxury. The computer
industry should be educated to assemble low priced read only hardware libraries, with good graphics and audio,
inclusive of solar power supply, available in many languages. Developed countries can take this basic step to help
the underdeveloped countries (which eventually will become future costumers). The distribution and testing of codes
in developed Countries could start by take advantage of existing projects and is a natural task particularly for
international organizations.
In parallel, computer experts should write the computational libraries implied in the bottom part of in Fig. 15.
The generalized feasibility to learn and computationally experiment different society models, a basic goal of our e-
learning proposal, will create more open minded people, and represent a constructive evolution for international
relations without the traditional use of violence. Since the research needed to write computer codes library is often
supported by academic institutions, the cost to users could be nearly nominal.
Today there is a strong activity in modeling world economy. The models available are often stochastic, both
qualitative and quantitative, and use large data banks on large computers. The reliability is rather modest but
improving with time and experience and with the evolution of computer industry. However, the goals of the models
are often limited to the financial considerations, like effect of inflation, borrowing, centralization, and globalization.
Differently from the scientific models, generally, there is no invariant, accepted base. Goals like global climate,
energy resources, population migration, population control, food distributions, and disarmament, all still
fragmentary. The realization of a single model on global social-economy, both reliable and predictive, is rather far
mainly due to pressure for quick results, fragmentation into any specific problems, and to the persistence of a non-
scientific mentality. We are of the opinion that much of today weakness in economy modeling is related also to lack
of an axiomatic base, of sufficient generality, reliable quantitative data, and poor methodology. The lesson learned
in the development of scientific method could help, and scientists should be more present.
To summarize: we know that for more than half a century a new tool is available, the computer; its use is
becoming more and more diffuse, particularly among the young generations. It is rather inexpensive, and the current
price could be notably reduced, particularly if assembled with the simplifications provided by the limitations
implicit in the assembling of the specific volumes of e-learning libraries. It must have the versatility to allow self-
teaching to the young people, stressing particularly modern science, world geography, history, economy, and the
different traditions and social models existing in different Country, eliminating, hopefully, many of the existing deep
cultural barriers. We know that e-learning can prepare young people from grammar school to college. We also
know that a more uniform cultural base is bound to bring about a better and new society. Ignorance often leads to
suspicions, incomprehension, fears, rivalry, wars, and wide-spread misery. The computer aided educational library
proposal is, all in all, a relatively simple task, in need mainly of good will, some specific knowledge and computer
experience.
The above tasks are obvious, but, previously, could not have been considered, because the time was not ripe;
now there are computers of different power and cost, there is, worldwide, a sufficient number of computer users, the
young generations are eager to be recognized; the popularity of Internet confirms the need and interest for wide-
spread information. The world instability needs more public attention, especially from computational experts. We
are of the opinion that today governments often are not ready, since submerged by the immediate problems
created in part by their inability to break with traditions. Thus, it seems reasonable for the computer experts to take
the initiatives.
In particular, it is somewhat surprising to see the how slowly the educational system is reactive to the technical
opportunities offered by e-learning and computer technology. With the new I Pad type technology and the available
experience from e-learning, the educational system (a major item in government budget) could be re-vitalize. E-
learning libraries for teaching, at many levels, can be optimally assembled and translate into many languages. The
young are still horded into classrooms, where teachers, often too old to have mastered new technologies, transmit
-hopefully correctly- century old notions to sometime unwilling youngsters. At the same time we learn from
statistical studies that the young generations spends daily more and more time at the television, at electronic games,
at the Internet. Thus the obvious question is why there are not attractive, wide-spread, low cost, carefully prepared e-
learning programs for people of all ages, from kindergarten to college, to third generation. Selflearning can be
promoted; it can complement today traditional school learning, or partially replace it, optimally utilize teaching
efforts and costs. If done properly it can help to eliminate insufficient education in emerging Countries, racism and
intellectual intolerance in any Country. Finally it can also represent a business opportunity in our global economy.
Perhaps one could recall that education has been traditionally used to conform individual mentalities to local
average opinions and traditions, thus a way to make more homogeneous our society knowledge. Education
constitutes the basic tool for cultural evolution provided it recognizes and makes use of the ever changing
opportunities coming from science and technology.

43
15. TODAY COMPUTATIONAL CHEMISTRY, SEEN FROM TACC-2012, AN INTER-
DISCIPLINARY CONGRESS

As previously stated, the advent of electronic computers and electronic communications is a milestone in human
evolution: science is profoundly affected by these technological advancements. This evolution, however, is evident
more in some human activity less in others. True cultural evolution is different from superposition of cultures;
the latter, however, often is simply the first stage in an evolutionary process. We are of the opinion that our society
is very far from a homogeneous economic, political, and educational level and the opportunities offered by the
computers are far from being fully exploited. Education has slowly changed, pragmatically and informally, mainly
adjusting to the changes by addition and sometime by uncritical superposition of criteria and facilities, seldom by
fully restructuring itself ex novo. University curricula and academic organizations suffer from the inability to
adequate the basic structure to the present computer era; inter-disciplinary research is accepted, but it is not at the
base of the university planning; indeed, the old disciplinary divisions are still present.
In general, today chemistry congresses are organized within national boundaries, or, if international, often
are restricted to one or few specific scientific fields, de facto neglecting that a most significant modern need in
science and technology includes a stress for an interdisciplinary research. The scope of the congress "Theory and
Application in Computational Chemistry", TACC-2012, has limits in its response to some of the above needs, but -at
least- has a well defined interdisciplinary character, implicit in its title, and evident from the preliminary schedule
of the congress given in Table 6.

TABLE 6. Session titles and session organizers in the TACC-2012 Congress.


 

 
  




  
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We recall that the first congress of the TACC series was held in 2004 in Gyeongiu Korea, organized by Prof.
Kwang S. Kim, Pho-ang University, in Korea. The second TACC congress was held in Shanghais, China, in 2008
organized by Prof. Danquin Wei, Jiao Tong University, Shanghai, China. The third congress is TACC-2012, will be
held at the University of Pavia, Italy, chaired by Prof. Enrico Clementi. Differently from traditional congresses, most
of the speakers for TACC-2012 have been selected from well recognized co-chairpersons. Indeed, today there are
too many fields present under the heading Computational Chemistry to be adequately known by a single person.

44
In Fig. 6 we provide the general agenda of the Congress, with the titles of the sessions and the names of the session
co-organizers, thus evidencing the interdisciplinary nature and the variety of computational models present in the
congress; the data reported in the table written about six months prior the congress start- are likely final. Being the
topics discussed at TACC-2012 very inter-disciplinary, the participants to the congress have the opportunity to
become more familiar with some of the congress topics by reading the chapters of this AIP volume Theory and
Applications of Computational Chemistry: The First Decade of the Second Millennium. The AIP volume is published prior to
the congress opening, in order to give an opportunity to reach the congress more informed on the very vast scope of
modern computational chemistry. Each TACC-2012 invited speaker was invited also to contribute to this AIP
Proceedings volume, thus ensuring that a sufficient number of invited speaker would provide an overall prospective
of the Congress and of modern computational chemistry; in our opinion this AIP volume has reached its goal.
TACC-2012 has given space also to the recent progress in computer hardware; indeed, this entire paper has
stressed the symbiotic relations between computers -both availability and efficiency- and computational fields,
based on mathematics, physics and experimentation. Computational chemistry faces challenging problems;
computer simulations are essential to reach correct solutions, not only for the many unsolved problems typical of
today traditional chemistry but also for problems related to our society, like those related to disarmament, food
resources (quality, availability, distribution and storage), availability of new energy sources (cost, networks,
diversification), and more realistic forecast on the effects of population growth.
We recall that today the world fastest computer is the Japanese K computer268, 269; the previous leader is the
Chinas Tianhe-1A supercomputer, at the National Supercomputing Center in Tianjin, China; note that Tianhe-1A
had been the first Chinese computer to be ranked on top, signaling the countrys growing technological might270.
The fastest computer in the United States, at Oak Ridge National Laboratory, in Oak Ridge, Tenn., is an IBM
computer, placed third. The parallel K supercomputer architecture will be discussed in a special session the K
supercomputer day, chaired by Prof. Kimihiko Hirao. Recall that K is short to the Chinese symbol Kei, which
means 10 quadrillion, presently the ultimate goal for the number of calculations the computer can perform per
second. This most impressive machine outranks previous efforts by about a factor of ten in performance. With this
machine fundamental problems have a superior chance to approach reliable solutions, like problems of strong social
and public impact (for example related to wealth distribution, climatology, water and food preservation and
distribution). Hopefully, there will be an international collaboration effort, sharing the enormous potentiality of the
K computer. The TACC-2012 meeting hopes to foster this educational process. It is important, in the long range, to
realize that the K computer performance can be extended with different and future components, reducing the
operational cost and the physical size; note that to improve an existing machine is by far easier than to conceive it
from scratch and to assemble it for the first time. To stress the interdependence between computers hardware and
computations TACC-2012 will also present an exhibition complementing the lectures of the K supercomputer day.
All this brings us to look with great interest to the AIP chapter The Next Decade of Computers by Dr. Greg
Taylor, INTEL Fellow. New component technology is clearly the key factor to ensure continued advances in
computer performance271: there are limits, well exposed in Dr. Greg Taylor work. This chapter is an educational
initiative informing the TACC nano-material experts -in particular- on where to point their research goals, and the
computational community -in general- on what to expect for future computers. Gregs chapter is very informative,
clear and concise, pointing to the future challenges and limitations; we, the computer user community, need to keep
in mind this type of information
Storage has always been a basic component of any computer system; it has increased enormously since the very
early ferrite rings, but nevertheless it remains one of the basic limits of today computer performance. New ideas,
new physical models are needed as discussed by Dr. Stuart Parking, IBM Fellow. Note that, slowly, the storage
basic capacity and the computer circuit speed allow improved simulations on the activity in brain cortex. For
example, Ananthanarayan at al.272 have reported simulations performed on an IBM Blue Gene/P (with 147,456
processors and 144 TB main memories) on a cortex with 109 neurons and 1013 synapses, namely reaching the
complexity of the brain of a cut. Comparing to the human cortex the simulations has a scale that is roughly 1-2
orders smaller and has a speed 2-3 orders slower than real time. This is notable technical achievement, even if it
tells us how far we are from a more realistic simulation of a biological brain.
In this context we note that the progress of artificial intelligence is realistic and pragmatic not only for military
tasks, but more and more also for civilian applications like solution of biological problems. In this regard the chapter
Design of Modified Proteins using Knowledge-based Approaches by Yves Dehouck, Dimitri Gilis, and Marianne
Rooman is most instructive; the chapter Sampling and Statistics in Biomolecular Simulations by Hoon Sim,
Karthikeyan Diraviyam, Akansha Saxena and David Sept extends our confidence in future progress.
Modern Computational Chemistry is much concerned with biochemical and biophysical research areas often
addressed with Molecular Dynamics simulations. MD simulations coupled to sampling techniques are discussed in

45
the paper Molecular Dynamics Techniques in the Studies of the Bacterial Ribosome by Joanna Panecka and
Joanna Trylska. The critical paper Computational Approaches to Target Fishing and Ligand Profiling by Didier
Rognan shows how part of the once private data bank of bioactive screening in proteins is finally available to public
research and is becoming most effectively in helping drug design. Molecular Dynamics Simulation of Water in the
Low Temperature Region by A. Krallafa, A. Adda, A. Seddiki and M. Dauchez discuss the structure of liquid
water, MD simulations to study protein conformations are discussed in the papers Exploring Folding Pathways of
Single Proteins Using Mechanical Manipulation by Ptur Heidarsson and Ciro Cecconi and in the work
Narrowing the Gap in Understanding Protein Structure and Function through Computer Simulations by Hong
Guo. The paper Minimalist Models for Biopolymers: Open Problems, Latest Advances and Perspectives by Fabio
Trovato and Valentina Tozzini is a modern and careful analysis for research in biophysics and biochemistry. The
chapter Nanotechnology Drives a Paradigm Shift on Protein Misfolding Diseases and Amyloidosis by Vittorio
Bellotti and Monica Stoppini show how pronounced and valuable is the merging of modern medicine with
biochemistry and nano-technologies. Finally the chapter Structure of Crown Ethers by A. A. El-Azhary, N. Al-
Jallal, A. Al-Kahtani, N. Al-Badri, K. Al-Farhan, and M. Al-Qunaibit, reporting a state of the art study with density
functional on a specific class of materials, reminds us that DFT is the commonly semi-empirical model used in
many quantum chemical simulations.
Quatum chemical theories, the starting point of computational chemistry, are discussed in several AIP papers
like a) Semi-classical Instanton Theory of Nonadiabatic Reaction Rate Constant. I. Formulation by Yoshiaki
Teranishi, Hiroki Nakamura, and Sheng H. Lin, b) Recent Advances in Spin-Free State-Specific and State-
Universal Multi-Reference Coupled Cluster Formalisms: A Unitary Group Adapted Approach by Rahul Maitra,
Debalina Sinha, Sangita Sen, Avijit Shee and Debashis Mukherjee, c) AGP: Search for The Consistent RPA
Reference State Yngve hrn, d) Concepts of Chemical Bonding from Electron Propagator Theory by J. V.
Ortiz. The paper by Wenjian Liu The `Big Picture' of Relativistic Molecular Quantum Mechanics remind us that
non relativistic quantum chemistry, only an approximation to the relativistic quantum chemistry, is less and less
acceptable due to the increase in computer power and theoretical advances available this century. The chapter by
Yuki Ohtsuka and Seiichiri Ten-no reports on new electron correlation computations with the Monte Carlo
approach. H. Nakatsuji T. Miyahara and J. Hasegawa deals with the important topic of molecular spectroscopy of
biological photo-materials. George Heimel, Ingo Salzmann and Norgbert Koch provide an excellent account On
the Fundamental Processes in Molecular Doping of Organic Semi-conductors. Jean-Marie Andr paper Quantum
Chemistry, Band Structures and Polymers remind us that polymer chemistry, one of the most important
development in last century chemistry, has many modern ramifications and a solid computational base. Xiaohu Li
and George C. Schatz paper QM/MM studies of gas-liquid collisional energy transfer deals with a most important
chemical aspect of modern chemistry, the study of interfaces. Finally, Stefano Pelloni, Guglielmo Monaco,
Riccardo Zanasi, and Paolo Lazzeretti in the paper Beyond NICS brings about a novel view on aromaticity, with
a discussion on nucleus-independent chemical shift, (NICS), connecting various benchmarks and hypnotises on
aromaticity, a multidimensional phenomenon presently not fully understood.
Nano-materials are very present in TACC-2012 as evidenced in AIP papers like a) Nanoscale chemical mapping
through plasmonic tips on AFM-based cantilevers by M. Patrini, F. De Angelis, R. Proietti Zaccaria, M. Francardi,
M. Lazzarino, L. Businaro , E. Di Fabrizio dealing with new methods to analyze material at the atomic level, b)
Controlling Drug efficiency by encapsulation into carbon nanotubes: a theoretical study of the antitumor Cisplatin
and the anti-HIV TIBO molecules by R.Bessrour, Y. Belmiloud, Z. Hosni and B. Tangour, and c) On the use of
symmetry in SCF calculations. The case of fullerenes and nanotubes by C. M. Zicovich-Wilson, Y. Nol, A. M.
Ferrari, R. Orlando, M. De La Pierre and R. Dovesi.
These titles are indicative on computational advances of the last ten years and suggest new horizons which are
simply staggering, pointing to a drastically new science and technology. It appears that we are moving from fantasy
to the reality of novel devices and methods for knowledge acquisition. The computational topics of TACC-2012
have been recently augmented with a few additions, three added lectures forming a special session, which
provides an opportunity to learn from colleagues from Arab Countries not only on their scientific contribution to
computational chemistry, but also on some of the challenges in Arab Countries horizons ensuing the Arab Spring.
We have previously noted the chapters by Bessrour, Belmiloud, Hosi, and Tangour with a most interesting view on
recent political events; the chapter by A. Krallafa, A. Adda, A. Seddiki and M. Dauchez, has a competent appendix
concerning practical and realistic step taken in the education system after the Arab Spring; finally in the chapter by
A. A. El-Azhary, N. Al-Jallal, A. Al-Kahtani, N. Al-Badri, K. Al-Farhan, and M. Al-Qunaibit there is an appendix
commenting on the Arab Spring as seen from a Country essentially unaffected by the recent political changes in the
Arab world. Two thousand year ago the lands facing the shore of the Mediterranean Sea had a rather uniform
cultural level, with Athens, Alexandria and Rome as centers of culture, science and technology. The hope is that the

46
Arab Spring eventually will at least bring collaboration and constructive co-existence among all countries on the
Mediterranean shore.

16. CONCLUSIONS

In this work the initial part given in Sections 1 to 13, follows traditional computational chemistry schemes;
Sections14-15 are -at a first glance- somewhat different, since attempting to go somewhat deeper into the events
which have lead to the existence of computational sciences, in general, computational chemistry, in particular.
Chemistry is one among the many fields of human knowledge, all interconnected, either very tightly or more
loosely. We have chosen to analyze these fields under a mathematical-computational view point, a prospective
which has eventually lead to hypothesize an ordered set of computational models, the Global Simulation Approach.
It is up to each computational chemist to select how to work in his field, either by staying into the main traditional
core of computational chemistry (sketched in Fig. 14 and in the Fig. 6) or considering super-positions to other fields
(sketched in the bottom part of Fig.15) including some traditionally not considered part of scientific knowledge.
Both avenues are needed to foster progress.
Computational chemistry started last century with computations in quantum chemistry; today it has in an
interdisciplinary mode- expanded outside chemistry into many areas of science and tomorrow it is expected to enter
into new one. This represents an enormous potential field of applications, which will shape the future not only of
Science and Technology but also of our society. In particular, social and economical models are expected, finally, to
be based also on scientific methodology, with an axiomatic base which will eventually correct those traditional
errors which have lead to the difficulties experienced not only in the last centuries but also most recently.
Last century, computational chemistry has permeated physical chemistry where formal solutions with
corresponding equations were available from physics. In this century computational chemists will not only continue
to address the same class of problems (with obvious extensions and improvements), but hopefully will acquire a new
mentality and move into radically new frontiers.
Concerning the mentality, as a minimum, we expect a more determined effort toward an inter-disciplinary mode
of research. Further, computational chemistry likely will intensively make use of new approaches, for example those
related to artificial intelligence and exploit more and more the future opportunities derived from the availability of
new computer technology. Finally, we hope that scientists and science will have a larger role in shaping the future
rules of our society, by clearly distinguish between proper and improper concepts.
Concerning new frontiers, computational chemists are expected to expand their research at least into four
directions; a) improve the today wave function representations with explicit inclusion of time dependence and
relativistic effects, b) fully merge quantum chemistry with molecular dynamics, fluid dynamics and thermodynamics,
as well with engineering and environmental sciences, as indicated in Fig. 14, c) expand computer models into the
areas listed in Fig. 15, free from traditional constraints, d) hopefully, take an active role on a world-wide
educational effort, directed at improving our society, e) create a new vision for theoretical chemistry .
The first and the second directions a) and b) are rather obvious extrapolations on past and recent events.
Hopefully, the second direction b) will bring about realistic simulations and modeling explaining details of the
mechanisms of life in cells, a future conquest expected to become at least as significant in the XXI century as
quantum theory was in the XX century. The trend of progress for new materials starting from dye chemicals in the
past, to polymers after Second World War, to nano-materials after fullerene, will continue with quasi-crystals, room
temperature super-conductors, novel pharmacological products and special functions materials.
The third direction c) is a bit problematic particularly for what concerns economic models, presently strongly
integrated with the centers of political power. Rationally, the standard logical rigor of the scientific method -today
basic to computational chemistry and physics and more and more to science in general- should permeate existing
social and economical models, eventually proposing new ones. Further, the new super-computers are expected to be
used as essential tools to create interdisciplinary knowledge on truly complex social problems. Traditions and new
models once more are colliding, being this a de facto rule for progress.
Concerning the fourth direction we note that at list by words there is a growing international consensus. We have
simply pointed out that the scientific community should become more involved and participative to social progress.
The author of this chapter considers as a tragedy the present misuse of computational opportunities (basic to gain
and spread knowledge). The tentative proposal d) is simply an attempt to regain some of the lost time in a
particularly turbulent international period. For an initial -but necessarily short- period of time some of the present

47
TACC organizers could become a contact point for those scientists willing to work at the preparation of educational
libraries for e-learning: a world-wide educational effort to foster better human conditions.
Finally, the fifth point auspicates new theoretical directions in chemistry. Presently we have theory of matter as
proposed from physics, and translated into quantum chemistry, mathematical models (often phenomenological)
and a very large amount of laboratory data in need of rationalizations. Chemistry, however, is mainly concerned
with transformation of matter, and creation of new materials with specific properties. All this points to theories of
reactions and non equilibrium thermodynamics. Perhaps we should extend and generalize basic research concepts
and attempt to build a theoretical chemistry capable to predict the existence and properties of new classes of
chemicals rather than simply rationalize a posterior what has been create in the laboratory.

ACKNOWLEDGMENTS
This chapter summarizes work performed with the essential collaboration of Clementis many co-workers from
many countries; from the numerous citations to Prof. Giorgina Corongiu, her collaboration impact clearly emerges.

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28. S. Golden, Rev. Mod. Phys. 32, 322-327 (1960).
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30. P. Pariser and R. G. Parr, J. Chem. Phys. 21, 466-471 (1953).
31. K. S. Pitzer and E. Clementi, J. Am. Chem. Soc. 81, 4477-4485 (1959).
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43. E. Clementi, D. L. Raimondi, and W. P. Reinhardt, J. Chem. Phys. 47, 1300-1307 (1967).
44. E. Clementi, J. Chem. Phys. 36, 33-44 (1962).
45. J. W. Linnet, The electronic structure of molecules (A new approach). Methuen, London, 1964.
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59. E. Clementi, Tables of Atomic Functions, IBM J. Res. and Dev., Supplement 9, 2-19 (1965).
60. E. Clementi, J. Chem. Phys. 40, 1944-1945 (1964).
61. C. Roetti and E. Clementi, J. Chem. Phys. 60, 3342-3342 (1974).
62. E. Clementi and C. Roetti, Atomic Data and Nuclear Data Tables 14, 177 (1974), pp. 177-478.
63. E. Clementi, J. Chem. Phys. 39, 487-488 (1963).
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65. E. Clementi, J. Chem. Phys. 39, 175-179 (1963).
66. E. Clementi, J. Chem. Phys. 42, 2783-2787 (1965).
67. E. Clementi and A. Veillard, J. Chem. Phys. 44, 3050-3053 (1966).
68. A. Veillard and E. Clementi, J. Chem. Phys. 49, 2415-2421 (1968).
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73. E. Clementi, J. Chem. Phys. 38, 2780-2782 (1963).
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85. E. Clementi and J. W. Mehl, IBM System/360. IBMOL-5 Program. IBM Research Report RJ#853, 1971.
86. E. Ortoleva, G. Castiglione and E. Clementi, IBMOL-7, Computer Phys. Comm. 19, 337-357 (1980).

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107. D. Frye, A. Preiskorn, G. C. Lie and E. Clementi, J. Chem. Phys. 92, 4948-4955 (1990).
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115. F. Van Duijeneveldt, IBM Tech. Report RJ#945, 1971.
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119. C. Froese-Fischer, Atomic Data and Nuclear Data Tables 4, 301-399 (1972).
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121. C. F. Bunge, J. A. Barrientos, A. Vivier Bunge and J. A. Cogordan, Phys Rev. A 46, 3691-3695 (1992).
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126. R. J. Boyd and C. A. Coulson, J. of Physics A 6, 782-793 (1973).
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138.S. J. Chakravorty and E. R. Davidson, J. Phys. Chem. 100, 6167-6172 (1996).
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140. E. Clementi, J. Chem. Phys. 46, 3851-388 (1967).
141. E. Clementi, J. Chem. Phys. 47, 2323-2334 (1967).
142. E. Clementi and J. N. Gayles, J. Chem. Phys. 47, 3837-3841 (1967).
143. G. Corongiu, D. Estrin, G. Murgia, L. Paglieri, L.Pisani, J. D. Watts and E. Clementi, Int. J. Quantum
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144. E. Hollauer, D. F. Hoffmann and E. Clementi, E. Methods and Techniques in Computational Chemistry:
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145. K. Anderson, M. P. Flscher, R. Lindh, P. . Malmqvist, J. Olsen, B. O. Roos and A. J. Sadlej, University
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147. L. Pisani and E. Clementi, Methods and Techniques in Computational Chemistry: METECC-94, E.
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148. E. Clementi, J.-M. Andr, M.-C. Andr, D. Klint and D. Hahn, Acta Physica Hungaricae 27, 493-521
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149. E. Clementi, J. Mehl and W. von Niessen, J. Chem. Phys. 54, 508-520 (1971).
150. G. Giunchi, E. Clementi, M. E. Ruiz-Vizcaya and O. Novaro, Chem. Phys.Letters 49, 8-12 (1977).
151. O. Novaro, E. Blaisten-Barojas, E. Clementi, G. Giunchi and M. E. Ruiz-Vizcaya, J. Chem. Phys. 68,
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152. H. Kistenmacher, H. Popkie and E. Clementi, J. Chem. Phys. 59,1325-1336 (1973).
153. H. Kistenmacher, G. C. Lie, H. Popkie and E. Clementi, J. Chem. Phys. 61, 546-561 (1974).
154. G. C. Lie, and E. Clementi , J. Chem. Phys. 62, 2195-2199 (1975).
155. G. C. Lie, E. Clementi and M. Yoshimine, J. Chem. Phys. 64, 2314-2323 (1976).
156. O. Matsuoka, E. Clementi and M. Yoshimine, J. Chem. Phys. 64, 1351-1361 (1976).
157. G. C. Lie and E. Clementi J. Chem. Phys. 64, 5308-5309 (1976).
158. E. Clementi, H. Kistenmacher, W. Koos and S. Romano Theor. Chim. Acta 55, 257-266 (1980).
159. R. O. Watts, E. Clementi and J. Fromm, J. Chem. Phys. 61, 2550-2555 (1974).
160. J. Fromm, E. Clementi and R. O. Watts, J. Chem. Phys. 62, 1388-1398 (1975).
161. J. W. Kress, E. Clementi, J. J. Kozak and M. E. Schwartz, J. Chem. Phys. 63, 3907-3928 (1975).
162. E. Clementi and R. Barsotti, Theor. Chim. Acta 43, 101-120 (1976).
163. E. Clementi and R. Barsotti, Chem. Phys. Letters 59, 21-25 (1978).
164. E. Clementi and G. Corongiu, J. Chem. Phys. 69, 4885-4887 (1978).
165. E. Clementi, F. Cavallone and R. Scordamaglia, J. Am. Chem. Soc. 99, 5531-5544 (1977).
166. G. Bolis and E. Clementi, J. Am. Chem. Soc. 99, 5550-5557 (1977).
167. L. Carozzo, G. Corongiu, C. Petrongolo and E. Clementi, J. Chem. Phys. 68, 787-793 (1978).
168. S. Romano and E. Clementi, Int. J. Quantum Chem. 14, 839-850 (1978).
169. E. Clementi, G. Corongiu and G. Ranghino, J. Chem. Phys. 74, 578-588 (1981).
170. E. Clementi, G. Ranghino and R. Scordamaglia, Chem. Phys. Letters 49, 218-224 (1977).
171. E. Clementi, J. Mol. Liquids 42, 233-239 (1989).
172. M. Aida, G. Corongiu and E. Clementi, Int. J. Quantum Chem. 42, 1353-1381 (1992).
173. F. Parak, H. Hartmann, M. Schmidt, G. Corongiu and E. Clementi, Eur. Biophys. J. 21, 313-320 (1992).
174. C. A. Venanzi, H. Weinstein, G. Corongiu and E. Clementi, Int. J. Quantum Chem. S 9, 355-365 (1982).
175. E. Clementi, G. Corongiu, B. Jonsson and S. Romano, J. Chem. Phys. 72, 260-263 (1980).
176. G. Bolis, M. Ragazzi, D. Salvaderi, D. R.Ferro and E. Clementi, Int. J. Quantum Chem. 14, 815-838
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177. S. Fornili, D. P. Vercauteren and E. Clementi, J. Mol. Catal. 23, 341-356 (1984).
178. K. S. Kim and E. Clementi, J. Am. Chem. Soc. 107, 5504-5513 (1985).
179. K. S. Kim, D. P. Vercauteren, M. Welti, S. Chin and E. Clementi, Biophys. 47, 327-335 (1985).
180. R. Scordamaglia, F. Cavallone and Clementi, J. Am. Chem. Soc. 99, 5545-5550 (1977).
181. E. Clementi, G. Corongiu and F. Lelj, J. Chem. Phys. 70, 3726-3729 (1979).
182. E. Clementi and G. Corongiu, Biopolymers 18, 2431-2450 (1979).

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184. E. Clementi and G. Corongiu, Chem. Phys. Letters 60, 175-178 (1979).
185.E. Clementi and G. Corongiu, J. Chem. Phys. 72, 3979-3992 (1980).
186. G. Corongiu and E. Clementi, Biopolymers 20, 551-571 (1981).
187. E. Clementi, IBM J. Res. and Dev. 25, 315-326 (1981).
188. E. Clementi and G. Corongiu, Biopolymers 21, 763-777 (1982).
189. E. Clementi and G. Corongiu, Biomolecular Stereodynamics, Vol. I, edited by R. H. Sarma, New York,
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190. E. Clementi and G. Corongiu, J. Biol. Phys. 11, 33-42 (1983).
191. E. Clementi and G. Corongiu, Physical Foundation of Protein and Nucleic Acid Functions, Advances in
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192.L. Leherte, G.C. Lie, K.N. Swany, E. Clementi, E. G. Derouane, J.-M. Andr, Chem. Phys. Letters 145,
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193.E. Clementi, Determination of Liquid Water Structure, Coordination Numbers for Ions and Solvation for
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194. E. Clementi, Computational Aspects for Large Chemical Systems, Lecture Notes in Chemistry, 19, Berlin,
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195. V. Carravetta and E. Clementi, E. J. Chem. Phys. 81, 2646-2651 (1984).
196. U. Niesar, G. Corongiu, E. Clementi, G. R. Kneller and D. K. Bhattacharya, J. Phys. Chem. 94, 7949-
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197. G. Corongiu and E. Clementi, J. Chem. Phys. 97, 2030-2038 (1992); ibid. Errata 97, 8818 (1992).
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201. P.-O. Lwdin, Adv. Chem. Phys. 2, 207-322 (1959).
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203. L. Pisani and E. Clementi, J. Chem. Phys. 101, 3079-3084 (1994).
204. A. Veillard and E. Clementi, Theoret. Chim. Acta 7,133-143 (1967).
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215. G. Corongiu, private communication.
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227. G. Corongiu and E. Clementi, J. Chem. Phys.131, 034301-16 (2009).
228. G. Corongiu and E. Clementi, J. Chem. Phys. 131, 184306-14 (2009).
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231. K. S. Kim, M. Dupuis, G. C. Lie and E. Clementi, Chem. Phys. Letters 131, 451-456 (1986).
232. D. A. Estrin, L. Paglieri, G. Corongiu and E. Clementi, J. Phys. Chem. 100, 8701-8711 (1996).
233. H. Popkie, H. Kistenmacher and E. Clementi, J. Chem. Phys. 59, 1325-1336 (1973).
234. H. Kistenmacher, H. Popkie, E. Clementi and R. O. Watts, J. Chem. Phys. 60, 4455-4465 (1974).
235. G. C. Lie and E. Clementi, Phys. Rev. 33, 2679-2693 (1986).
236. E. Clementi and G. Corongiu, Int. J. Quantum Chem. S10, 31-41 (1983).
237. J. H. Detrich, G. Corongiu and E. Clementi, Chem. Phys. Letters 112, 426-430 (1984).
238. G. Corongiu, Int. J. Quantum Chem. 42, 1209-1235 (1992).
239. G. Corongiu and E. Clementi, J. Chem. Phys. 98, 4984-4990 (1993).
240. G. Corongiu and E. Clementi, J. Chem. Phys. 98, 2241-2249 (1993).
241. E. Clementi, G. Corongiu and F. Sciortino, J. Mol. Struct. 296, 205-213 (1993).
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249. D. K. Bhattacharya, W. Xue and E. Clementi, MOTECC-91, edited by E. Clementi, Leiden, ESCOM
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250. R. Panda, V. Sonnad and E. Clementi, MOTECC-91, edited by E. Clementi, Leiden, ESCOM Publishers,
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251. J. von Neumann, Theory of Self Reproducing Automata, Univ. of Illinois Press, 1966.
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253. U. Frish, B. Hasslacher and Y. Pomeau, Phys. Rev. A Letters 56, 1505-1508 (1986).
254. U. Salzner, P. Otto and J. Ladik, J. Comp. Chem. 11, 194-204 (1990).
255. W. Hackbusch, Multigrid Methods and Applications in Computational Mathematics. Vol. 4, Heidelberg,
Springer Verlag, 1985.
256. W. Hockney, Parallel Computers Architecture, edited by W. Hockney and C. R. Jesshope, Bristol, Adam
Hilger, 1981.
257. Scientific Computing Associates, Yale University, New Haven, Connecticut, 1987.
258. E. Clementi, J. Detrich, S. Chin, G. Corongiu, R. Caltabiano, A. Carnevali, J. Helin, M. Russo, A. Gnudi
and P. Palamidese, Structure and Dynamics of Nucleic Acids, Proteins, and Membranes, edited by E.
Clementi and S. Chin, New York, Plenum Press, 1986, pp. 403-450.
259. E. Clementi, G. Corongiu, J. Detrich, S. Chin and L. Domingo, Int. J. Quant. Chem. S 18, 601-618 (1984).
260. E. Clementi, G. Corongiu, J. H. Detrich, H. Khanmohammadbaigi, S. Chin, L. Domingo, A. Laaksonen
and H. L. Nguyen, Physica B 131, 74-102 (1985).
261. K. D. Gibson, S. Chin, M. R. Pincus, E. Clementi and H. Scheraga, Supercomputer Simulations in
Chemistry, Lecture Notes in Chemistry 44, edited by M. Dupuis, New York, Springer-Verlag, 1986, pp.
198-213.
262. M. Wojcik, G. Corongiu, J. H. Detrich, M. M. Mansour, E. Clementi and G. C. Lie, Supercomputer
Simulations in Chemistry, Lecture Notes in Chemistry 44, edited by M. Dupuis, 1986, pp. 224-245.
263. W. L. Luken, N. Y. Liang, R. Caltabiano, E. Clementi, R. E. Bacon, J. M. Warrenand W. F. Beausoleil,
IBM Research Report, March 18, 1987, KGN-111.
264. E. Clementi and G. Corongiu, Parallel Computing 25, 1583-1600 (1999).
265. E. Clementi, Proceedings of the Third International Conference on Supercomputers, Boston, St.
Petersburg, Florida, Vol. 1, 1988, pp. 63-78.

53
266. J. H. Detrich and D. Folsom, Proceedings of the Third International Conference on Supercomputers,
Boston, St. Petersburg, Florida, Vol. 1, 1988 pp. 99-120.
267. E. Clementi, G. Corongiu, M. Dupuis, G. C. Lie and V. Sonnad, Proceedings of the Third International
Conference on Supercomputers, Boston, St. Petersburg, Florida, Vol. 1, 1988, pp. 240-259.
268."Japanese K Computer Is Ranked Most Powerful". The New York Times, 20 June 2011.
269. "Japanese supercomputer 'K' is world's fastest". The Telegraph, 20 June 2011.
270. Supercomputing in China. Wikipedia, the free encyclopedia, 2012.
271. SGI, Intel plan to speed supercomputers 500 times by 2018, Computer World, June 20, 2011.
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Performance Computing Networking, Storage Analysis, New York, USA, ACM, 2009.

54
 The Next Decade of Computing
Greg Taylor

Intel Labs, Hillsboro OR USA, Greg.Design.Taylor@intel.com

Abstract. Questions of power and power density are limiting the design of present day systems and will define how
future computing systems are built and operated. The need for energy efficiency in computation will drive us towards
more parallel and more heterogeneous computing systems of many forms: mixtures of large and small general purpose
processor cores with special purpose computational blocks that can very efficiently solve a narrower range of problems.
High performance computing has evolved from performance at any cost to the delivery of energy efficient computation.
This change in direction is driven by multiple factors and will impact computing is different ways. The cost of electricity
for running and cooling an HPC system is now comparable to the cost of the capital to build such a system while power
density limits how tightly such systems can be packed. So how are HPC systems going to evolve over the next decade in
response to these pressures?
Keywords: Moores Law, High Performance Computing.
PACS: 01.30.Rr

INTRODUCTION
Over the past 60 years high performance computing (HPC) has become essential to the advancement of a broad
range of scientific problems. For most of this period improvements in HPC were focused just on raising the
performance of computers. As we approach the exaFLOP level of performance additional factors are becoming
critical to the delivery of increasing computational capacity. The scaling of CMOS technology that we have
benefitted from for the past several decades is changing and this change is being reflected in the systems that are
becoming available. Total power and power per die have reached practical limits that have required changes to the
way that chips are designed.

Figure 1. High performance computing development since 1993.[1]

TECHNOLOGY FUNDAMENTALS
The exponentially increasing capability of the integrated circuits that drive the performance of modern computers
is the fulfillment of Moores Law. This Law is a prediction made by Gordon Moore in 1965 that integrated
circuit component count would roughly double every year, and is shown in Figure 2.[2] This was later reformulated
as integrated circuit capability would double every 24 months and has held for 45 years. It has led us from chips
with 10 transistors apiece to the present day with billions of transistors on a single die, and is not showing signs of
slowing down. At its root, Moores prediction is an economic one: he pointed out that for each technology there is a

Theory and Applications in Computational Chemistry: The First Decade of the Second Millennium
AIP Conf. Proc. 1456, 55-61 (2012); doi: 10.1063/1.4730642
2012 American Institute of Physics 978-0-7354-1057-2/$30.00

55
number of transistors per die that minimizes cost per transistor, and with each new technology that number
approximately doubles.

Figure 2. Original graph of Moores Law.[2]

Before taking a more detailed look at the future of integrated circuits it is useful to understand some of the
fundamentals of the CMOS technology that is its basis. At a high level, the interesting attributes of the technology
are its speed, power, density, and cost. The speed of a CMOS device is roughly proportional to the supply voltage,
VCC, minus the transistor threshold voltage, Vt. The power consists of two components, the active power consumed
by switching the output of a gate and the leakage power that arises because transistors are imperfect switches. The
active power is proportional to the square of the voltage times the switching frequency, or assuming that the
switching frequency is proportional to the voltage, approximately VCC3. The leakage power also tends to be a cubic
or higher function of the supply voltage. Combining these two relations shows that raising the operating voltage of a
CMOS gate raises its performance, but raises its power much faster. Conversely, reducing the operating voltage
reduces performance, but reduces power even more. Moores Law describes the expected density and cost scaling.
In 1974 Denard described a set of scaling equations that could be applied to describe the relationship between
two MOS technologies, summarized in Table 1.[3] By industry convention each new generation of technology has
scaled using a value of = 1.4 for a 30% reduction in feature size and a 50% reduction in area per component. The
overall impact of Denard scaling is that switching to a new technology permitted the use of twice as many transistors
in an integrated circuit at a 40% higher operating frequency while consuming a constant amount of power and
silicon area.
Table 1. Scaling Results for Circuit Performance.[3]
Device or Circuit Parameter Scaling Factor
Device dimension tox, L, W 1/
Doping concentration Na
Voltage V 1/
Current I 1/
Capacitance A/t 1/
Delay time per circuit VC/I 1/
Power dissipation per circuit VI 1/2
Circuits per unit area 2
Power density VI/A 1

It is particularly worth noting that because supply voltage, and consequently supply current, were each reduced
by 30% per generation the power per gate was reduced by 50% in switching from an older technology to a newer
one. Because of this reduction in power it is possible to double the number of transistors that are used within a
constant power budget. The Denard scaling equations held for many generations of technology, but started to break
down around the 90 nm technology node in 2004. In part this was because along with other device parameters the

56
transistor threshold voltage, Vt, was also scaled down, leading to an exponential increase in leakage through the
transistor. Since transistors had nearly zero leakage in the 1970s it had been possible to ignore this feature of
Denard scaling for many years. When this leakage started approaching the active power dissipation of the integrated
circuits, scaling it was no longer affordable. Slowing the scaling of Vt in turn slowed the scaling of the supply
voltage, V, which was the primary source of power reduction in Denard scaling. In the extreme case where voltage
is held constant, utilizing all of the doubled transistor count that is available on a new technology would result in
doubling product power. This rapidly became unsustainable and led to the end of Denard scaling and to power
becoming the dominant issue in microprocessor design.
Over the past two decades microprocessor technology has delivered approximately 1000x improvement in
performance. Of that gain approximately 100x was delivered by improvements in transistor performance, with
microprocessor architecture and design accounting for the remaining 10x.[5] Furthermore, the transistor
performance improvement was due to a combination of shrinking transistor feature sizes and an increase in
transistor leakage currents. Because microprocessors are now designed to operate in a power constrained
environment this latter component of performance increase will no longer be available, raising the focus on more
radical changes to transistors and more energy efficiency in architecture and design.

ARCHITECTURE
Just as there is a simple, empirical law describing transistor counts, there is Pollacks Rule describing how
effectively integrated circuit designers can turn those transistors into performance.[4,5] This rule states that the
performance of a single processor grows as the square root of its complexity, as measured by area or transistor
count. If you want to double performance you need to quadruple transistor count. Fortunately Moores Law has
provided many doublings of transistor count, making this tradeoff very acceptable for the past 40 years. Since in the
absence of deliberate effort to manage power it also tends to be proportional to complexity, increasing the
performance of a single microprocessor core tends to make the core less energy efficient. History notwithstanding,
clearly if we can take advantage of parallel processors then we can deliver performance more economically and
more energy efficiently than if we need to rely on only one high performance microprocessor, as seen in Figure 3.

Intel 4004, 1971 Intel 8088, 1978 Intel Nehalem-EX, 2009

1 core, no cache 1 core, no cache 8 cores, 24 MB cache
23k transistors 29k transistors 2.3B transistors
Figure 3. Evolution of Intel Microprocessors 1971 to 2009.[5]
There is a limit to the improvement in performance that can be obtained from parallel processors working on a
fixed size problem, given by Amdahls Law. In general programs written for parallel execution have a portion that
must be executed serially.[6] If the portion of the program that can be executed in parallel is given by P, then the
speed-up that can be achieved by using N parallel processors is given by:
1
S= (1)
P
(1 P ) +
N
The effect of this limit is shown in Figure 4, where it can be readily seen that the maximum speed up that can be
obtained is 1/(1-P), even with an unlimited number of processors available.

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 Figure 4. Amdahl's Law
In counterpoint to Amdahls Law is Gustafsons Law.[7] Gustafson observed that rather than trying to reduce the
time needed to solve a fixed size problem, parallel processing is generally used to increase the size of the problem
that can be solved in a fixed time. If the portion of a problem that must be executed serially is a fixed fraction of
the time available, then size of the problem that can be solved by using N parallel processors is given by:
S = N (1 ) (2)
This result is shown in Figure 5, showing that even though parallelism cant reduce the execution time of fixed size
problems to an arbitrarily small time, it clearly does permit the solution of larger problems in a fixed time.

Figure 5. Gustafson's Law

Pollacks Rule is driving high performance computing in the direction of increasing parallelism. Meanwhile the
end of Denard Scaling has led to microprocessor design being dominated by power concerns. If many processors are
simply integrated on a single integrated circuit die, then the power of this die will grow proportionally to the number
of processors. One way to prevent this growth is to turn off inactive blocks. On older, low leakage CMOS
technologies inactive blocks of a chip can have their clocks shut off to eliminate any active power. In this manner
floating point units in processors have been shut off while inactive for more than a decade. For more savings in high
performance, high leakage processes the power supply for inactive blocks can be shut off. While this approach is
very effective, restoring these blocks to full performance generally incurs a delay penalty which makes it difficult to

58
apply this technique with a very fine granularity. Recent multi-core microprocessors have applied this approach to
shut off inactive cores, allowing a limited power budget to be applied only to the active blocks.[8]
The performance and the power of a computer are impacted not just by the computation done in a
microprocessor, but also by the data moved through the system. Comparing the typical energy used to execute an
instruction with that required for a floating point operation, its clear that the actual computation is only a small
portion of the overall energy. Additional portions are the energy needed to move data within the processor and the
energy that is used in a processor to fetch and decode instructions. Looking first at data movement, a typical double
precision floating point operation uses 16 bytes of data and produces an 8 byte result. If these operands are read
from the cache memory on the processor die, then bringing the data to the floating point unit consumes
approximately as much energy as the operation itself. If just one operand needs to be read from off-chip DRAM then
moving that data will consume 60 times as much energy as the computation itself. Clearly both the the design of the
memory system of a computer, as well as the structuring data to minimize data movement during computation are
critical to energy efficient operation.
Table 2. Energy per operation.[9]
Operation Approximate energy
Instruction Execution 5-10 nJ
FP operation 200 pJ
Byte read from cache 10-20 pJ
Byte read from DRAM 1.5 nJ
Microprocessors are capable of very general computation. By designing specialized hardware it is possible to
significantly reduce or even eliminate the power that is spent on fetching and decoding instructions. A common
example of this is the Graphic Processing Unit (GPU) that is included in most single user computers, often
integrated onto the microprocessor die. This unit generates the graphics that are displayed to the user more
efficiently than the same display can be generated by a general purpose CPU made from equivalent technology. On
the hand, the GPU can only perform a limited range of computations and requires support from a CPU to run an
operating system. A more extreme example is a security processor that is only capable of encrypting and decrypting
data using a few fixed algorithms, but executes these algorithms with great efficiency. Errore. L'origine
riferimento non stata trovata. shows that there are a range of options for implementing a function that trade off
flexibility and energy efficiency over several orders of magnitude between software on a microprocessor, Digital
Signal Processors (DSP), and dedicated hardware.

Figure 6. Flexibility versus Energy Efficiency. [10]

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 FUTURE SCALING
Given that power concerns are currently dominating the design of computer systems at all scales from handheld
cell phones to supercomputers, the future of computing will be driven by the need for energy efficiency. This
efficiency will be delivered through the design of increasingly heterogeneous systems. This heterogeneity will take
multiple forms: similar microprocessors with different area/performance tradeoffs, dissimilar microprocessors, and
microprocessors combined with a wide variety of special function units. Evidence of this is already available in the
form of different performance cores in a single System on Chip (SoC) as well as in graphics processing units that are
integrated with the most recent microprocessors.
Parallel floating point operations are increasingly available in microprocessors, as evidenced by the addition of
vector operations such as SSE, SSE2, and SSE3 in the case of Intel microprocessors.[11] When used these units
dramatically increase the performance and the energy efficiency of computation. On the other hand, these units are
readily turned off when not in use limiting their power impact on tasks that do not involve many floating point
operations. By virtue of being included inside the microprocessor compilers can transparently take advantage of
these units.
Chips with cores that offer different performance levels are one approach to improving energy efficiency. The
serial portions of a problem can be run on a large, high performance core, while the parallel portions are run on an
array of small, efficient cores. This combination yields the best of both worlds, taking advantage of the high
performance core to minimize the time that the rest of the processor is waiting for serial operations to complete
while running parallel operations efficiently. Unfortunately the schedulers that assign tasks to cores today can not
readily deal with asymmetric cores and do not efficiently utilize such systems, placing more work on the
programmer to efficiently utilize the available computational resources.
Further heterogeneity is already being made available in the form of graphics processors and other special
function units. The ease with which a programmer can take advantage of these units varies. In the case of GPUs,
OpenCL and CUDA are languages that permit program portability and eliminate the need to target just a single
hardware platform. Accelerators targeting cryptography, signal processing, networking, and other applications offer
significant performance benefits within their targeted domains but typically require that programs are targeted at
specific pieces of hardware with little portability. If a special function unit matches the needs of a computation
particularly well, then targeting just a single hardware platform may be justified by the performance and energy
efficiency gains that result from using it.
In the past processors were designed for the general case, with capabilities added only when they benefited most
or even almost all of the programs that might be run on that processor. With the numbers of transistors per chip
continuing to grow exponentially while power budgets remain flat, we are likely to see units added that provide
significant benefits to only a minority of the tasks faced by the processor and are simply shut off to conserve power
when not needed. A range of such units may be able to offer improve performance and energy across a wide range
of applications even though no single application would utilize all of them and most would only use one. This
creates the possibility that in extreme cases it may even make sense to define new special function units that are
added to general purpose microprocessors to accelerate the kernels of algorithms where that would have been
unthinkable in the past.
In all of these machines energy efficiency will demand that the data that is used by a computation be organized to
maximize locality. Algorithms will need to be developed to minimize the need to move data and maximize the reuse
of data that is already locally available. Doing tens of extra operations instead of moving one operand from DRAM
saves energy. And the savings can be even greater if the data is even further away on another processor die.

CONCLUSION
Moores Law has led to dramatic improvements in available computational capability. Most of that performance
improvement in the past has come from increases in transistor density and speed. In the future transistor speed
improvements are like to be more modest, leaving more of the task of providing future performance improvement to
the designers of microprocessors. This in turn is driving computers in the direction of increasing numbers of cores
and increasing the heterogeneity of the computational units that are available. As a result obtaining an acceptable
fraction of a systems capability to solve a given problem will likely require that algorithms be adapted to minimize
the movement of data within a computer and to take maximum advantage of the available functional units.

60
 ACKNOWLEDGMENTS
This work was inspired by Shekhar Borkar, who has been making predictions of microprocessor evolution for
many years. Further refinement came through interaction with many talented engineers from across Intel.

REFERENCES
1. www.top500.org.
2. G. Moore, Cramming more components onto integrated circuits Electronics, Vol. 38, Number 8, April 19, 1965.
3. R. H. Denard, et al, Design of Ion-Implanted MOSFETs with Very Small Physical Dimensions, IEEE Journal of Solid
State Circuits, Vol. SC-9, Oct. 1974, pp. 256-268.
4. F. Pollack, Pollacks Rule of Thumb for Microprocessor Performance and Area,
http://en.wikipedia.org/wiki/Pollacks_Rule.
5. S. Borkar and A Chien, The future of microprocessors, Communications of the ACM , Volume 54, Issue 5, May 2011.
6. G. Amdahl, Validity of the single processor approach to achieving large scale computing capabilities, AFIPS Spring Joint
Computer Conference, 1967.
7. J. Gustafson, Reevaluating Amdahls Law, Communications of the ACM , Volume 31, Number 5, May 1988.
8. R. Kumar and G. Hinton, A Family of 45nm IA Processors, International Solid State Circuits Conference, Feb. 2009, pp.
58-59.
9. S. Borkar, The Truths & Myths of Embedded Computing, Cool Chips XIV, Yokohama Japan, April 2011.
10. B. Brodersen, System on a Chip Design, http://bwrc.eecs.berkeley.edu/Classes/EE225C/Lectures/lec3_soc.pdf.
11. Intel 64 and IA-32 Architectures Software Developer's Manual Combined Volumes 2A, 2B, and 2C,
http://www.intel.com/content/www/us/en/architecture-and-technology/64-ia-32-architectures-software-developer-instruction-
set-reference-manual-325383.html

61
 The `Big Picture' of Relativistic Molecular Quantum
Mechanics
Wenjian Liu

Beijing National Laboratory for Molecular Sciences, Institute of Theoretical and Computational Chemistry, State
Key Laboratory of Rare Earth Materials Chemistry and Applications, College of Chemistry and Molecular
Engineering, and Center for Computational Science and Engineering, Peking University, Beijing 100871, People's
Republic of China, liuwjbdf@gmail.com

Abstract. The most fundamental aspects of relativistic molecular quantum mechanics are highlighted to depict the `big
picture' of the field.
Keywords: relativistic Hamiltonians, relativistic wave functions, relativistic molecular properties
PACS: 31.15.aj, 31.15.am, 31.30.jc

INTRODUCTION
The first decade of this second millennium has witnessed fundamental breakthroughs in the field of relativistic
molecular quantum mechanics (MQM). The state-of-the-art methodologies for electronic structure1-4 and properties5
have just been summarized by the principle developers. Yet, it is still necessary to highlight the most fundamental
issues on the relativistic Hamiltonians, wave functions and properties, so as to depict the `big picture' of relativistic
MQM.

RELATIVISTIC HAMILTONIANS
Unlike nonrelativistic MQM, where the many-electron Schrdinger-Coulomb equation serves as the solely basis,
the very first question to be addressed in relativistic MQM is `What equation is to be solved?' This is by no means
trivial. The simplest way towards a relativistic many-electron Hamiltonian is just to replace the nonrelativistic
kinetic energy operator in the Schrdinger-Coulomb Hamiltonian with the one-electron Dirac operator. However,
the resulting first-quantized, configuration-space Dirac-Coulomb (DC) Hamiltonian has serious problems. First, its
self-adjointness and existence of bound electronic states remain unclear, although there has been some indirect
evidence6-8 showing that it does not have bound electronic states. Second, it conserves the number of electrons, at
variance with the true physics where it is the charge instead of the number of particles that is conserved. Third, it
suffers from the (in)famous continuum dissolution problem or the Brown-Ravenhall disease6 due to the underlying
empty Dirac picture. Fourth, it is not an approximation of quantum electrodynamics (QED), the Holy Grail of
electromagnetic interactions between charged particles. Fifth, it contains some unphysical ingredients, e.g., the
negative energy states (NES) are anti-correlating (i.e., energy increasing when included in the correlation treatment)
instead of correlating (i.e., energy lowering). Therefore, such a Hamiltonian should definitely be dumped even if it
were self-adjoint and had bound states. Recently, Kutzelnigg9 introduced a Fock-space approach, where the DC
operator in Fock space and the vacuum polarization are the essential ingredients. The formulation appears to be a
natural approximation of bound-state QED in Coulomb gauge by neglecting transversal photons. In essence, it is a
mathematical representation of the static filled Dirac picture. The charge conservation as well as the avoidance of
the Brown-Ravenhall disease are thereby materialized by construction. Although it is not necessary, the no-pair
approximation can here be introduced naturally by confining the indices of the second-quantized DC operator to
positive energy states (PES) only. This is conceptually different from the ad hoc configuration-space formulation,
where the introduction of the no-pair approximation is a must10 to avoid the Brown-Ravenhall disease. However, a
critical analysis11 reveals that this (no-photon-no-time) Fock-space formulation still does not give rise to the correct
prescription for the correlation contribution of NES: They are also anti-correlating, opposite to the parent (with-
photon-with-time) QED approach. Even the one-body terms involving NES are different from those of QED. The
underlying reason is that the filled Dirac sea, as seen by the electrons, is an intrinsically dynamical entity and must

Theory and Applications in Computational Chemistry: The First Decade of the Second Millennium
AIP Conf. Proc. 1456, 62-66 (2012); doi: 10.1063/1.4730643
2012 American Institute of Physics 978-0-7354-1057-2/$30.00

62
hence be treated in a time-dependent manner. This can further be understood as follows. Under the no-pair
approximation, the system of electrons is a closed, stationary system and can hence be treated with both time-
dependent and time-independent approaches. However, upon lifting the PES projection, the number of electrons is
no longer conserved and the system becomes hence an open, non-stationary subsystem coupled to the negative
energy sea, just like the well-known `Schrdinger cat' entangled with the environment. A time-dependent treatment
is hence mandatory even if the target two-electron property is formally stationary, particularly because the positive
and negative energy electrons propagate in opposite directions in both space and time. This feature has tacitly been
assumed in QED (through the electron propagator, a Wick time-ordered contraction) but not in the (no-photon-no-
time) Fock-space approach. In addition, the Fock-space DC Hamiltonian, like any second-quantized Hamiltonians,
is incompatible with explicitly correlated wave function methods.
It is clear that neither the configuration-space nor the Fock-space formulation of relativistic MQM has taken a
right step to go beyond the no-pair approximation, although they do agree with QED on the special case of one-
electron properties even with virtual pairs11. This essentially means that one should generally work either with the
no-pair approximation or with QED, not anything in between. Under the no-pair approximation, it is perfectly
legitimate to include also the instantaneous Breit term describing the leading magnetic and spin-other-orbit
interactions. Noticeably, the no-pair energy is always dependent on the mean-field potential generating the orbitals,
resulting in an intrinsic uncertainty of order ( ZD ) , with Z being the nuclear charge and D the fine structure
3

constant. This is in sharp contrast with the nonrelativistic FCI (full configuration-interaction) which is potential
independent. Fortunately, this uncertainty can readily be removed by including the QED one-body counter terms
involving NES11,12. Then, anything beyond this level can be ascribed to QED effects arising from retardation,
quantization of the electromagnetic field, and nuclear recoil. That is, it is the `(time-independent) potential-
independent no-pair approximation + ( time-dependent) perturbative QED' approach11 that should be advocated for
electronic structure calculations. This is in the spirit of `relativistic QED' where relativity is treated to infinite order
in Z D while QED is treated at lowest orders in D , at variance with `nonrelativistic QED' where both relativity and
QED are treated at lowest orders. Note in passing that the often adopted combination of a no-pair calculation only
with radiative QED corrections is somewhat problematic for the missing contributions of NES to correlation are of
the same order of ( ZD ) as the leading QED (Lamb shift) corrections. Whether the application of `full QED' to
3

systems of more than 3 electrons can be made in the near future remains a big question.
Staying within the no-pair approximation, one is free to choose either the four-component DC/DCB Hamiltonian
or its exact two-component (X2C) counterpart1-3,13,14. Anyhow, four- and two-component methods, whether
correlated or not, can be and have been made identical in all the aspects of accuracy, simplicity, and efficiency15.
The above relativistic Hamiltonians refer to the space-fixed frame of reference (laboratory axes). How to
transform them to the body-fixed frame of reference remain to be explored16. Such `relativistic molecular
Hamiltonians' are needed for rotational spectroscopy.

RELATIVISTIC WAVE FUNCTIONS

As stressed above, irrespective of the self-adjointness or boundedness, it makes no sense to directly solve the
first-quantized, configuration-space many-body Dirac equation. In other words, the term `exact relativistic wave
function' is physically meaningless. Instead, it is the no-pair projected equation that should be solved. An immediate
question is then `How to do relativistic explicit correlation?' The problem is of two folds. On one hand, the no-pair
DC/DCB Hamiltonian has a finite spectrum defined by the PES projector, meaning that the effect of explicitly
correlated trial wave functions (geminals) depending explicitly on the interelectronic distances is just null. On the
other hand, the analysis of the asymptotic behavior of a no-pair wave function at the coalescence point of two
electrons is hardly possible, simply because there does not exist a unique and exact PES projector. Moreover, the
asymptotic behaviors of the no-pair wave functions with different projectors are not necessarily the same.
Fortunately, both issues can properly be resolved. First, the incompatibility problem can be resolved by the extended
no-pair projection11. Second, the analytical structures8,17 of the wave functions of the first-quantized DC/DCB
Hamiltonian can directly be transplanted to the no-pair wave functions, at least up to first order in the fluctuation
potential8. As the singularities of the DC/DCB wave functions at the coalescence point of two electrons are rather
weak18 and extremely short-ranged, they are not really important for the calculation of the electronic energy thanks
to the suppression by the volume element 4S r122 for very small r12 Instead, it is the extended region away from
the coalescence point and the overall shape of the correlation hole that are really important. This region is still

63
governed by the behaviors in the nonrelativistic limit19. Therefore, nonrelativistic correlation factors can directly be
used. In short, the extended no-pair projection combined with a nonrelativistic correlation factor renders four-
component relativistic explicitly correlated methods completely parallel to the nonrelativistic counterparts20-22.
Unfortunately, the algebraic X2C two-component Hamiltonians1-3,13,14 cannot be adapted to accommodate such
explicitly correlated methods.
The next relevant question, which is common to both the relativistic and nonrelativistic regimes, is `How to
make local representations of wave functions?' Here the localization of both occupied and virtual orbitals plays an
essential role. In this regard, the recently proposed `top down localization'23,24 and `bottom up localization'25
schemes work equally well. In particular, the idea of `from fragments to molecule'25 leads automatically to intra- and
inter-fragmental increments will well defined correlation domains. Interestingly, the idea of `from fragments to
molecule' for synthesizing molecular wave functions25 and that of `from atoms to molecule' for synthesizing
molecular Hamiltonians15 share the same mathematics (a unique matrix block-diagonalization that least changes the
diagonal blocks) and differ only in the manipulations of physical localities of relativity and correlation/excitation.
Undoubtedly, nearly degenerate, strongly correlated systems remain a great challenge. Multi-reference wave
function methods are computationally too expensive. In particular, the `gold method' of multi-reference coupled-
cluster is still in its infancy. Here one may wonder if such a `first static then dynamical' scenario using a common set
of orthonormal orbitals for all determinants is the only means. It is likely that the inverse scenario1, i.e., `first
dynamical then static' using different sets of nonorthogonal orbitals for different configurations (physical charge and
spin distributions, molecular fragments, orbital domains), is more promising.

RELATIVISTIC PROPERTIES
There exist in the Dirac picture two classes of physical properties, electric and magnetic, represented by even
(diagonal) and odd (off-diagonal) operators, respectively. The former includes, e.g., electric dipole moment,
electronic structure/excitation, etc. While relativistic wave function methods suitable for electronically excited states
are still under development26, relativistic time-dependent density functional methods27-29 can now routinely be
applied to medium-sized molecular systems containing heavy elements with very much the same accuracy as the
nonrelativistic counterparts. More intricate are magnetic properties such as nuclear magnetic resonance (NMR)
shielding constant. As the Dirac operator is linear with respect to the vector potential, the expression for NMR
shielding is formally very simple: It consists only of a single term, the so-called paramagnetism. However, the
familiar diamagnetism known from nonrelativistic theory30 is missing. This is not only a conceptual but also a
computational problem. Conceptually, the diamagnetism corresponds to the rigid motion while the paramagnetism
to the polarization of the electron cloud under the influence of external magnetic fields. A spherical atom represents
the extreme case of picture change: The `Schrdinger atom' is purely diamagnetic while the `Dirac atom' is purely
paramagnetic. Computationally, the numerical results are extremely demanding on basis functions of high angular
momenta. The hunting for the missing relativistic diamagnetism has a long history, starting from the year of 196231.
However, the problem has fully been understood only rather recently32,33, see Ref.5 for a recent review. It turns out
that the diamagnetism emerges naturally only if the magnetic balance condition is explicitly incorporated. As a
matter of fact, this can be done in many different but equivalent ways. The heavy demand on basis sets gets
alleviated automatically: Standard energy-optimized basis sets already lead to essentially converged shieldings. The
X2C counterparts34 can be formulated in very much the same way as the X2C Hamiltonians for electronic structure.
Yet, there exist some caveats on the no-pair approximation here. The sizeable contributions of NES survive even to
the nonrelativistic limit in the formulations without an explicit diamagnetism, such that the diamagnetism is entirely
missed under the no-pair approximation. Even with an explicit diamagnetism, the contributions of NES still amount
to order ( ZD ) or ( ZD ) , which cannot be ignored for accurate absolute shieldings. It is even that, neglecting
2 4

terms of ( ZD ) , a first order coupling approximation, provides very accurate estimates of relative shieldings,
2

whereas neglecting terms of ( ZD ) , a second order coupling approximation, leads to spurious results due to
4

imbalanced treatment of NES. How to account for the effect of NES on NMR shielding at a correlated level of wave
function theory still remains to be explored. Here, the formulation must follow QED. Another related property is the
nuclear spin-rotation (NSR) constant. Its nonrelativistic formulation30,35 has been in existence for more than six
decades but the relativistic counterpart is still missing. According to the recent analysis16, there is no direct
relationship between the NSR constant and the NMR shielding in the relativistic regime, although they are related in
a simple way in the nonrelativistic limit. The implications of such findings deserve great attentions.

64
 CONCLUSIONS AND OUTLOOK
The most fundamental issues on the three components (i.e., Hamiltonians, wave functions, and properties) of
relativistic MQM are briefly highlighted. Compared with nonrelativistic MQM, the complications of relativistic
MQM stem mainly from the negative energy branch of the spectrum. It turns out that only QED, an intrinsically
time-dependent approach, provides the correct prescription for the contributions of NES to electron correlation.
Nevertheless, it can be envisaged that the no-pair DC/DCB equation and its X2C counterpart will still serve as the
cornerstone for routine calculations. The underlying uncertainty of order ( ZD ) can readily be removed so as to
3

achieve a `potential-independent no-pair approximation'. Further combined with the explicit and/or local
representations of the wave functions as well as the proper formulations of magnetic properties, it is justified to say
that the `big picture' of relativistic MQM has been established. The major `bottleneck', an engineering issue, remains
efficient implementations of the methods for investigating relativistic effects in heavy-element chemistry and
physics. The use of full molecular symmetry in terms of the Kramers-paired double-group symmetry functions36
should be very rewarding.

ACKNOWLEDGMENTS
The research of this work was supported by grants from the National Natural Science Foundation of China
(Project No. 21033001).

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1. W. Liu, Mol. Phys. 108, 1679-1706 (2010).
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6. R. E. Brown and D. G. Ravenhall, Proc. R. Soc. A 208, 552-559 (1951).
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11. W. Liu, Phys. Chem. Chem. Phys. 14, 35-48 (2012).
12. J. Sapirstein, K. T. Cheng, and M. H. Chen, Phys. Rev. A 59, 259-266 (1999).
13. The generic acronym `X2C', pronounced as ecstacy, for exact two-component Hamiltonians resulted from intensive
discussions among H. J. Aa. Jensen, W. Kutzelnigg, W. Liu, T. Saue, and L. Visscher during the Twelfth International
Conference on the Applications of Density Functional Theory (DFT-2007), Amsterdam, 26-30 August, 2007.
14. W. Liu and D. Peng, J. Chem. Phys. 131, 031104-1-4 (2009).
15. D. Peng, W. Liu, Y. Xiao, and L. Cheng, J. Chem. Phys. 127, 104106-1-15 (2007).
16. Y. Xiao and W. Liu (unpublished).
17. W. Kutzelnigg, "Generalization of Kato's Cusp Conditions to the Relativistic Case" in Aspects of Many-Body Effects in
Molecules and Extended Systems, Lecture Notes in Chemistry Vol. 50, edited by D. Mukherjee, Publisher City: Springer,
Berlin, 1989, pp. 353-366.
18. The wave functions of the first-quantized Dirac-Coulomb-Gaunt Hamiltonian are even regular at the coalescence point of two
electrons8.
19. T. Kato, Commun. Pure Appl. Math. 10, 151-157 (1957).
20. C. Httig, W. Klopper, A. Khn, and D. P. Tew, Chem. Rev. 112, 4-74 (2012).
21. L. Kong, F. A. Bischoff, and E. F. Valeev, Chem. Rev. 112, 75-107 (2012).
22. S. Ten-no, Theor. Chem. Acc. 131, 1070-1-11 (2012).
23. B. Jansk, S. Hst, K. Kristensen, and P. Jgensen, J. Chem. Phys. 134, 194104-1-9 (2011).
24. P. de Silva, M. Giebutowski, and J. Korchowiec, Phys. Chem. Chem. Phys. 14, 546-552 (2012).
25. F. Wu, W. Liu, Y. Zhang, and Z. Li, J. Chem. Theor. Comput. 7, 3643-3660 (2011).
26. T. Fleig, Chem. Phys. 395, 2-15 (2012).
27. J. Gao, W. Liu, B. Song, and C. Liu, J. Chem. Phys. 121, 6658-6666 (2004).
28. J. Gao, W. Zou, W. Liu, Y. Xiao, D. Peng, B. Song, and C. Liu, J. Chem. Phys. 123, 054102-1-13 (2005).
29. R. Bast, H. J. Aa. Jensen, and T. Saue, Int. J. Quantum Chem. 109, 2091-2112 (2009).
30. N. F. Ramsey, Phys. Rev. 78, 699-703 (1950).
31. M. M. Sternheim, Phys. Rev. 128, 676-677 (1962).

65
32. W. Kutzelnigg, Phys. Rev. A 67, 032109-1-12 (2003).
33. Y. Xiao, W. Liu, L. Cheng, and D. Peng, J. Chem. Phys. 126, 214101-1-11 (2007).
34. Q. Sun, W. Liu, Y. Xiao, and L. Cheng, J. Chem. Phys. 131, 081101-1-4 (2009).
35. G. C. Wick, Phys. Rev. 73, 51-57 (1948).
36. D. Peng, J. Ma, and W. Liu, Int. J. Quantum Chem. 109, 2149-2167 (2009).

66
 AGP: Search for The Consistent RPA Reference State
Yngve hrn
QTP, Departments of Chemistry and Physics, University of Florida, Gainesville, FL, 32611-8435, USA

Abstract. The Random Phase Approximation (RPA) with exchange applied to molecular electronic structure can yield excel-
lent excitation energies, but suffers from instabilities resulting in imaginary excitation energies when the single determinant
Hartree-Fock reference state does not correspond to an absolute energy minimum. It has been shown that an Antisymmetrized
Geminal Power (AGP) state is a consistent RPA reference state that cures such instabilities and permits the simultaneous
calculation of ground and excited electronic states with correct energy separation over all geometries. Here we revisit this old
theoretical development in the hope that new applications can be found.
Keywords: ion-atom collisions, charge transfer, symmetry constraints
PACS: 30.31, 31.15.ag, 31.15.X-

INTRODUCTION
The Random Phase Approximation (RPA) with exchange, or equivalently, the Linearized Time-Dependent Hartree-
Fock (LTDHF) or Coupled Hartree-Fock approximation, like the Hartree-Fock (HF) approximation, is a natural
starting point in electronic structure theory. These approximations are so-called mean eld theories that can be
arrived at in many different ways. Here we take the propagator vantage point (see [1]). When A and B are two electron
eld operators, or more generally sums of products of such, the spectral representation of a corresponding propagator
can be expressed as

0|A|mm|B|0 0|B|mm|A|0
A; BE = [ ] (1)
m E Em + E0 + i E + Em E0 i
in terms of energy eigenstates of the electronic Hamiltonian in Fock space. The propagator satises the equation of
motion

EA; BE = [A, B] + [A, H] ; BE , (2)

that is, a chain of equations, the termination of which constitutes various approximations.
For A = ar and B = as , i.e. simple electron eld operators dened in terms of an orthonormal orbital basis, the prop-
agator is the so-called electron propagator. The geometric approximation [1] of Eq.(2) yields the HF approximation.
In a nite basis the the unitary transformation x,which diagonalizes the Fock matrix, x Fx = leads to the SCF eld
and their adjoints and generates the consistent SCF ground state
operators bm = r ar xrm

|0 = b1 b2 bN |vac (3)

for the N lowest spin orbital energies m . One can identify the electron attachment energies m = Em (N +1)E0 (N) for
the spin orbitals m unoccupied in the reference (ground) state and the detachment energies m = Em (N 1) E0 (N)
for m occupied in the reference state. Dening the excitation and de-excitation operators

bm for m unocc.
Qm =

(4)
bm for m occ.
and Qm one nds the various particle and hole states |m = Qm |0 orthogonal and non-interacting across the
electronic Hamiltonian H such that

m|n = 0|Qm Qn |0 = mn (5)

m|H|n = 0|Qm HQn |0 = m mn ,
Theory and Applications in Computational Chemistry: The First Decade of the Second Millennium
AIP Conf. Proc. 1456, 67-72 (2012); doi: 10.1063/1.4730644
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67
since the so called "killer condition" Qm |0 = 0 is satised.
This is the essence of a consistent model, that is, one where the only choice is the computational orbital basis and
everything else follows from the equations of motion.
For excitations within the N-electron space one considers the excitation propagator P(E) with, say, A = bl bk = qi
and B = bk bl  = q j . We choose the labeling such that 0|bl bl |0 = 1, and 0|bk bk |0 = 0.
Collecting all these propagators in a matrix array
 
q; q E q; qE
P(E) =
q ; q E q ; qE

is convenient for further analysis. It is readily seen that

0|[qi , qj ] |0 = 0|[qi , q j ] |0 = i j , (6)

0|[qi , q j ] |0 = 0|[qi , qj ] |0 = 0, (7)

0|[qi , H] , qj ] |0 = 0|[qi , H] , q j ] |0 = Ai j , (8)

and
0|[qi , H] , q j ] |0 = 0|[qi , H] qj ] |0 = Bi j . (9)
In terms of orbital energies and two-electron integrals these matrix elements are

Ai j = (k l )i j kl  ||k l (10)

Bi j = kk ||l  l.

Iteration of the equation of motion or the so-called geometric approximation yields

   
1 0 A B
P(E) = E 1 + E 2 +,
0 1 B A

which can be summed to

 1
E1 A B
P(E) . (11)
B E1 A
A diagonal form can be derived (see [1]), such that
   
Z Y (E1 w)1 0 Z Y
P(E) . (12)
Y Z 0 (E1 + w)1 Y Z
Comparing the (m, n) element of P in the geometric approximation with the corresponding element in, say, the
q; q  one can make the identications

Zmk = k|qm |0 and Ymk = 0|qm |k, (13)

and wk = Ek (N) E0 (N). Because

Z Z Y Y = 1 (14)
we can conclude that
 
k| qm Zmk qmYmk

|0 = 1, (15)
m
means that the excitation operator
 
QK = bk bl Z(k,l)K bl bkY(k,l)K

(16)
k,l

68
creates an excited state |K from the ground state reference |0 i.e.

QK |0 = |K. (17)

The consistency criterion now requires the de-excitation operators to satisfy the relation

QK |0 = 0, (18)
the so-called "killer" condition. This is not true for the HF ground state because bk bl |0
= 0. The consistency can
then only be reached when the elements Y(kl)K are zero or simply neglected. The latter approximation, which has been
referred to as the Tamm-Dancoff approximation (TDA) means that all excited states are represented as monoexcited
CI states out of the HF state. But in general the Y -elements do not vanish and points to an inconsistency in the Hartree-
Fock based RPA, and means that one cannot identify individual stationary states in this approximation. This can be
remedied in practice by introducing a correlated reference state.
One approach is to attempt a solution of Eq.(18) as was done by Linderberg and hrn [2, 3], who used a generator
coordinate representation of the N-electron state vector to show that the "killer" condition was satised by an
antisymmetrized geminal power (AGP) state. This kind of state vector, which is a BSC state projected onto the N-
electron space has, in a somewhat restricted form, been applied to RPA calculations on small molecular systems with
results that compares well with extensive CI calculations.

THE AGP STATE

The AGP state was rst introduced to electronic structure theory in the context of the N-representability problem [4]
and saw some early applications [5].
We consider r = 2s spin orbitals {i } and expand a two-electron function (geminal) as
s
g(1, 2) = gi |i (1)i+s (2), (19)
i=1

with |i i+s  a Slater determinant. The corresponding two-particle density operator associate with the geminal g is
simply

D2 (g) = |gg|, (20)

and the normalization of the coefcients is chosen as
s
Tr{D2 (g)} = = 1 = |gi |2 . (21)
i=1

The one-particle density operator D1 (g) associated with the geminal g has the eigenvalues (occupation numbers)
{ni , 1 ni r} dispalying at least the double degeneracy

ni = ni+s = |gi |2 (22)

for 1 ni s, due to the antisymmetry of g.
The natural spin orbitals of D1 (g) are {i , 1 i r, i.e the canonical spin orbitals of g. It then follows that
s
D1 (g) = n j [| j  j | + | j+s  j+s |] (23)
j=1

with

Tr{D1 (g)} = 2. (24)

Expressing the complex geminal coefcients as
1/2
g j = n j ei j (25)

69
with the phase 0 j 2. The AGP state dened as
N
|AGP |gN  = COAS g(2i 1, 2i) (26)
i=1
with C the normalization constant and OAS the antisymmetric projector, can be expanded in the conguration form as

1/2
|gN  = SN (n j1 n j2 . . . n jN )1/2 ei( j1 + j2 +... jN )
1 j1 ... jN s
| j1 j1 +s . . . jN jN +s , (27)

where SN is the normalization

SN = n j1 n j2 . . . n jN , (28)
1 j1 <...< jN s

which is the symmetric function of order N of the occupation numbers {ni , 1 i s}.
The one-particle reduced density operator D1 (gN ) has the same natural orbitals as D1 (g), but different occupation
numbers (eigenvalues)

Nj, 1 j r (29)
which are related to those of D1 (g) by

SN
N j = SN1 n j . (30)
nj
The one-particle density operator for the AGP state is then
s
D1 (gN ) = N j [| j  j | + | j+s  j+s |], (31)
j=1

with

Tr{D1 (gN )} = 2N. (32)

The representation of D2 (gN ), the second-order reduced density operator associated with the AGP state and
expressed in terms of the two-particle space formed by the canonical spin orbitals of the geminal g, is particularly
simple.
When the basis is ordered as

{{|i i+s , 1 i s}, {|i j , 1 i j 2s, i + s = j}}, (33)

the two-particle reduced density matrix has the form of a two diagonal blocks.There is an s s block B with off-
diagonal elements

2 SN+1
B j, j+s;k,k+s B jk = n j nk ei(k j ) SN1
1/2 1/2
, (34)
n j nk
for 1 j = k s, and diagonal elements

SN
B j, j+s; j, j+s B j j = n j SN1 . (35)
nj
for 1 j s. There is also a diagonal block T of dimension 2s(s 1) 2s(s 1) with non-zero elements only on the
diagonal

2 SN
Ti j;i j = ni n j SN1 , (36)
ni n j

70
for 1 i < j 2s, and i = j.
The total energy of the AGP state is a functional of the geminal g, and can be expressed as

E(g) = Tr{hD1 (gN )} + Tr{VD2 (gN )}. (37)

The matrix elements of h and V in the canonical basis of g are
1
hi j = i| 2 Zk |Rk r|1 | j, (38)
2 k

for 1 i, j 2s and with Rk the position coordinate of nucleus k, and

Vi j;kl = i j|kl i j|lk i j||kl (39)

for 1 i < j 2s and 1 k < l 2s. In detail the total electronic energy is

s
SN
E(g)SN = n j n j (h j j + h j+s j+s +  j j + s|| j j + s)
j=1
 
1/2 1/2
2S
ei(k j ) kk + s|| j j + s
N+1
+ 2 n j nk
1 j<ks n j nk
2 SN
+ n j nk
n j nk
( jk|| jk + k j + s||k j + s
1 j<ks
+k + s j||k + s j + k + s j + s||k + s j + s) (40)

An important special case occurs when g is a spin singlet, and consequently also gN is a singlet.state. This occurs
when, say, j and j+s have the same spatial part and opposite spins. The Eq.(40) simplies to

s
SN 1
E(g)SN = 2 nj (h j j +  j j| j j)
j=1 nj 2

1/2 1/2
2S
(ei(k j kk| j j)
N+1
+ 2 n j nk
1 jz,ks n j nk
2 SN
+ n j nk
n j nk
(4k j|k j 2k j| jk) (41)
1 j<ks

after summation over spin.The rst and third terms have a form similar to that of the Hartree-Fock energy, except that
the electron charge is distributed over all the orbitals that represent the geminal. Also, the two-matrix does not have
the simple factored form of that of the Hartree-Fock approximation. The second term can be considered a form of
electron pair correlation energies where the phase relationships between geminal components are important for the
contribution of these terms to the total restricted form of the AGP energy.
The energy optimization of the highly nonlinear parameter space of the AGP has been a stumbling block, but some
recent advances [6] offer new ways to solve this problem.
Also the concept of generalized AGP states (GAGP) have been introduced to represent odd electron systems. These
are states with an orbital product multiplying a geminal power under the antisymmetrizer and is also the general form
of the excited states generated by the RPA excitation operators [7, 8, 9, 10].
A number of application of RPA excitation (polarization) propagator with a restricted AGP reference using quite
limited basis sets have been made to small molecular systems [11, 12]. Ground and a few excited states were
calculated producing accurate energy splittings over all geometries and transition moments in excellent agreement
with conguration interaction calculations employing large basis sets.

71
 ACKNOWLEDGMENTS
The contributions to the study of the AGP and the RPA by many students and colleagues are gratefully acknowledged.
In particular, the seminal contributions by Jan Linderberg and Brian Weiner are noted.

REFERENCES
1. J. Linderberg, and Y. hrn, Propagators in Quantum Chemistry, Wiley and Sons, New York, 2004.
2. J. Linderberg, and Y. hrn, Int. J. Quantum Chem. 12, 161 (1977).
3. Y. hrn, and J. Linderberg, Int. J. Quantum Chem. 15, 343 (1979).
4. A. J. Coleman, J. Math. Phys. 13, 214 (1972).
5. S. Bratoz, and P. Durand, J. Chem. Phys. 43, 2670 (1965).
6. B. Weiner, and J. V. Ortiz, J. Chem. Phys. 117, 5135 (2002).
7. J. Linderberg, Israel J. Chem. 19, 93 (1980).
8. J. V. Ortiz, B. Weiner, and Y. hrn, Int. J. Quantum Chem. S15, 113 (1981).
9. H. J. Jensen, B. Weiner, and Y.hrn, Int. J. Quantum Chem. 23, 66 (1982).
10. O. Goscinski, and B. Weiner, Phys. Rev. A 25, 650 (1982).
11. B. Weiner, H. J. Jensen, and Y. hrn, J. Chem. Phys. 80, 2009 (1984).
12. E. Sangfelt, R. Roychowdhury, B. Weiner, and Y. hrn, J. Chem. Phys. 86, 4523 (1987).

72
 Concepts of Chemical Bonding from Electron Propagator
Theory
J. V. Ortiz a
a
Department of Chemistry and Biochemistry, Auburn University, Auburn AL 36849-5312, U. S. A.

Abstract. Electron propagator theory provides a conceptual foundation for relating electron binding energies, Dyson
orbitals, transition probabilities, total energies and other properties to each other. The Dyson equation may be expressed
such that generalizations from self-consistent field theory are emphasized and one-electron concepts are retained as much
as possible. Generalized Fock operators and the energy-dependent self-energy operators that occur in the Dyson equation
may be systematically improved and offer a means to describe orbital relaxation and differential correlation contributions
to electron binding energies. Recent examples of progress in the derivation and implementation of approximate self-
energies are discussed, including low-order, perturbative expressions, employment of fractional occupation numbers,
improved virtual orbitals and renormalized techniques that are required for the description of strong correlation effects. A
variety of applications of these methods is briefly reviewed.
Keywords: electron propagator, Dyson orbital, self-energy, pole strength, superoperator theory, P3 and P3+
approximations, BD-T1 approximation, TOEP2 approximation, QVOs method
PACS: 31.15.ae

INTRODUCTION

Facts are the air of scientists. Without them you can never fly. Linus Pauling

You have to have a lot of ideas. First, if you want to make discoveries, it's a good thing to have good ideas. And
second, you have to have a sort of sixth sensethe result of judgment and experiencewhich ideas are worth
following up. Linus Pauling

In addition to the efficient, reliable calculation of molecular properties, contemporary molecular electronic
structure methodology is now impressively adept at the generation of numerical facts. Considerable effort is being
applied to refinement of models so as to optimize agreement with experimental data. The recognition of patterns
that relate molecular structure, energetics, spectra and reactivity to each other also is an important aim of molecular
electronic structure theory. Orbital concepts continue to play an important role in providing succinct and predictive
pictures of electronic structure. Theories that offer interpretive transparency through such concepts in addition to
predictive accuracy and computational efficiency therefore remain worthy of continued development.

The capabilities of electron propagator theory (1,2) may be introduced through a consideration of the Dyson
equation in its inverse, quasiparticle form

[F + ()] = ,

where F is a generalized Fock operator, (E) is the self-energy operator, is a Dyson orbital and is an electron
binding energy (3,4,5). Each of these objects may be understood as a generalization of the familiar
pseudoeigenvalue problem represented by the Hartree-Fock equations. Instead of a Fock operator that is dependent
solely on the occupied orbitals contained in a Slater determinant, one may construct a generalization of it that is
related to a one-electron, reduced density matrix, , such that

Frs = hrs + pq (rs||pq) pq.

In the latter equation, the usual notation for one-electron (h) and Mulliken two-electron matrix elements is
employed. The density matrix usually refers to an N-electron reference state, but generalizations to ensembles or

Theory and Applications in Computational Chemistry: The First Decade of the Second Millennium
AIP Conf. Proc. 1456, 73-80 (2012); doi: 10.1063/1.4730645
2012 American Institute of Physics 978-0-7354-1057-2/$30.00

73
other situations in which particle number is not strictly conserved may be considered. Inclusion of correlation
contributions to the density matrix generates energy-independent, Coulomb-exchange terms in the Dyson equation.
Other correlation effects and the description of orbital relaxation effects in final states are incorporated in the
energy-dependent term, (E). This operator, like the exchange contribution to F, is highly nonlocal. The energy-
dependence of the self-energy operator indicates that the Dyson equation may be solved for electron binding
energies in an iterative fashion, with successive guesses for the electron binding energy being inserted as arguments
of (E) until agreement with an eigenvalue of F+(E) is achieved. To each electron binding energy, t, there
corresponds a Dyson orbital, t, which describes the effects of electron attachment or removal on the electronic
structure of the reference state. Normalizations of the Dyson orbitals (which on the basis of the pseudoeigenvalue
equation above are indefinite) are fixed by the following definitions for electron detachment,

t(x) = N0.5N(x,x2,x3,x4,,xN)*N-1,t(x2,x3,x4,,xN)dx2dx3dx4dxN,

and for electron attachment,

t(x) = (N+1)0.5N+1,t(x,x2,x3,x4,,xN,xN+1)*N(x2,x3,x4,,xN,xN+1)dx2dx3dx4dxNdxN+1 .

Dyson orbitals may considered to be overlap functions between the N-electron reference state, N, and final states
with N1 electrons. To determine the correct normalization of each Dyson orbital from eigenfunctions obtained
from the Dyson equation, the pole strength, Pt, is evaluated at E = t according to:

Pt = [1 - <t|(E)t>/E]-1 .

Normalizations of the Dyson orbitals are set such that <t|t> = Pt. Pole strengths may vary between 0 and 1 and are
indices of the importance of correlation in describing a transition between states with N and N1 electrons. Neglect
of the self-energy operator produces Dyson orbitals that are normalized to unity. Correlation states, such as shake-
ups observed in photoelectron spectra or Feshbach states seen in electron scattering, appear as a consequence of the
energy-dependence of the self-energy operator.

Dyson orbitals and electron binding energies may be used to construct ground-state properties. The one-electron
density matrix of the N-electron system may be related to Dyson orbitals corresponding to electron detachment
energies via the summation

(x,y) = t Pt t(x)*t(y)

where the Dyson orbitals are normalized to unity and the summation excludes Dyson orbitals for electron
attachments. Because all Dyson orbitals for electron detachments are included in the summation, the number of
terms far exceeds N. Total energies of N-electron reference states may be expressed according to another summation
over electron detachment transitions such that

EN = 0.5 t Pt [<t|ht> + t] .

The two latter expressions may be regarded as generalizations of the Dirac density matrix and the standard
relationship between total and orbital energies that are foundations of Hartree-Fock theory. Pole strengths instead
orbital occupation numbers provide weights for each term.

Dyson orbitals and their pole strengths provide transition probabilities for a variety of ionization phenomena that
give rise to electrons in continuum orbitals. For example, certain kinds of photoionization intensities and electron-
scattering cross sections may be determined according to

It = k Pt |<t|T>|2

where It represents a transition probability or intensity involving a final state t, T is a transition operator (such as the
dipole-moment operator), is a one-electron, continuum wavefunction and t is a Dyson orbital normalized to
unity. When such expressions are physically valid, intensities are proportional to pole strengths.

74
Neglect of the self-energy operator and employment of an idempotent recovers the Hartree-Fock special case of
the Dyson equation with the usual Coulomb-exchange potential. The Dyson orbitals become canonical, Hartree-
Fock orbitals with pole strengths equal to unity and the corresponding electron binding energies equal those of
Koopmanss theorem.

Under the auspices of superoperator theory, one may derive systematic improvements to Hartree-Fock results. The
density matrix employed in the evaluation of the F matrix may be augmented with corrections based on standard
perturbation theory (2,4). Self-consistent evaluation of is incorporated in various schemes (2,4,6). Care must be
taken to retain the correct trace, N, in order to obtain approximations that are suitable for large molecules (7). Of
greater importance are approximations to the energy-dependent self-energy matrix. A closed expression for the r,s
matrix element reads

rs(E) = (ar|f)(f|(E-)f)-1(f|as) .

In the latter expression, the simple annihilation operators, {a}, and their orthogonal complement operators, {f},
reduce the number of electrons by one when acting on a reference state. Operators products with n annihilators and
n-1 creators (a) are included in {f}. Evaluation of these matrix elements requires the introduction of a superoperator
metric,

(W|X) = <Ref| [W,X]+|Ref>

in which W and X are members of the primary (simple annihilator) or orthogonal complement operator spaces (8).
The superoperator Hamiltonian is related to the second-quantized Hamiltonian, H, via

X = [H,X] .

Various finite-order and renormalized approximations to (E) have been derived. When Hartree-Fock
wavefunctions and perturbative corrections are the basis of the derivations, the lowest-order terms occur in the first
order of the fluctuation potential for (ar|f), where

(ar|aaaiaj) = (ri||aj)

(ar|aiaaab) = (ra||ib) .

The usual choice of occupied (i,j,k,), virtual (a,b,c,) and general (p,q,r,) spin-orbital indices is made here. For
the inverse matrix that occurs in the self-energy expression, the corresponding zeroth order terms are

(abakal| aaaiaj) = ab ki lj (ei + ej ea),

(ajacad| aiaaab) = ij ac bd (ea + eb ei) .

Canonical Hartree-Fock orbital energies (ep) occur in the latter expressions, in which i<j, k<l, a<b and c<d. Thus,
the simplest self-energy correction to the results of Koopmanss theorem has the following, second-order form:

(2)rs(E) = a, i<j (ri||aj)(is||ja) (E+ea-ei-ej)-1 + i, a<b |(ra||ib)(as||bi) (E+ei-ea-eb)-1 .

Only Hartree-Fock contributions to the reference states and triple field operator products are used in the derivation
of the latter approximation. Correlated corrections to reference states and higher field operator products underlie
self-energy approximations of third or larger order (9).

75
 LOW-ORDER SELF-ENERGY APPROXIMATIONS
The second-order self-energy has limited predictive capabilities. Electron binding energies obtained with the
second-order self-energy approximations exhibit average errors of approximately 1 eV even for valence ionization
energies of closed-shell molecules. Even larger discrepancies occur in the calculation of core binding energies. Only
a primitive description of correlation states, such as shakeups, is offered at this level of theory. Electron affinity
predictions also are unreliable.

However, for outer valence ionization energies of closed-shell molecules (i.e. those below 15-20 eV), numerical
experience has shown that the off-diagonal matrix elements of the self-energy operator in the canonical, Hartree-
Fock orbital basis are seldom important. Instead of diagonalizing the matrix F + (E) for various values of E, it is
usually sufficient to employ the diagonal self-energy approximation in which the Dyson equation has the following
simplified form

Er = er + rr(Er) .

(The diagonal self-energy approximation sometimes is called the quasiparticle approximation.) A few iterations with
respect to Er generally suffice to obtain a converged electron binding energy. Pole strengths also are simply
expressed, where one evaluates the following expression with E equal to the converged value:

Pr = (1 - rr(E)/E)-1 .

The corresponding Dyson orbital is proportional to a canonical, Hartree-Fock orbital, where

r(x) = Pr0.5 HFr(x) .

The number of arithmetic operations in calculations that employ the diagonal, second-order approximation to the
self-energy operator has a cubic scaling factor. Only a partial integral transformation to the canonical, Hartree-Fock
orbital basis is required for a given electron binding energy. Pole strengths evaluated with diagonal, low-order self-
energies that are less than 0.85 indicate that more exact methods should be employed.

Diagonal self-energy matrix elements in third order involve quintuple summations instead of the triple summations
seen in second order (2,4). An efficient organization of these summations results in an algorithm whose bottleneck
has a fifth-power arithmetic scaling factor. Electron repulsion integrals with every combination of occupied and
virtual orbital indices occur in the formulae. Even with these disadvantages, the average error for valence ionization
energies of closed-shell molecules is still above 0.5 eV. Whereas second-order results generally overestimate
corrections to Koopmans results and third-order results do the opposite, various schemes for estimating higher-order
corrections have been based on ratios of second and third-order terms. The Outer Valence Green Function (OVGF)
approximations (2,4) employ such arguments and have been successful in producing ionization energies of
molecules and electron detachment energies of anions that are on average within 0.25 eV of experiment.

Because the arithmetic and storage bottlenecks of these computations are determined by a self-energy term which
involves electron repulsion integrals with four virtual orbital indices, another method which avoids this term was
derived and implemented. This partial, third-order (P3) approximation (10,11) also has found wide use in
calculations on the ionization energies of large, organic molecules, with average errors that are somewhat lower than
those of the OVGF methods. Its arithmetic bottleneck has a quadratic dependence on the number of occupied
orbitals and a cubic dependence on the number of virtual orbitals. An extension of this procedure that estimates
higher-order corrections through the evaluation of ratios of second and third-order terms has recently been
introduced (12). This extension, known as P3+, has the advantage of also producing accurate electron detachment
energies of closed-shell anions, with average errors below 0.2 eV. It therefore is suitable for the study of anions
embedded in one or more solvation spheres that are described quantum mechanically.

A versatile generalization of the diagonal, second-order method may be derived by introducing grand-canonical
ensemble averages to the evaluation of superoperator Hamiltonian matrix elements in the expression for (E)

76
(13,14). With grand-canonical Hartree-Fock occupation numbers, Nr, the self-energy matrix elements read

(2)rs(E) = t, u<v (ru||tv)(us||vt) (E+et-eu-ev)-1 [(1-Nu-Nv)Nt + NuNv].

Evaluation of a diagonal element of this self-energy matrix requires electron repulsion integrals which share a
common index and therefore the transformation from the contracted Gaussian basis to its molecular orbital
counterpart has a fourth-power arithmetic scaling factor. The transition operator method (15) incorporates
relaxation effects in a single orbital energy by assigning a fractional occupation number to it. The usual choice is
0.5. Thus, the orbitals which emerge from the transition operator methods self-consistent field (SCF) procedure
diagonalize a modified Fock matrix whose elements depend on spin-orbital occupation numbers:

Frs = hrs + t (rs||tt)Nt .

Transition orbital energies may considered approximations to SCF results. From the perspective of Janaks
theorem (16), which relates occupation numbers, orbital energies and total energies by the relation

et = Etot/Nt ,

one may consider the transition orbital energy to be a one-point quadrature of the integral

(SCF)t = 01 et dNt .

For core ionization energies where orbital relaxation effects dominate those of electron correlation in determining
corrections to Koopmans results, the transition operator method provides a superior reference orbital energy.
Corrections from the diagonal, second-order self-energy method with transition operator reference ensembles
provide an efficient and accurate way to make quantitatively accurate predictions for core ionization energies. The
second-order, transition operator electron propagator method (TOEP2) is capable of producing outer valence
ionization energies with accuracy that is markedly superior to that produced with the diagonal, second-order
approximation based on ordinary Hartree-Fock orbitals. At the cost of repeating a reference SCF procedure for each
final state, one may obtain valence ionization energies with average errors of only 0.35 eV (13). As in other
calculations that employ the diagonal self-energy matrix approximation, the Dyson orbitals corresponding to these
electron binding energies are equal to the product of the transition orbital and the square root of the pole strength.

The chief arithmetic and storage bottlenecks presented by methods that require the evaluation of third-order self-
energy terms arise because of the dimension of the virtual orbital space. In the OVGF methods, where all third-order
diagrams are calculated, the need for electron repulsion integrals with four virtual indices has stimulated the
development of a variety of algorithms that avoid the explicit evaluation and storage of this large matrix (5,17,18).
This advantage is offset by increased arithmetic operations. In the P3 and P3+ methods, the need for these integrals
is eliminated for electron detachment energies and integrals with three virtual indices occur in the formula for only
one self-energy term which must be calculated just once.

A more compact virtual orbital space therefore would extend the applicability of these diagonal self-energy
approximations to large molecules or facilitate calculations with larger atomic basis sets. A criterion of relevance
for a given electron binding energy is provided by the corresponding effective, one-electron density difference
matrix (19). For diagonal, second-order calculations, the virtual-virtual block of this matrix is easy to evaluate.
After obtaining a converged electron binding energy corresponding to occupied orbital i where

Ei = ei+ ii(Ei) ,

the corresponding virtual-virtual elements of the density difference matrix read

i
Dab = - k<l (ik||al)(Ei + ea ek el)-1 (ik||bl) (Ei + eb ek el)-1

+ jc (ia||jc)(Ei + ej ea ec)-1(ib||jc)(Ei + ej eb ec)-1 .

77
Diagonalization of this matrix produces eigenvalues that may be positive or negative. Those eigenvectors whose
absolute eigenvalues exceed a certain threshold are retained. The Fock matrix is constructed in this reduced space of
virtual orbitals and diagonalized. The resulting, reduced set of canonical virtual orbitals then is used in the
calculation of self-energy terms that are needed for calculations beyond second-order (20). For every electron
binding energy, a different set of improved virtual orbitals is produced. This procedure (quasiparticle virtual orbitals
or QVOs) has been found to be highly efficient. Reductions of 50% of the virtual orbital space typically introduced
discrepancies with ordinary calculations that are less than 0.05 eV (21). When reductions of the same size are made
by merely omitting the highest virtual orbitals of the unaltered canonical set, much higher discrepancies are
introduced.

RENORMALIZED SELF-ENERGY APPROXIMATIONS

Whereas low-order methods generally suffice for the assignment of outer valence and core electron binding energies
of closed-shell molecules, there are many other circumstances where infinite-order, or renormalized, self-energy
approximations are needed to obtain reliable results. Under these conditions, explicit evaluation of matrix elements
of the self-energy operator is abandoned in favor of diagonalization of the superoperator Hamiltonian matrix (22).
The latter matrix is defined in terms of the operator manifold in the same way as the usual Hamiltonian matrix is
defined by a set of configurations. Because the primary space of annihilation operators is associated with the Fock
matrix according to

(ar|as) = Frs ,

one can readily recognize that the Dyson equation in matrix form,

[(a|a) + (a|f)(f|(-)f)-1(f|a)]c = c ,

is a partitioned version (23) of the Hermitian eigenvalue problem for the superoperator Hamiltonian matrix,

C = C

where c is the primary operator sector corresponding to simple annihilation operators in the eigenvector C. Pole
strengths for a given w are determined by the magnitude of the c component of the corresponding eigenvector Cw
such that

P w = c w c w ,

where CwCw = 1. Dyson orbitals thus are obtained from

w = q q cqw ,

where {q} is the set of orthogonal orbitals that are used to construct the a and f ionization operators. Renormalized
methods may be defined in terms of the operator manifolds that are included in the matrix and the approximations
that apply to each block. For example, the two-particle-hole Tamm-Dancoff approximation (2) employs simple
annihilation operators and products of two annihilators and one creator. All blocks of are correct through first
order in the fluctuation potential. This method corresponds to a self-energy matrix that includes all second-order
terms plus so-called ring and ladder diagrams in all orders. By including third order terms in the primary-primary
(or F) block and second order terms in the off-diagonal blocks that couple simple annihilators to triple operator
products, one produces the 3+ approximation (24). In addition to the renormalizations corresponding to rings and
ladders that obtain for 2ph-TDA, the 3+ method recovers all third-order self-energy terms. A self-consistent
evaluation of the one-electron density matrix used in calculating the F block of gives rise to the third order
algebraic diagrammatic construction (2), also known as ADC(3). The nondiagonal, renormalized, second-order
approximation (25), or NR2, retains first order couplings between triple field operators and second order couplings
between triple and simple field operators that suffice to recover all terms in the P3 self-energy. The ADC(4) method
(26), which retains all fourth order terms in the self-energy, requires the introduction of quintuple field operator

78
products and higher order treatments of blocks that also occur in the ADC(3) version of . All of these
approximations are based on Hartree-Fock reference states with corrections provided by the usual perturbative
arguments. To describe correlation states such as shakeups at even a qualitatively reasonable level, it is necessary to
introduce approximations that consider all first order couplings between triple field products with two occupied and
one virtual indices. When pole strengths descend below 0.85, renormalized methods also become necessary.

A versatile renormalized method (3), is provided by using the orbitals generated in a Brueckner doubles (BD),
coupled-cluster (27) calculation. These orbitals do not diagonalize the Fock matrix, but they can be brought to
semicanonical form, where the occupied-occupied and virtual-virtual blocks of F are diagonal. The double
replacement amplitudes (t2) of the cluster operator are used to improve the ground-states with which matrix
elements are evaluated. All couplings between simple and triple field operators are evaluated through first order in
the t2 amplitudes, except those that connect two-particle-one-hole and two-hole-one-particle operators. This
approximation, known as BD-T1, has been applied to core and outer valence ionization energies of closed-shell
molecules, to electron detachment energies of closed-shell anions and to molecules with substantial diradical
(biconfigurational) character. Average errors are approximately 0.2 eV for valence ionization energies and 0.1 eV
for electron affinities.

REPRESENTATIVE APPLICATIONS
In recent years, the application of the approximations discussed above has spanned several kinds of molecular
systems. In each case, the behavior of electron binding energies has been related to molecular structure through the
examination of Dyson orbitals. Electron propagator calculations on fullerenes, macrocyclic molecules and
nucleotides have been reviewed (17,18). For the latter class of anions, changing patterns of localization in the
Dyson orbitals have been related to Coulombic and dispersive interactions between base and phosphate fragments.
Negative electron detachment energies of multiply-charged, macrocyclic anions associated with repulsive Coulomb
barriers have been considered and the patterns of Dyson orbitals have been related to the deployment of negatively
charged substituents (28). Photoelectron spectra of solvated anions have been tackled with highly efficient electron
propagator methods in combination with Monte Carlo sampling of solvent configurations (29). Contrasting patterns
of delocalization from solute to solvent have been seen in the Dyson orbitals. Diffusely bound electrons in Rydberg
molecules and double Rydberg anions have been described in terms of extravalence atomic contributions (30). Final
states with qualitatively strong correlation effects have been assigned for macrocyclic molecules and the low pole
strengths that accompany even low-energy transitions in these systems have been described (31). Relationships
between Fukui functions and Dyson orbitals have been discussed (32). The role of Dyson orbitals in determining the
efficacy of molecular wires has been reconsidered and corresponding computational strategies have been
implemented (33). Photoionization cross sections evaluated with transition operators that include all electric and
magnetic multipole contributions have been calculated with Dyson orbitals and simple descriptions of
photoelectrons (34). A variety of photoelectron spectra of gas-phase cluster anions and molecules have been
assigned and the results have been interpreted on the basis of Dyson orbitals and their dependence on molecular
structure (35).

CONCLUSIONS
Electron propagator theory provides a versatile means of calculating electron binding energies and relating these
quantities to Dyson orbitals, total energies and other properties. The Dyson equation provides a systematic
procedure for the derivation and implementation of useful approximations. Recent developments in low-order self-
energy approximations, employment of fractional occupation numbers and optimization of virtual orbitals have
increased the scope of applications to larger systems, including condensed-phase species where averaging over
many solvent configurations is necessary. Renormalized approximations provide an opportunity to consider
transitions where differential correlation effects are qualitatively important while retaining a one-electron portrait of
electronic structure to the extent that it is appropriate to do so. These tools have been applied to a variety of
molecular systems for the purpose of assigning spectra. Conceptual connections between electron binding energies,

79
Dyson orbitals and qualitative notions of electronic structure continue to emerge from the development and
application of electron propagator methodology.

ACKNOWLEDGMENTS
The National Science Foundation provided support for this research through award CHE-0809199 to Auburn
University.

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Ragavachari and G. W. Trucks, Chem. Phys. Lett. 164, 185-192 (1989).
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80
 Recent Advances in Spin-Free State-Specific and State-
Universal Multi-Reference Coupled Cluster Formalisms: A
Unitary Group Adapted Approach
Rahul Maitra, Debalina Sinha, Sangita Sen, Avijit Shee and Debashis Mukherjee

Raman Center for Atomic, Molecular and Optical Sciences,

Indian Association for the Cultivation of Science,
Kolkata 700 032, INDIA.

Abstract. We present here the formulations and implementations of Mukherjee's State-Specific and State-Universal
Multi-reference Coupled Cluster theories, which are explicitly spin free being obtained via the Unitary Group Adapted
(UGA) approach, and thus, do not suffer from spin-contamination. We refer to them as UGA-SSMRCC and UGA-
SUMRCC respectively. We propose a new multi-exponential cluster Ansatz analogous to but different from the one
suggested by Jeziorski and Monkhorst (JM). Unlike the JM Ansatz, our choice involves spin-free unitary generators for
the cluster operators and we replace the traditional exponential structure for the wave-operator by a suitable normal
ordered exponential. We sketch the consequences of choosing our Ansatz, which leads to fully spin-free finite power
series structure of the direct term of the MRCC equations. The UGA-SUMRCC follows from a suitable hierarchical
generation of the cluster amplitudes of increasing rank, while the UGA-SSMRCC requires suitable sufficiency conditions
to arrive at a well-defined set of equations for the cluster amplitudes. We discuss two distinct and inequivalent
sufficiency conditions and their pros and cons. We also discuss a variant of the UGA-SSMRCC, where the number of
cluster amplitudes can be drastically reduced by internal contraction of the two-body inactive cluster amplitudes. These
are the most numerous, and thus a spin-free internally contracted description will lead to a high speed-up factor. We refer
to this as ICID-UGA-SSMRCC. Essentially the same mathematical manipulations provide us with the UGA-SUMRCC
theory as well. Pilot numerical results are presented to indicate the promise and the efficacy of all the three methods.
Keywords: Multi-Reference Coupled Cluster Theory, State-Specific MRCC, State-Universal MRCC, Spin-Free, Unitary
Group Approach, Partially Internally Contracted
PACS: 31.15-P, 31.15.A-, 31.15.V-, 31.15.bw

INTRODUCTION
In this article we will present a succinct overview summarizing the recent advances in spin-free formulations of
Multi-Reference Coupled Cluster theory (MRCC) which have emerged over the last few years. Our developments
will encompass spin-adaptations of both State-Specific (SS) and State-Universal (SU) MRCC, using a spin-free
generalization of the JM-like cluster Ansatz. Although several different MRCC formalisms, essentially of the SS
variety, have been put forward over the last 15 years 1-9, proper spin-adaptations of such formulations-except for
those based on Fock-Space (FSMRCC) 10-13-have proved to be an arduous task and have not been explored to the
extent it should have been. This article would mainly emphasize the aspects of spin-adaptation of SS and SUMRCC
formalisms recently developed by our group. We will, thus, focus more on recent advances rather than giving an
exhaustive summary of the spin-orbital based formalisms.
Unlike the FSMRCC which is designed to study energy differences of spectroscopic interest, it was thought at
one time that the SUMRCC, which works in a model space of fixed number of active electrons, is tailored better to
treat state energies per se of pronounced multi-reference character and hence, suitable for studying potential energy
surfaces (PES) involving dissociation and real and avoided curve-crossings. However, being an effective
Hamiltonian formalism 10-12 the SUMRCC theory is seriously plagued by intruder states 14-17 and has not been very
successful in application to PESs. Intermediate Hamiltonian based formalisms 18-19 have been suggested from time to
Theory and Applications in Computational Chemistry: The First Decade of the Second Millennium
AIP Conf. Proc. 1456, 81-96 (2012); doi: 10.1063/1.4730646
2012 American Institute of Physics 978-0-7354-1057-2/$30.00

81
time to get around this difficulty although it was becoming increasingly clear that SSMRCC formalisms, targeting
only the state of interest, could alleviate the intruder state problem1-3. Such spin-orbital based SSMRCC
formulations have been evolving for more than a decade now and among them the formulations suggested by our
group (which are generically classified as SSMRCC, also known as MkMRCC) have been the most widely studied 7-
9, 20-22
SSMRCC makes use of the JM-based multi-exponential Ansatz whose spin-adaptation has been a real
challenge. The same problem has been faced in the spin-adaptation of SUMRCC as well which also uses the JM
Ansatz. This article will delineate our recent attempts to generate spin-free SSMRCC as well as SUMRCC using
spin-free wave operator which is inspired by the JM Ansatz but is very different in structure. The spin-free
formulation essentially leads to spin-free working equations, which has been accomplished by the use of spin-free
unitary generators in the wave operator. We will generically indicate this as Unitary Group Adapted MRCC (UGA-
MRCC).
We should point out that there exist many variants of MRCC in the literature which are SS in nature. Several
recent monographs have presented a comprehensive survey of these various formulations which also includes
computation of properties via analytic gradients 23-24. We refer the readers to these review papers for a thorough
overview.
The paper is organized as follows:
In the second section we will introduce our spin-free multi-cluster Ansatz and motivate towards such choice. In
this section we will also emphasize the specific advantages of this Ansatz in a singles and doubles (CCSD)
truncation scheme.
The third section consists of 3 parts:
In the first subsection we will develop the UGA-SSMRCC following closely the genesis of parent SSMRCC.
Recently, we have also suggested a partially internally contracted variant of SSMRCC where the pure inactive
excitations are treated in an internally contracted manner 25-29. This is called Internally Contracted for Inactives-
SSMRCC (ICI-SSMRCC). In the second subsection we will discuss the UGA version of this ICI-SSMRCC known
as UGA-ICI-SSMRCC.
The third subsection will discuss UGA-SUMRCC.
All these developments explore the simplifications brought about by the SD truncation of the cluster operators.
The fourth section will discuss the implementation of all the three theories above along with illustrative
examples.
The last section provides a summary and our outlook towards the future.

CHOICE OF THE SPIN-FREE MULTI-EXPONENTIAL CLUSTER ANSATZ

Choice of Spin-Free Cluster Operators

In the traditional JM multi-exponential Ansatz, the wave operator is written as:

= exp(T ) | | (1)

where is a model determinant and T , the cluster operator associated with , excites it to all the virtual
determinants l by lifting some electrons from the spin orbitals occupied in to those occupied in l . Since
each component of T involves spin orbital labels which do not appear both in destruction and in creation
operators, all the components of T commute and the Baker-Campbell-Hausdorff (BCH) expansion of the
transformed Hamiltonian H = exp(T ) H exp(T ) terminates after the quartic power of T . For a spin-free
formulation, however, the various components of T do not commute in general. Instead of a general abstract
discussion of this issue, we illustrate here using an example why this is so. For a more comprehensive general
discussion of the problem, we refer to our article in the first TACC meeting and our forthcoming publications 30-31.
In close conformity with the structure of the JM Ansatz, we impose on a multi-exponential cluster Ansatz of the
form:

82
 = | | (2)

where is the cluster wave operator for the model function and contains the cluster operator T . The model
function is a Configuration State Function (CSF) containing a closed shell 'core' part, hereafter denoted as
| 0 and a fixed number of occupancies of a set of active orbitals which are in general partially occupied in various
. In what follows, we denote by indices i, ,j,..... etc. the inactive doubly occupied or core orbitals and by u ,v ,....
etc. the active orbitals. The virtual functions l can have a number of virtual orbital occupancies. We denote by
indices a ,b,... etc. the virtual inactive orbitals. For a CSF having a certain number of single occupancies of
active orbitals, the generation of a l involving a certain change of orbital occupancy cannot generally be
described by any excitation operator involving just those orbital labels. Let us consider for example, the case of a
doublet when all but one active orbital u are doubly occupied and we look at the possible excitations involving a
replacement of orbital i with orbital a. A virtual function, thus, will have single occupancies involving orbitals i, u
and a. There are two linearly independent doublet spin functions corresponding to these occupancies which will
require two linearly independent cluster operators in T . Clearly it's not possible to define two cluster operators
involving just the indices i and a and one possibility is to consider a one-body excitation operator replacing i with a
and a two-body operator replacing iu with ua. Thus, although the excitations are single we would require both a one-
body and a two-body operator with a 'spectator' excitation involving the active orbital u. To have a spin-free
formulation, we choose to use the spin-free unitary generators in our T s and the above excitations can be written

as T ia {Eia } and T ua ua
iu {Eiu } where {..} indicates normal ordering with respect the core | 0 as the vacuum. Since

the active orbital index u appears both in destruction and creation operators, the various components of T will not
ua
commute with the operator {Eiu } when they involve the orbital u either in the upper or in the lower indices. This is
the usual feature for all the operators of T with active indices and thus in general the components of T will not
commute among themselves. This implies that a naive parametrization of = exp(T ) will lead to a non-
terminating power series in T in a BCH expansion. Although, such exponential parametrization has been
considered from time to time, for a spin-free theory involving one CSF 33-34 the aspect of non-terminating power
series is a matter of concern considering its complexity. This is the reason why we must search for a more
convenient cluster expansion representation for where such a non-terminating power series will not appear.

Choice of the Cluster Ansatz

Some reflections indicate that a normal ordered Ansatz = {exp(T )} will not involve contractions between
the various non-commuting components of T because of the normal ordering. One would imagine then that such a
normal ordered Ansatz, rather than a pure exponential one is a more convenient and compact choice leading to a
terminating power series in T of our spin-free MRCC working equations. We show in the third section that such is
indeed the case.
Since T s are defined by a set of cluster amplitudes involving orbital labels and a set of unitary generators E,
they are space-spin scalars and their actions on a CSF automatically lead to a set of virtual CSFs l . As we
have already indicated, since we consider our formulations in a CCSD truncation scheme, it is possible to uniquely
classify all the distinct spin-free generators that one can form out of the various orbitals. A preliminary discussion of

83
these choices has already appeared in the article of the first TACC volume 35. However, we will innumerate them
here once more for the sake of continuity.

TABLE (1). List of one and two body cluster operators

We should note here that we have omitted from our excitation manifold the operators involving direct spectator
au vu au
excitations of the types {Eiu } , {Eiu } and {Evu } , since their actions on are respectively equal to those of
a v a
{E }nu , {E }nu and
i i {E }nu where nu is the occupancy for the active orbital u. We should also note that at
v
the CCSD approximation level, the various distinct excitations listed above are independent of the number of active
orbitals in the set or their spin-multiplicity. For the derivation of the working equations to follow, we express

T = t I {EI } where I and A are strings of orbital indices involving core and active occupied and virtual
A A

IA

and active unoccupied or singly occupied orbitals of .

Because of the spin-degeneracy of the spin eigenfunctions for more than two active electrons, in general, there is
more than one CSF having the same active orbital occupancies. In our formulation, we choose the s to be
Gel'fand states which fixes the spin eigenfunctions. Our choice is dictated primarily by the ease with which matrix
elements involving Gel'fand states can be computed 36-37.However, the l s are not Gel'fand states.
Our Ansatz for can only have a finite power n of T , when Tn acts on , since there are no
T T contractions and thus valence occupancies get reduced after the action of each T with valence destruction
operators on . In contrast, a pure exponential like exp(T ) , will involve T T contraction and thus have
arbitrary high power of such cluster operators. It might then appear that the pure exponential is richer in structure.
However, this is offset by the non-terminating nature of the 'direct' term of the MRCC equations. Datta and
Mukherjee recently proposed a combinatoric open shell MRCC Ansatz (COS-MRCC) 41-42, where T T
contractions are allowed, but the factors accompanying a power n of T are equal to the inverse of 'automorphic'
factors, rather than 1/n!. The COS-CC Ansatz is richer in structure as compared to the normal ordered Ansatz but
generation of the working equations is somewhat more complex. Our working equations are, in contrast, much
simpler and our results indicate that we do not lose that much of accuracy.

DEVELOPMENT OF UGA-SSMRCC AND UGA-SUMRCC

Before discussing the spin-free formulations, we want to briefly recall the corresponding spin orbital based
MRCC formulations. This will serve two useful purposes: (a) to introduce the various entities necessary for our

84
formulation and (b) to underline certain specific features of the spin orbital based formalisms which are equally
desirable in the spin-free formulations to follow.
Although historically, the first use of the JM Ansatz was in the SUMRCC formalism, we prefer to discuss the
corresponding spin-orbital based SSMRCC formalism first.
The SSMRCC formalism was based on a zeroth order wave function 0 = c where the reference
determinants of span a CMS. The exact function is generated by the action of a state specific of the JM
form on the zeroth order wave function. Since a given virtual function l can be generated by the action of the
cluster operators in T on its own , the number of cluster amplitudes is far greater than the number of equations
to determine them. This implies an essential redundancy in the cluster amplitudes. To resolve the redundancy, some
sufficiency conditions were proposed with a view to satisfying the desirable goals of avoiding intruders and
explicitly maintaining size-extensivity. The working equations for determining the cluster amplitudes read as:
l | H ,ex | c + l | exp( T + T ) | H c = 0, , l (3)

where H = exp(T ) H exp(T )

and H ,ex is its excitation component leading from to l
and H is given by:

H = | H | (4)
The first term is called the 'direct term' and the second term is called the 'coupling term' since it couples the
cluster amplitudes of various model functions. Due to the presence of the coupling term, the intruder free nature and
rigorous size-extensivity of the formalism is maintained.
The energy is obtained by solving the equation:


| H | c = Ec (5)

The above equations are solved in a coupled manner to get the target energy and the relaxed coefficients. The
size extensivity of the energy and the connectedness of the cluster amplitudes were proved in 3. Since the number of
inactive doubles are the most numerous, Mukherjee et. al. also proposed a partially contracted variant where the
inactive doubles are treated in a -independent manner 43. It has been found that this dramatic reduction in the
number of cluster amplitudes does not necessarily lead to deterioration of the quality of the energy. Size-extensivity
of the theory is also maintained. This has been called the ICID-SSMRCC. The Ansatz for the wave operator is:
= exp(Ti ) exp(T ) | | (6)

where, Ti s are the inactive double excitations and the T s are the rest.
The corresponding working equation for inactive double cluster amplitudes read as:
1 1 
| Y li 2 H ,i 2 | c2 + | Y ( 2 T
li 2 i1
2
+ Ti1 2 Ti1 Ti1 ) | H c = 0 (7)
2

while the equation for the -dependent cluster amplitudes has the form:
l | exp(T ) H ,ex | c + l | exp(T ) | H c = l | exp(T ) | c E (8)

where the transformed Hamiltonian, H is:

H = exp( Ti ) H exp(Ti ) (9)

and, H = exp( T ) H exp(T ) is given by:

85
 H = exp( T ) H exp(T ) (10)

We now come to historically the oldest SUMRCC theory. Jeziorski and Monkhorst defined a state universal
which generates exactly N set of eigenfunctions k (k=1,...N) starting from N linearly independent unperturbed
combinations 0k .

N
k = 0 k = exp(T ) c k
=1 (11)
k = 1,....N
Using the linear independence of the function 0k the Bloch equation leads to:
l | exp(T ) H exp(T ) | l | exp( T ) exp(T ) | | H eff | = 0, , l (12)

where { } is the set of virtual functions obtained by single and double excitations of T acting on .
l

Interestingly, unlike the SSMRCC theory described above, the total number of cluster amplitudes for all l and
exactly matches the number of Equations in (12) and hence there is no redundancy. The energies Ek are
obtained by diagonalization of the matrix H eff =

| exp( T ) H exp(T ) | .
Jeziorski and Monkhorst proved the size-extensivity and the connectedness of the cluster amplitudes 38-39. We are
now in a position to discuss the UGA versions of the corresponding SS and SUMRCC theories. We present only the
final working equations here and would like to refer to our forthcoming publications for the details of their
derivations and the proof of their size-extensivity 30-31.

Scheme UGA-SSMRCC

Our Ansatz for , analogous to that in Equation(3), is

= 0 = {exp(T )}| c (13)

where the reference function 0 is given by | 0 = | c . The Schrdinger equation for is,

H = E (14)
where H is written in normal order with respect to the core function | 0 as the vacuum as:
H = 0 | H | 0 + {Fc } + {V } (15)

0 | H | 0 is the unperturbed core energy and {Fc } is the core Fock operator:
{Fc } = p | f c | q{Eqp } { f c }qp {Eqp } (16)
p ,q

{V} is the two-body Coulomb operator in normal order and { f c }qp has the form
{ f c }qp = hqp + i|0 (2vqipi vqiip ) (17)
In Equations (16) and (17) above, p,q,... denote general orbitals. Using a set of sufficiency conditions, very
similar to what was used in the parent SSMRCC and equating 1-, 2-body projections of the entire composite
H onto l s one can obtain the working equations. Two different sets of UGA-SSMRCC equations for

86
determining the cluster amplitudes can be obtained depending on the sufficiency conditions used. Each can be
shown to be size-extensive, and inequivalent and each is free of intruders. We will henceforth denote them as
scheme-A and scheme-B. We do not want to go into the details here but merely present the working equations:

Scheme-A


l |{H }ex | c + l |{exp(T + T )}| H c l | {exp(T )W }ex | c = 0, , l (18)

In Equation (18) above, we have introduced a composite {

AB} defined as the sum of all possible contractions of
operators of A with those of B. With this notation H is given by:
H =H  exp(T ) (19)

In H , the various powers of T are not contracted amongst themselves, ensuring the termination of the series
in T after the quartic power. W can be defined as the connected 'closed' operators of H cl of various ranks
which can excite to . An operator {...}ex is an 'excitation' operator which leads to the virtual CSF by acting

on the model CSFs. H is given by

H = | H | = | W | (20)
Scheme-B

In this scheme, the MRCC working equations for determining T are given by

l |{H ex}| c +l | {exp( T +T )}ex | H c l |{exp(T +T )exp(T )W }ex | c = 0, , l (21)

A perusal of the structure of the Equations (18) and (21) indicates that the coupling term in scheme-A is simpler.
Although it does not necessarily indicate at this stage that the energies of scheme-A are necessarily better than those
from scheme-B, all the results obtained by us till date show that their performances are very similar. This will be
amply demonstrated in the 4th section. In both the schemes, the energy is obtained by diagonalizing the matrix H
and homing into the desired eigenvalue. We refer to our forthcoming paper for details 30.

Scheme UGA-ICID-SSMRCC
In UGA-ICID-SSMRCC the Ansatz for our wave function, in a way exactly analogous to that in the parent ICI-
MRCC, is given by:
| = exp(Ti ) {exp(T )} | c (22)

In the Ansatz above, the normal ordering in exp(Ti ) is omitted since all components of Ti commute. Just as for
the UGA-SSMRCC, here also we can generate two size-extensive inequivalent formalisms, to be referred to again as
schemes A and B. In both the schemes, the equations for the inactive cluster amplitudes remain the same, and are
given by:

| Y li 2 {H }exi | c2 + | Yli 2 {exp(T T )}exi | H c c = 0

(23)

where H is given by exp( Ti ) H exp(Ti ) and, H is given by:


H = H exp(T ) (24)

87
Yli 2 are the set of 2h-2p inactive de-excitations.
We now provide the working equations for the -dependent cluster amplitudes of schemes-A and B which are
exact analogues of the UGA-SSMRCC.

Scheme-A

l |{H }ex | c + l |{exp(T + T )}| H c l | {exp(

 T )W }ex | c = 0, , l (25)

and

Scheme-B

 
l |{H ex}| c +l | {exp( T +T )}ex | H c l |{exp(T +T )exp(T )W }ex | c = 0, , l (26)


where H is given by

H = | H | (27)

and W can be defined as the connected 'closed' operators of H cl of various ranks which can excite to . We
refer to our forthcoming publication for details 32.

Scheme UGA-SUMRCC
Proceeding in a way exactly analogous to the spin orbital based SUMRCC we use the normal ordered JM ansatz
N
and write the exact functions k = {exp(T )}| c k . Using the same kind of mathematical manipulations as
=1
were effected in obtaining the UGA-SSMRCC equations, we are led to the following equations for determining the
cluster amplitudes for T .

l |{H }| l | {exp( T ) exp(T )exp(T )W }| = 0 l , (28)

where H is as defined in Equation (19) and W is defined after Equation (19) .

After solving for T the energies Ek are obtained by diagonalizing the matrix of the effective Hamiltonian
H eff = |{H }| :


H c = Ek c k
eff k (29)

Again we refer to our forthcoming paper for details 31.

MOLECULAR APPLICATIONS
In the following subsections, we present some of the comprehensive results for all the schemes developed above.
The first subsection covers the application of the UGA-SSMRCC and UGA-ICID-SSMRCC and the second
subsection covers the applications of the UGA-SUMRCC. In all the applications, we have taken up to three-body
residue blocks.

88
 UGA-SSMRCC and UGA-ICID-SSMRCC Schemes
To test the efficacy of our recently developed UGA-SSMRCC and UGA-ICID-SSMRCC we present here the
PES for two prototypical systems,LiH and BH. As an example of a triplet state we also look at the near equilibrium
energy of O2 in its ground state. While (2, 2) CAS space has been used for LiH and BH, O2 is a single
configuration system. For our applications, we choose the natural orbital basis for LiH and BH. For O2 the orbitals
are automatically natural. We have noticed that the behavior using the pseudo-canonical orbitals is also very similar.
We compare the results of LiH and BH with the corresponding FCI results. Our results indicate that the performance
of our UGA-SSMRCC and the UGA-ICID-SSMRCC formulations is quite satisfactory, both in terms of the absolute
and the non-parallelity error. We present below the PES of LiH with cc-pVQZ basis and for BH with cc-pVTZ
basis.All the electrons were correlated. We have used GAMESS (US)-2007 40 for generation of orbitals, integrals
and FCI values.

LiH Molecule

Fig.1 displays results of schemes A and B for UGA-SSMRCC. On the same graph the FCI values are also shown
but they are shifted down by 3mH to avoid overcrowding. Fig.2 shows the energy difference of schemes A and B
with respect to FCI in milli-hartree scale which clearly indicates that the performance of both the schemes is very
similar. We have also verified that for the dissociation of LiH the absolute error is also within tens of micro hartrees.
Both the state-specific schemes produce almost similar non-parallelity error and this is equally true for the partially
internally contracted versions. It is quite clear that the inclusion of dynamical correlation produces quantitatively
quite accurate PES for the LiH molecule.

FIGURE 1. PEC for LiH using natural orbitals; ccpVQZ Basis, CAS(2,2) using Scheme-A and Scheme-B.

89
 FIGURE 2. Energy Difference Emethod EFCI for LiH using natural orbitals; ccpVQZ Basis, CAS(2,2) using
Scheme-A and Scheme-B.

BH Molecule

The two graphs in Fig.3 display the UGA-SSMRCC and UGA-ICID-MRCC results for the PES of BH using natural
orbitals. Fig.4 shows energy differences from FCI in milli-hartrees.
In our computation we choose (2,2) CAS with 3 and 4 as active orbitals. Thus the CAS consists of
1 = [core]3 2 , 2 = [core]3 4 and 3 = [core]4 2 . Near the equilibrium geometry, the ground state is well
described by the configuration
3 = [core]4 2
However, in the large intermolecular distances 3 and 4 orbitals become quasi-degenerate and hence a true
multi-reference description is needed to have quantitatively correct behavior of the molecule in its ground state.
It should be noted that all the variants of both the formalisms work quite well over the entire potential energy
curve. At this point we should mention that the UGA-ICID-SSMRCC schemes produce somewhat better results in
terms of less non-parallelity error than the corresponding UGA-SSMRCC formulations. This may be attributed to
the fact that due to the partial internally contracted description of the inactive two-body cluster operators, there is
greater effect of the coupling between the different model functions and the virtual space. A perusal of Equation (23)
indicates that its first term on the left involves a summation over all model CSFs ab
for every tij , which shows

that equation for each tijab sees the presence of all the s.
The relative energy difference between the UGA-SSMRCC and the corresponding ICID-SSMRCC schemes
shows very little non-parallelity error indicating a very good agreement between the different spin-adapted MRCC
schemes and the corresponding partially internally contracted versions and thereby, their viability.

90
 FIGURE 3. PEC for BH using natural orbitals; ccpVTZ Basis, CAS (2, 2) using Scheme-A and Scheme-B.

FIGURE 4. Difference for BH using natural orbitals; ccpVTZ Basis, CAS(2,2) using Scheme-A and Scheme-B.

91
 Triplet ground state of O2

3
We have computed the triplet ground electronic state B1g for O2 molecule using GAMESS(US)-2007 cc-
pVDZ basis, using scheme A and scheme B, both for the UGA-SSMRCC and the UGA-ICI-SSMRCC versions. The
triplet ground state is a single CSF state with the configuration
0 =| (core)b2 g b3 g
For the comparison with the spin-orbital based SSMRCC formulations, we have also computed the state energy
for M s =0 state. For, M s =1, The spin-orbital based theory SSMRCC leads to spin-contamination error for O2 .
However in our spin-free theory, there is no such error, which is a major advantage.
In Table.2 we present UGA-SSMRCC and UGA-ICID-SSMRCC of O2 triplet ground state at bond distance of
2.267671 a.u.

TABLE (2). Triplet Ground State of O2 molecule using cc-pVDZ basis in its ground state at 2.267671 a.u
Method Energy
UGA-SSMRCC (scheme-A) -149.97793131
UGA-SSMRCC (scheme-B) -149.97889363
UGA-ICID (scheme-A) -149.97948140
UGA-ICID (scheme-B) -149.97919885
Spin-Orbital based SSMRC -149.97838768
with Ms = 1

UGA-SUMRCC Scheme
We present here two sets of numbers, one for doublet radicals and another for excited states closed shell
molecules. For both these two types of states, we take the vacuum, | 0 as the Hartree-Fock function of the closed
shell ground state. The molecules are so chosen that the Hartree-Fock function provides an adequate description of
the ground state, i.e. single reference in character.
. +
As illustrative examples, we choose OH as radical and excited state of CH .
We will compare our methods with EOM-CC, COS-CC and ROHF-CCSD to substantiate our demand of
balanced description of the target state. The deviations of the results of the methods from FCI (M-FCI) are presented
in millihartrees where FCI is available.

OH . Radical
.
The ground state equilibrium geometry of OH shows O-H bond length of 1.8324672 a.u. In our calculation we
have taken C2V symmetry of the molecule and Z axis as the principal axis. The model space for this case consists of
the 1h states generated from the valence 1b1 and 1b2 orbitals. Our results show very good agreement with the FCI
value in comparison with EOM-CC and ROHF-CCSD. Both for our case and EOM-CC the chosen reference is
closed shell which is different from the target state. But our theory provides a scheme conducive to incorporation of
orbital relaxation which alleviates the disadvantage of not choosing the orbitals of target state, which EOM-CC
cannot provide. ROHF-CCSD,on the other hand, uses the orbitals of the target state which is open shell in character.
Therefore in this route of computation we get spin contaminated results. The difference in values between these two
theories (ROHF-CCSD and UGA-SUMRCC) gives an estimation of error due to spin contamination.The closest
spin-free analogue of JM ansatz is the COS-CC ansatz of Datta et al 41 but it has the disadvantage of operational
complexity. However,as evidenced by Table.4, calculation with cc-pVTZ basis shows that the difference of COS-
CC values and that of our method is,of the order of, hundredth of a milli-hartree. It thus seems to us that our
formulation provides a very good compromise between the complexity of COS-CC and ours in the sense that, we
achieve very similar accuracy.

92
 TABLE (3). Doublet radical state of OH molecule using 6-31G** basis in its ground state equilibrium geometry
Energy of 1(a.u.)
2
Method M-FCI (mH)
UGA-SUMRCC -75.546521 -0.035
ROHF-CCSD -75.544403 2.083
EOM-CC -75.551026 -4.540
FCI -75.546486

TABLE (4). Doublet radical state of OH molecule using cc-pVTZ basis in its ground state equilibrium geometry
Energy of 1(a.u.)
2
Method
UGA-SUMRCC -75.646581
COS-CC -75.646612
ROHF-CCSD -75.644768
EOM-CC -75.645004

Excited States of CH +

To compute the excited states of CH + we choose its closed shell ground state as the vacuum | 0 .C-H bond
length is taken as 2.137280 a.u. Our model space consists of the various h-p excited states. We have considered
different choices of model space for the application of our method. In one choice we take 3a1 from the occupied
level and 1b1 , 1b2 , 4a1 from the unoccupied level. In another choice 2a1 , 4a1 are chosen from the occupied level
and the unoccupied level remains same as the previous case.
Computation of excited states dominated by h-p states on a vacuum presents a very interesting feature arising
from the \emph{incompleteness} of such model spaces. As Mukherjee 44-47 has shown, generation of size extensive
energies starting from incomplete active spaces requires abandoning the traditional intermediate normalization of the
wave operator. In addition, due to the incompleteness of the active space excitations are possible in T which
contain only active labels, which may be considered as excitations into the complementary active space to the
chosen incomplete space. However, a remarkable property of such model spaces is that, if only the excited state
energies are our quantities of interest and not the associated eigen functions, then, intermediate normalization of the
wave operator responsible for generating the energy can be maintained 48-49. Since in this article we are interested in
1h-1p excited state energies only, we can pretend that our incomplete active space supports intermediate
normalization and yet retains size extensivity.
For the one-dimensional model space 1 state energy has better correspondence with the FCI energy in
comparison to the two dimensional model space. The reason may be attributed to the presence of an intruder state
which shows up in CI calculations and is evidenced by increasing non-hermiticity of the H eff matrix in successive
iterations. The 2 state energy, on the other hand, gives a wrong estimate because of insufficient description of
model space. But, 2 state energy is not that drastically different from FCI value as it has less contribution from
3

upper excited states. Consideration of two dimensional model spaces for triplet states, therefore, gives correct
estimate of energy in comparison to singlet state. We note that our schemes slightly overestimate the FCI value,
presumably due to some multi-reference character of the ground state.

93
 TABLE (5). Singlet excited states of CH+ molecule using cc-pVDZ basis in its ground state equilibrium geometry
Method Model 1 1 M-FCI 2 1 M-FCI 1
M-FCI
Space (a.u.) (mH) (a.u.) (mH) (a.u.) (mH)
UGA-SUMRCC 1 -37.886482 -0.356 - - -37.502612 -6.543
UGA-SUMRCC 2 -37.888591 -2.465 -37.465082 21.141 - -
EOM-CCSD -37.883039 3.087 -37.471764 14.459 -37.491904 4.165
FCI -37.886126 -37.486223 -37.496069 -

TABLE (6). Triplet excited states of CH+ molecule using cc-pVDZ basis in its ground state equilibrium geometry
Method Model 1 3 M-FCI 2 3 M-FCI 3
M-FCI
Space (a.u.) (mH) (a.u.) (mH) (a.u.) (mH)
UGA-SUMRCC 1 -37.962951 -1.61 - - -37.583491 2.397
UGA-SUMRCC 2 -37.962379 1.038 -37.633288 -3.934 - -
EOM-CCSD -37.959286 2.055 -37.628451 0.903 -37.579111 6.777
FCI -37.961341 - -37.629354 -37.585888 -

SUMMARY AND FUTURE OUTLOOK

We have presented in this article a brief overview of our recent attempts to generate spin-free versions of state-
specific (SS) and state-universal (SU) MRCC. The formalisms are accomplished via the use of spin-free Unitary
Generators in defining the cluster operators T for model CSFs . The inherent non-commutativity of such
operators would lead to non-terminating power series in the transformed Hamiltonian
H = exp(T ) H exp(T ) if an exponential parametrization of the cluster expansion is invoked leading to
rather unwieldy expressions for the MRCC working equations. We have shown in this article how a normal ordered
exponential representation of the cluster expansion of the wave operator can alleviate this problem and can provide
us with a finite power series expansion involving T of the transformed Hamiltonian, terminating at the quartic
power. The normal ordering is defined with respect to the closed shell common part | 0 of the CSFs . The
CSFs are Gel'fand states thereby making use of unitary group adaptation. The UGA-SSMRCC and UGA-
SUMRCC formalisms are briefly discussed and their working equations are presented. The UGA-SSMRCC requires
imposition of suitable sufficiency conditions to eliminate redundancy of the cluster amplitudes {t } . It is explained
that there can be two distinct schemes A and B, which are both size-extensive and intruder free. The working
equations for scheme-A are simpler and, since both schemes perform similarly, we will prefer scheme-A for
implementation in future. Assuming the double excitations Ti , involving only the inactive orbitals, to be independent
of , drastic reduction of the number of cluster amplitudes can be achieved; and we have called such theories as
UGA-based ICID-SSMRCC (ICID implying internally contracted treatment of the inactive doubles). The UGA-
ICID-SSMRCC can also have their corresponding A and B-schemes and both are presented. The numerical results
amply demonstrate that UGA-SSMRCC and its ICID-variety work very well for PES and that UGA-ICID-SSMRCC
results are comparable in accuracy to those of UGA-SSMRCC despite a significant reduction in the number of
cluster amplitudes. The UGA-SUMRCC theory also works very well when there are no intruders and we have
demonstrated its efficacy by applying it to single point computation of energies of doublet and triplet states.
A persistent criticism of the SSMRCC formalism has been the use of redundant cluster amplitudes and the use of
a set of sufficiency conditions where there is insufficient coupling between the virtual functions l | and the
different model CSFs . For more than two active electrons, absence of such coupling leads to deterioration of the
PES when delocalized active orbitals are used. With localized active orbitals, however, there is a dramatic

94
improvement in the quality of the PES for systems with more than two active electrons 50-51. The ICID-SSMRCC
formulation, however, involves more complete coupling and thus is expected to perform better than the SSMRCC
itself. Validity of this expectation should be explored in our UGA formalisms. Another aspect of SSMRCC
requiring attention is its lack of invariance with respect to rotation among active orbitals. We surmise that the
normal ordered cluster Ansatz suggested in this article has the potential to at least ameliorate, if not eliminate
altogether, the orbital non-invariance issue. Exploration of such aspects will keep us engaged in the near future.

ACKNOWLEDGMENTS
R.M., D.S. and A.S. thank IACS and DST (India) for their research fellowships. S.S. thanks CSIR(INDIA) for
SPM fellowship. D.M. thanks the Alexander von Humboldt Foundation for the Humboldt Research Award and
Department of Science and Technology, India for conferring on him the J. C. Bose National fellowship. D.M. also
thanks India-European Union Science and Technology cooperation Agreement for MONAMI project, and the Indo-
Swedish bilateral project for research support.

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96
 Explicitly correlated projector Monte Carlo method based
on Slater determinants (PMC-SD-F12 method)
Yuhki Ohtsuka and Seiichiro Ten-no*

Graduate School of System Informatics, Kobe University, Kobe 657-8501, Japan

Abstract. We propose the explicitly correlated projector Monte Carlo method based on Slater determinants (PMC-SD-
F12 method) for accurate calculations of correlated wave functions. The F12 similarity transformed Hamiltonian is used
to calculate the transition probabilities, weights, and electronic energies in the PMC-SD-F12 method. Test applications
show that the energy convergence against the quality of basis set is accelerated compared to the PMC-SD method. The
correlation energy using aug-cc-pCVQZ basis gave good agreement with the best values available in the literature.
Keywords: Quantum Monte Carlo, Full-CI, F12 method
PACS: 71.10.-w

THEORY
The diffusion Monte Carlo (DMC) or the projector Monte Carlo (PMC) method can simulate the exact wave
function without the limitation of basis functions because electrons are expressed as particles. Anti-symmetry of the
electronic wave function is usually taken into account by using the node of a guide function. Consequently, the
accuracy of the DMC method depends strongly on the accuracy of the trial wave function.
We have proposed an alternative PMC method based on Slater determinants (PMC-SD method) [1, 2]. As
illustrated in Figure 1, the use of Slater determinants as walkers fulfills the anti-symmetry of electrons
automatically, and no additional information such as nodes of trial wave functions is required. As a result, the
accuracy of the PMC method depends mainly on the number of walkers and converges to the full configuration
interaction (CI) limit with the number of walkers.

Diffusion Monte Carlo method Present (PMC-SD) method

Monte Carlo simulation Monte Carlo simulation

Electrons are expressed as particles. Electrons are expressed as Slater determinants.

Trial wave function is required. Trial wave function is not required.

FIGURE 1. Schematic comparison between the diffusion Monte Carlo and PMC-SD methods

In the PMC-SD method, the formal solution of the imaginary-time Schrdinger equation,

Theory and Applications in Computational Chemistry: The First Decade of the Second Millennium
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97
 ( )
+ = exp H , ( ) () (1)
is simulated by the Monte Carlo method using Slater determinants with their signs as walkers. The PMC-SD wave
function can be obtained by the normalization of distribution of Slater determinants (electronic configurations) as
follows.
1
PMC-SD ( ) = nI ( ) I = CI ( ) I (2)
( nI ( ) ) I
2
I

Here, nI () is the number of walkers whose electronic configurations are I at imaginary time . The
distribution varies in the Monte Carlo simulation, and a stationary distribution is obtained after an adequate number
of steps. The transition probability from the configuration I to J is defined as the norm of the matrix element
between I and J of the imaginary-time propagator, which is approximated by the linear term practically,

( )
I exp H J I 1 H J . ( ) (3)

The transition from I to J is accepted for a generated random number smaller than or equal to the transition

( )
probability. For a negative transition matrix element I 1 H J , the sign of the configuration is changed as
follows.
I J (4)
The walker is multiplied by the weight,
(
I 1 H I ) , (5)
(
1 I 1 H J )
if the transition is rejected. In this study, the PMC-SD energy at imaginary time was calculated using the
intermediate normalization.
EPMC-SD ( ) = 0 H PMC-SD ( ) (6)
Here, PMC-SD ( ) is the intermediate normalized PMC-SD wave function,

()
PMC-SD =
()
PMC-SD C
= 1.0 0 + 1
C
1 ++ N
()
N ,
()
() C0 () ()
(7)
C0 C0
where 0 is usually the Hartree-Fock configuration. The PMC-SD energy is defined as the time averaged energy
after the stationary distribution was obtained at 0 ,
1 n
0 H PMC-SD ( 0 + i ) .
EPMC-SD =
n i =1
(8)

In this study, we combine the PMC-SD and F12 methods [3] to approach the exact wave function. In the present
PMC-SD-F12 method, the Hamiltonian in the PMC-SD method is replaced with the F12 similarity transformed
Hamiltonian,
H F12 = exp( Q ) H exp( Q ) , (9)
with the excitation operator,
1
 Q = Q1212 ij E i E j , (10)
4 i , j ,
where E pq is the unitary group generator, and 12 is the rational generator [4],
3 1
12 = f12 ( + p12 ), . (11)
8 8
in conjunction with the Slater-type geminal correlation factor [5],

98
 1
f12 = exp( r12 ) , (12)

and p12 is a permutation operator over the spatial part of the electronic coordinates. We have used the standard
notations i,j, for occupied orbitals, ,, for virtual orbitals in the complete basis set, and p,q, for general
orbitals. The strong-orthogonality projection operator takes either of the forms
Q12 = (1 P1 )(1 P2 )(1 V1V2 ) (Ansatz 1), (13)
Q12 = (1 O1 )(1 O 2 )(1 V1V2 ) (Ansatz 2), (14)
, V , and P onto the occupied, virtual and general orbitals spaces in the given
with the projection operators, On n n
basis set, respectively.
The transition probability and weight are changed accordingly to
( )
I 1 H F12 J (15)
and
( )
I 1 H F12 I
, (16)
(
1 I 1 H F12 J )
respectively.
The PMC-SD-F12 energy is also calculated using the F12 similarity transformed Hamiltonian.
EPMC-SD-F12 ( ) = 0 H F12 PMC-SD-F12 ( ) (17)
For the Ansatz 1, it is sufficient to consider only extra two-electron terms linear to  Q in the similarity
transformed Hamiltonian H F12 . Although three- and four-electron interactions contributes to PMC-SD-F12
calculations for the Ansatz 2, we truncate H F12 at the two-electron term of the double contraction in  Q in this
particular work. The detail of the implementation will be discussed in more detail elsewhere [6]. The F12 similarity
transformed Hamiltonian accelerates the basis set convergence of the PMC-SD method.

RESULTS
We show the preliminary results of PMC-SD and PMC-SD-F12 for the Ne atom in the ground state. Two
of the Anstze 1 and 2 were employed for comparison. For the number of Monte
different projection operators Q12
Carlo steps, 20,000 steps were used for the convergence to the stationary distribution, and the PMC-SD and PMC-
SD-F12 energies were defined as the average energies over the subsequent 10,000 steps. The numbers of walkers
were 2107, 5107, and 2108 for the aug-cc-pCVXZ basis (X=D, T, and Q), respectively. As shown in TABLE I,
the energy convergence of the PMC-SD method with respect to the quality of the basis set was accelerated in the
F12 method. The PMC-SD and PMC-SD-F12 (Ansatz 1 and modified Ansatz 2) energies using aug-cc-pCVQZ basis
were -128.916 (1), -128.925 9(9), and -128.934 4(9) Eh, respectively. The PMC-SD-F12 energy (modified Ansatz 2)
was very close to the DMC result [7], -128.933 9(3) Eh. Although our result is higher than the total energy of
CCSDT-R12 [8], -128.937 7 (4) Eh by 3mEh, the main source for the discrepancy is the Hartree-Fock description
with the aug-cc-pCVQZ basis.
We plan to report on PMC-SD-F12 results for quasi-degenerated systems.

TABLE I Total energies (in Eh) by the PMC-SD and PMC-SD-F12 methods using aug-cc-pCVXZ
(X=D, T, and Q) basis.
aug-cc-pCVXZ
Method D T Q
PMC-SD -128.752 8 (6) -128.878 0 (8) -128.916 (1)
PMC-SD-F12 (Ansatz1) -128.811 5 (4) -128.898 7 (9) -128.925 9(9)
PMC-SD-F12 (Ansatz2) -128.878 0 (7) -128.922 (1) -128.934 4(9)

99
 ACKNOWLEDGMENTS
This work is partly supported by the Grant-in- Aids for Scientific Research (B) (No. 00270471) from the Japan
Society for the Promotion of Science (JSPS) and the Strategic Programs for Innovative Research (SPIRE), MEXT,
and the Computational Materials Science Initiative (CMSI), Japan.

REFERENCES
1. Y. Ohtsuka and S. Nagase, Chem. Phys. Lett., 463, 431-434 (2008).
2. Y. Ohtsuka and S. Nagase, Theor. Chem. Acc., 130, 501-505 (2011).
3. W. Klopper, F.R. Manby, Ten-no, and E. F. Valeev, Int. Rev. Phys. Chem., 25, 427-468 (2006).
4. S. Ten-no, J. Chem. Phys., 121, 117-129 (2004).
5. S. Ten-no, Chem. Phys. Lett., 398, 56-61 (2004).
6. Y. Ohtsuka and S. Ten-no, in preparation (2012).
7. M. D. Brown, J. R. Trail, P. Lpez Ros, and R. J. Needs, J. Chem. Phys., 126, 224110-1-6 (2007).
8. T. Shiozaki, M. Kamiya, S. Hirata, and E. F. Valeev, J. Chem. Phys., 130, 054101-1-10 (2009).

100
 SAC-CI Methodology Applied to Molecular Spectroscopy
and Photo-Biology

J. Hasegawa,a T. Miyahara,b H. Nakashima,b and H. Nakatsujib

a
Fukui Institute for Fundamental Chemistry, Kyoto University, Kyoto, Japan
b
Quantum Chemistry Research Institute (QCRI), JST CREST, 1-36 Goryo-Oohara, Nishikyo-ku, Kyoto, Japan

Abstract. The SAC-CI method was applied to the spectroscopy of radical cations and anions of various organic
molecules. It was also applied to photo-biology, in particular, to elucidate the bio-molecular color-tuning mechanism of
human visions and to the circular dichroism spectroscopy that is used to understand the helical structures of DNA and
RNA.
Keywords: SAC-CI Method, Radical Cations and Anions, Human Vision, Color-Tuning Mechanism, Circular Dichroism,
DNA, RNA
PACS: 31.15.ag, 31.15.bw, 31.15.vj, 87.64.-t

SPECTROSCOPY OF RADICAL CATIONS AND ANIONS

The SAC/SAC-CI method is a well-established method for studying ground, excited, ionized and electron
attached states of molecules published in 1978 [1-3]. It is widely distributed through Gaussian 09 [4].

Some years ago, Prof. T. Shida published a number of experimental VUV spectra of radical cations and anions of
organic molecules [5]. We investigate here the electronic excitation spectra of the radical anions of cyano-
compounds [6] whose electron affinities are positive. The SAC-CI theoretical spectra reproduced reasonably well
the experimental spectra and could give fine assignments of the observed peaks. We also studied radical cations and
anions of several hydrocarbons whose electron affinities are negative. The pairing theorem valid in Hckel theory
could be observed in the experimental and SAC-CI spectra.
The figure below shows the excitation spectra of the radical anion of 1,4-dicyanobenzene [6].

Theory and Applications in Computational Chemistry: The First Decade of the Second Millennium
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101
The SAC-CI theoretical spectrum reproduces well the experimental spectrum observed originally by Shida[5].
Moreover, an extremely weak *(SOMO) * peak at near infrared region (1.5 eV) was show to exist by the
present SAC-CI calculations [6]. So, when Prof. T. Shida re-examined his experimental spectrum, such weak peak
was confirmed to exist as a real state.

COLOR TUNING MECHANISM IN HUMAN VISION

In human visual cone pigments, human blue (HB), rhodopsin (Rh), human green (HG) and human red (HR), the
central chromophore is retinal, commonly. Then, how and why such large spectral shifts occur? We studied this
subject using SAC-CI/MM method dealing with retinals and the surrounding proteins [7,8]. The table below is the
central data and shows the SAC-CI excitation energies of the retinals in various cone pigments.

The values of the excitation energies (Eex) of retinal in different cone pigment agree well with the experimental
values [9-11]. By analyzing these SAC-CI results, we would be able to elucidate the bio-molecular mechanism of
the color tuning in human visions. For HB, the structural effect of retinal itself and the effect due to the surrounding
proteins are important. For the Rh, HG, and HR, the effects due to the surrounding proteins are dominant. The
importance of the hydrogen bonding network near the retinal was shown important as the color-tuning mechanisms.
We briefly explain the analyses of the color-tuning mechanisms in some details below.

First, the SAC-CI calculations, which are performed with the active site (AS) model under electrostatic
potential (ESP) of the MM region (in opsin), show reasonable agreement to the experimental excitation energies
of four pigments. The SAC-CI values for HB, Rh, HG and HR are 2.94, 2.45, 2.32 and 2.08 eV, respectively, while
the experimental absorption energies are 2.99, 2.49, 2.33 and 2.20 eV, respectively. The observed absorption peaks
are assigned to the first excited states that have the largest oscillator strength in this energy region. They are the -*
HOMO-LUMO transitions. By analyzing these SAC-CI results, we could elucidate the bio-molecular mechanism of
the color tuning in human visions.

The figure below shows the decomposition analyses of the absorption energy shift, when Rh is used as a
reference.

102
The structural effect of the chromophore itself (0.24 eV) is an important factor in the spectral blue shift of HB, while
it is very small for the other pigments, HG (0.00) and HR (-0.03). For HB, the overall ES effect due to the
surrounding protein amounts to 0.32 eV of the overall spectral blue shift of 0.49 eV. On the other hand, the spectral
red shifts of HG (0.13) and HR (0.37) are dominated by the protein ES effect (0.08 eV for HG and 0.33 eV for HR).
The counter ion QM effect gives essentially no contribution to the specific spectral shift among the cone pigments.

The figure below shows the structural difference of the retinal PSB (protonated Schiff base) in HB, Rh, HG and
HR. The torsion around C6-C7 bond is large for HB but small for Rh, HG and HR. Therefore, the excitation energy
is blue-shifted for HB, because the rotation around C6-C7 bond reduces the conjugation.

The figure below shows the MO distributions and protein ESP. The LUMO of the retinal chromophore is
localized mainly on the Schiff base side of the -chain, while the HOMO is localized on the other -ionone ring side.
The HOMO-LUMO transition is, therefore, an intra molecular electron transfer from the ring to the N region. As a
result, the excitation is affected by the external ESP, which gradually becomes more and more negative from the
ring toward the N atom in all the retinal proteins. The N-to-C5 differences in the ESP are -0.15, -0.11, -0.10 and -
0.07 au for HB, Rh, HG and HR. Under these protein ESPs, the HOMO-LUMO gaps increase by 0.69, 0.44, 0.37
and 0.15 eV in HB, Rh, HG and HR, respectively, in comparison with the isolated bare chromophore. The table
above shows that the excitation energies of the pigments correlate well with the N-to-C5 ESP differences.

103
 The figure below shows amino acid sequences important for color tuning. Serine at position 186 gives red shift
contributions in Rh, HG and HR but very small effect in HB. The Cl- binding site, which is composed of positions
181, 184 and the Cl-, gives red shift contribution in both HG and HR, although the Cl- itself has a blue shift
contribution. HR is characterized by amino acids at positions 187, 261, 268 and 269, because these amino acids
contribute to blue shift in HB, Rh, HG but red shift in HR. Tryptophan at position 265 in Rh (281 in HR) contributes
to red shift.

104
 The figure below shows hydrogen-bonding network for HB, Rh, HG and HR. In Ser 186 of Rh and in Ser 202 of
HG and HR, the OH directions are parallel to the retinal -skeleton, resulting in a spectral red shift, since they create
a positive ESP around the Schiff base part. The OH group of Ser 183 in HB, however, is perpendicular to the -
skeleton, so its effect is negligible. These OH directions are controlled by the hydrogen-bonding networks and are
energetically stable.

Ser 289 in HB increases the excitation energy, but Ala 308 in HR itself has the red shift effect. Ser 289 in HB
mediates the hydrogen-bonding network. This residue tunes the excitation energy by controlling the OH direction of
serine residues at position 183. If an alanine is at position 289, a serine at 183 would contribute to the spectral red
shift as in Rh, HG and HR.

The conformations of His 197 in HG and HR are different. This arises from the differences in the local cavity
environment and hydrogen-bonding pattern. The main chain part of His 197 interacts with Ser 202 in HG but with
Cys 203 in HR. Consequently, the C=O orientation in Cys 203 changes in HR, which results in the spectral red shift.
It is, however, very difficult to determine the origin of this spectral difference.

The figure below shows three amino acids in (a) HR and (b) HG active site. Positive and negative areas are
indicated by deep red and purple, respectively.

At positions 261 and 269 in Rh, HR has dipolar Tyr 277 and Thr285, whereas HB, HG and Rh have nonpolar
phenylalanine and alanine residues. The OH groups of Tyr 277 and Thr285 in HR align such that the O atoms are
closer to the retinal chromophore, since the ESP created by the retinal PSB is positive around the -ionone ring side
of the chromophore, which decreases the absorption energy. Although all pigments have a cystein residue at position

105
187 in Rh, only Cys 203 in HR has a red shift effect. This difference arises from the C=O orientation of the peptide
bond which is controlled by the local hydrogen-bonding network.

At position 113 of the counter ion residue of the PSB, the amount of the red shifts is in the order of HB > Rh > HR
> HG, indicating that the counter ion residues are roughly controlling the spectral peak positions. In other words, the
counter ion effect does not explain the relative order of the excitation energies among the visual pigments.

Thus, we found that the color tuning is regulated by the amino acids at specific positions in the amino acid
sequence of the retinal proteins (HB, Rh, HG and HR) and by the structural effect of the retinal itself (HB alone).
This fact may imply that there are some genetic origins. The present theoretical study has thus shed light on the
physical and chemical origins of color tuning working behind the existing experimental findings.

CIRCULAR DICHROISM SPECTRA AND HELICAL STRUCTURE OF DNA

Circular dichroism (CD) spectra are widely used to study helical structures of DNA in solution. We study here
the CD spectra of B-DNA (right-handed double-helical structure) and Z-DNA (left-handed) composed of
deoxyguanosine (dG) and deoxycytidine (dC) [12]. In these DNA, the important factors affecting the CD and UV
spectra are (a) conformation of dG , (b) hydrogen-bonding interaction, (c) stacking interaction. These factors
determine the shape of the CD spectra of the Z-DNA and B-DNA.

The CD spectra of dG change dramatically along with the conformational change. The CD spectra of anti-dG is
opposite in sign to that of syn-dG and the CD spectrum of atni-dG is roughly similar to the CD spectrum of B-DNA,
while that of syn-dG is roughly similar to that of Z-DNA. However, the negative sign at around 300 nm of CD
spectra, which is one of the features of Z-DNA, does not appear in the SAC-CI CD spectrum of syn-dG. Therefore,
we can conclude that the negative sign of CD spectra is not derived from the monomer of dG. Since the nucleic acid
bases interact with other nucleic acid bases through hydrogen-bonding and/or stacking structures, the dimer models
with hydrogen-bonding or stacking are calculated by the SAC-CI method.

106
 The figures above are the comparisons of the SAC-CI CD spectra of the dimer models with the experimental
ones [13] for Z-DNA and B-DNA. The dimer model represents either hydrogen-bonding interaction or stacking
interaction. In the figure, ZH model stands for the Z-DNA hydrogen-bonding model and ZS model stands for the Z-
DNA stacking model. At around 300 nm, only the SAC-CI CD spectra of ZS model have negative sign, while other
SAC-CI CD spectra are positive there. Therefore, we can say that the strong stacking interaction is the origin of the
strong negative peak of Z-DNA.

Next, the figures above are the comparisons of the SAC-CI UV and CD spectra with the experimental ones for
Z-DNA and B-DNA. They were obtained with the tetramer model that includes both hydrogen-bonding and stacking
interactions, simultaneously. The UV spectra are insensitive to the helical structure but the CD spectra sensitively
reflect the helical structures of DNA. Both the SAC-CI UV and CD spectra of tetramer models are in good
agreement with the experimental spectra, although the negative sign at around 300 nm is weak for Z-DNA, because
of the poorer basis set used in these calculations. But, we already know that this negative peak is due to the stacking
interaction in Z-DNA.

Thus, the important factors that affect the CD spectra of DNA are the (a) conformation of dG, (b) hydrogen-
bonding interaction and (c) stacking interaction, which are controlled by the helical structure of DNA. The strong
stacking interaction of Z-DNA is the origin of the strong negative sign at around 300 nm. The SAC-CI method can
make clear the details of the experimental CD spectra of DNA and RNA.

107
 ACKNOWLEDGMENTS
We acknowledge IMS computer center for letting us to use their high-performance computers. We also thank Dr.
K. Fujimoto at Kobe University and Prof. H. Sugiyama at Kyoto University for their active collaborations.

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1. H. Nakatsuji, K. Hirao, J. Chem. Phys. 68, 2053 (1978); H Nakatsuji, Chem. Phys. Lett. 59, 362 (1978), 67, 329, 334 ( 1979).
2. H. Nakatsuji In Computational Chemistry, Reviews of Current Trends; J. Leszczynski, Ed. World Scientific Vol. 2, 1997.
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4. M. Frisch, et al. Gaussian Suite of Programs
5. T. Shida, Physical Sciences Data 34 Electronic absorption spectra of radical ions; Elsevier, 1988.
6. H. Nakashima, T. Shida, and H. Nakatsuji, J. Chem. Phys. submitted.
7. K. Fujimoto, J. Hasegawa and H. Nakatsuji, Bull. Chem. Soc. Japan, 82, 1140 (2009).
8. K. Fujimoto, J. Hasegawa and H. Nakatsuji, Chem. Phys. Lett. 462, 318 (2008).
9. H. Kandori, Y. Shichida and T. Yoshizawa, Biochemistry (Moscow, Russ. Fed.) 66, 1197 (2001).
10. J. I. Fasick, N. Lee, D. D. Oprian, Biochemistry 38, 11593 (1999)
11. A. B. Asenjo, J. Rim, D. D. Oprian, Neuron 12, 1131 (1994).
12. T. Miyahara, H. Nakatsuji, and H. Sugiyama, to be submitted.
13. S. Tran-Dinh, J. Taboury, J. M. Neumann, T. Huynh-Dinh, B. Genissel, B. L. dEstaintot, and J. Igolen, Biochemistry 23,
1362 (1984).

108
 Quantum Chemistry, Band Structures and Polymers
Jean-Marie Andr

University of Namur, Department of Chemistry, PCI, rue de Bruxelles 61, 5000 Namur (Belgium)
Royal Academy of Science, Arts and Letters of Belgium, Palais des Acadmies, rue Ducale, 1, 1000 Bruxelles
(Belgium)

Abstract. A short review of the long way from the first calculations on polyenes after the second world war
to the recent electronic devices like Organic Light Emitting Diodes or Photovoltaic Cells is given. It shows
how quantum chemical methods on one side and synthesis or experiments have (or should have) interacted
as incentives to new methods and technologies.
Keywords: Ab initio calculations, Band Structure, Electrical conductivity of polymers, Electronic structure
of condensed matter
PACS: 31.15.A-, 71.20.-b, 72.80.Le, 71.20.Rv

EARLIER INTERESTS IN ELECTRONIC STRUCTURE OF POLYMERS

The development of molecular quantum chemistry after the second world has been mainly centered
on simple -containing systems. The usual model that has been retained for extended chains was mainly
the polyene (now renamed polyacetylene) chain:
...-CH=CH-CH=CH-CH=CH-CH=CH-CH=CH-CH=CH-...

Due to computing constraints, two elementary methodologies were generally used, the FE (Free
Electron) model and the HMO (Hckel Molecular Orbital) one, both having their counterpart in solid
state physics, i.e., the metallic model or the tight binding approximation. The expansion of color
photography in the late 40's oriented the application of the quantum methods towards the interpretation
of UV and visible spectra. It is in this context that emerged the standard principle about electrical
conductivity of extended chains, i.e., in order to have a metallic behavior, the chain should have a zero
energy gap (a zero transition energy). Otherwise, if a gap exists, depending on its size, a semi-
conducting or insulating state is observed. In the case of organic polymers, the existence or non-
existence of energy gaps was related very early on to the concept of bond alternation by the pioneering
work done by Kuhn in the late 1940s1. Indeed, Kuhn has shown that in the series of polymethine dyes,
the bond lengths between all the carbon atoms are equal due to a resonance balance between equivalent
extreme forms:
>N-(CH=CH-)nCH=N+< >N+=CH-(CH=CH-)n-N<
All carbon-carbon atoms in the skeleton have 50% double bond character. This fact was later
confirmed by X-ray diffraction studies. A simple FE model calculation shows that there is no energy
gap between the valence and conduction bands and that the limit of the first UV-visible transition for an
infinite chain is zero. Thus it correctly reproduces the first UV transition with a metallic extrapolation
for the infinite chain.
Conversely, in the polyacetylene series, CH2=CH-(CH=CH)n-CH=CH2, Kuhn has to perturb the
constant potential using a sinusoidal one in order to cover the experimental trends. The role of the
sinusoidal potential is to take into account the structural bond alternation between bond lengths of
single and double bond character. When applied to the infinite system, in this type of perturbed FE
model, a non-zero energy gap is obtained (about 1.90 eV in Kuhns calculation).
From that work, it became clear that the metallic character of the infinite chain heavily depended on
geometrical parameters, an alternating chain being semi-conductive, a regular one being possibly

Theory and Applications in Computational Chemistry: The First Decade of the Second Millennium
AIP Conf. Proc. 1456, 109-113 (2012); doi: 10.1063/1.4730649
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109
metallic. An energy gap opens up in the band structure if alternating bond interactions are present. This
forbidden gap is also related to Peierls distortion: a 1D metallic chain is unstable and tends to distort in
order to become semi-conducting or insulating and decreases its total energy (this behavior is similar to
a Jahn-Teller distortion). Thus, in a first approximation, the presence of high conductivity could
therefore, mean some equalization of the bonds.
For periodic systems in 2D, the model studied was a planar sheet of graphite. It is striking to note
that both polyenes and planar graphite would become of the greater practical interest with the discovery
of metallic conductivity in doped-polyacetylenes in 1977 and the synthesis of graphene in 2004, both
discoveries leading to the Nobel prizes of Heeger, MacDiarmid and Shirakawa in 2000 and of Geim and
Novoselov in 2010.

THE EARLY QUEST FOR ORGANIC CONDUCTOR

The quest for finding organic conductors is an old one. One of the famous theoretical chemists,
known for the publication in 1965 of the first ab initio calculations on significant organic molecules
(pyridine, pyrrole,) has started his scientific career in the 1950s by the experimental synthesis of
polyacetylene in the group of Giuseppe Natta. The explosive character of the compound ended
prematurely the experimental work of Enrico Clementi.
As far as we know, a pioneering work on the experimental measurements of energy gaps in
conjugated polymers has been published in 1963 by scientists of the Institut franais du ptrole (French
Institute of Petroleum)2. Polymers like polyacetylenes and polyparaphenylenes that would become of
interest in the field were already measured at this time. That paper served as a basis for our own 1967
quantum calculations of the energy gap of the same types of compounds by the Hckel methodology3.

As we have seen, the metallic character of is intuitively connected to a regular geometry of

conjugated CH-chains. Since the 1950s, even if experimental data were not available for large polyenes,
it was clear from data on related compounds (mainly on carotenes and similar molecules) that the
geometry of polyenic chains should bond alternating (ranging from 1.350 to 1.520 ) as confirmed by
the theoretical PPP simulations of the time (1.363-1.429 )4.

Thus, to get metallic conductivity would mean in a way or another some equalization of bonds: upon
doping, the charge transfer process would perturb the electronic distribution and make the chain more
regular. This idea that modification of orbital occupancy strongly perturbs the electron density and the
geometrical parameters was not new. It was, for example, already formulated by Pullman and Daudel in
1946 in the completely different field of chemical reactivity5. In their elegant paper, these authors show
by a simple summarized Hckel calculation that a local excitation of a polyene molecule (butadiene in
their calculation), leads to a rearrangement of the electronic density and constrains the molecule in a
geometry ideally suited for cyclization into cyclobutene.
The equalization of bonds in -conjugated chains under the effect of charge transfer or of electronic
excitation HOMOLUMO is easily explained by the topology of molecular orbitals since the LUMO
has nodes at intermediate sites with respect to those of the HOMO. Thus, under the effect of excitation,
simple bonds exhibit a larger double character while double bonds become more simple. It is
fascinating to realize that the experimental confirmation of photocyclization of cis-butadiene into
cyclobutene will only been published 15 years later6. We have here one of the significant examples to
be cited to chemistry students to convince them of the important role of combining theory and
experiment to generate innovation, the new field of photochemistry in the example cited.

For our concern, subjacent is the idea of doping: modifying the relative populations of HOMO or of
LUMO will have the effect of decreasing the amount of bond alternation.

110
 TOWARDS PHONON INDUCED CONDUCTIVITY OF POLYACETYLENE
A potentially innovative paper based on simple arguments is published7. In their paper, they
introduce implicitly even if unconsciously the concept of what will be called "solitons" 18 years later.
Instead of considering singlet polyacetylenes with even number of carbon atoms, they investigate the
electronic structure of the radical defect that will appear if the chain has an odd number of carbon
atoms.
Taking into account the Coulson-Rushbrooke theorem that states that, in an alternant system, the
Hckel -molecular orbitals of non-zero binding ( 0) pair (conjugate MO's) with opposite energies,
they observe that, in an odd polyacetylene chain, a non-bonding state should appear in the middle of the
energy gap:
...-CH=CH-CH=CH-CH.-CH=CH-CH=CH-CH=CH-...

As far back as 1962, Pople and Walmsley suggested we cite - that such unpaired electrons may be
detectable by electron spin resonance. The defect is able to travel through the molecule since its motion
depends only on a small displacement of one carbon atom.
It is clear that if we complement Pople & Walmsley conclusions by the idea of oxidative or
reductive doping, a first order explanation of high electrical conductivities would emerge including the
three striking experimental observations that will be made 15 years later:
1) a conductivity without spin,
2) a red shift of the first electronic transition under doping,
3) an increase of conductivity with temperature.
That idea will be largely developed in the Su, Schrieffer and Heeger (SSH) theory8. It is astonishing
that the SSH paper does not make an explicit reference to the Pople and Walmsley paper (even if there
is an indirect reference to the classical Salem's book9 on conjugated systems that contain an entire
chapter describing in detail Pople & Walmsley arguments. Also astonishing, is the fact that the
detection by ESR of Pople & Walmsley radical defects has been experimentally observed as soon as
196310. But the paper has been written in French during the greatness of de Gaulle's France and has not
received the diffusion it would have deserved.

The discovery in the late 1970s that doped organic polymers display high electrical conductivity
generated a substantial renewed research interest in the electronic structure of conjugated chains among
physicists and chemists alike.
On the theoretical side, an important consequence has been to draw attention to the vibrational
properties and force the development of efficient techniques for computing matrixelements of
differential operators and opening the interpretation of many spectroscopies and nonlinear optical
properties.

TOWARDS EFFICIENT AB INITIO PROGRAMS FOR POLYMERS

The first theoretical works on LCAO (Tight binding) techniques in polymer quantum chemistry
have been developed in the sixties11. Since then, the field has known a rapid development. An obvious
fact is that the interest of precise calculations of band structure has been of a direct efficiency in the
analysis of spectra obtained by the new Electron Spectroscopy for Chemical Analysis (ESCA) now
known as XPS that become generalized at the end of the sixties. Important successes haven been
obtained at that time in the understanding of the electronic band structure of polymer like
polyethylene12.
In the nineties, ab initio programs for polymers were developed and currently appplied in several
groups like Erlangen, Vienna, Budapest, Torino, Kingston and Namur, a common property being that
almost all polymer packages used standard "molecular" strategies taken from the historical IBMOL,
KGNMOL, GAUSSIAN or other series. In the nineties due to the need of having more realistic
computing time and of including more correlation effects, the strategy became more "polymer-minded"
than "molecule-minded" as exemplified by the works made in Namur, Gainesville or Torino (among

111
others). These algorithms have been mainly used for the 
     
  


  
 
 
 
  
 
  
    
   
  
    
 

 

    
  
   
 
 
  


TOWARDS TECHNOLOGIES BASED ON ORGANICS: OLED'S, AND

PHOTOVOLTAIC CELLS
Applications that are now spectacularly benefiting from the help of quantum chemistry are OLEDs
(Organic Light Emitting Diodes), photovoltaic cells and molecular sensors, among others. In Organic
LEDs, that have recently entered the market as elements of video displays, electrons and holes are
injected at the sides of a metal-organic interface and move in opposite directions under the effect of the
external electric field. When close enough, they recombine and form excitons (singlet or triplet). When
the excitons decay radiatively, the will emit light that can escape from the device.
The process is somewhat the opposite in Photovoltaic cells. Light is absorbed to form an exciton.
The exciton will migrate to the interfacial region between organic components. By electron transfer
between the donor and acceptor organics, the charges separate, move and are collected at the electrodes.

  


 



  

   !"#$%  
 

       
  &
  

 






 
It is clear from the previous few lines that theories of energy-transfer and of ET (Electron Transfer)
play now a major role in explaining phenomena and are now added to the arsenal of theoretical
methodologies besides the traditional quantum chemical techniques14.

CONCLUSIONS
The main conclusion is that the success of "a quantum chemistry applied to polymers" is due to a
close interconnection between analytical and computational approaches. We have tried to demonstrate
that we need to take into account electron-phonon interactions. In other terms, there exists now a timely
need to include translational, rotational, vibrational contributions and non-adiabatic approaches in our
models. Then the road will be open to complete nonequilibrium interpretations of the electronic
properties of macromolecules15.

ACKNOWLEDGMENTS
We thank Professor Enrico Clementi for his invitation to organize a session in TACC 2012 devoted
to Polymers. Our career has been dominated by our interactions Enrico Clementi by our various
sabbatical leaves in IBM San Jose (1968-69), in IBM Poughkeepsie (1983), in CRS4 Cagliari (1992)
and by many exchanges. We also thank the four speakers of this session who will develop in more
details some of the aspects presented in this overview: Profs. J.-L. Brdas (Georgia Tech. Institute), G.
Heimel (Humboldt U.), So Hirata (U. of Illinois), and C. Zannoni (U. Bologna).

REFERENCES
1. H. Kuhn, J. Chem. Phys., 17, 1198 (1949).
2. F.X. de Charentenay, P. Castel and Ph. Teyssi, Revue de l'Institut franais du ptrole, XVIII, 1226 (1963).
3. J.M. Andr, L. Gouverneur and G. Leroy, Bull. Soc. Chim. Belges, 76, 661 (1967).
4. J.M. Andr and G. Leroy, Theoret. chim. Acta (Berl.), 9, 123 (1967)
5. A. Pullman, R. Daudel, C. R. Acad. Sc., 222, 288 (1946).
6. R. Srinivasan, J. Am. Chem. Soc. 85, 4045 (1963).

112
7. J.A. Pople and S.H. Walmsley, Molec.Phys. 5, 15 (1962).
8. W.P. Su, J.R. Schrieffer, and A.J. Heeger, Phys.Rev., B22, 2099 (1980).
9. L. Salem, The Molecular Orbital Theory of Conjugated Systems, W.A. Benjamin, Inc., see p.521 and sq.
10. M. Nechstein, J. Polymer Sci. C1, 1367 (1963)
11. see, for example : J. Ladik, Acta Phys. Hung., 18, 173 (1965); J. M. Andr, L. Gouverneur and G. Leroy, Int. J.
Quant. Chem. 1, 427 (1967); G. Del Re, J. Ladik and G. Biczo, Phys. Rev., 155, 997 (1967); J. M. Andr, J.
Chem. Phys., 50, 1536 (1969).
12. J. Delhalle, J.M. Andr, S. Delhalle, J.J. Pireaux, R. Caudano, J.J. Verbist, J. Chem. Phys., 60, 595 (1974).
13. J.L. Brdas, B. Thmans and J.M. Andr, Phys. Rev. B26, 6000 (1982); J.L. Brdas, B. Thmans and J.M.
Andr, Phys. Rev. B27, 7827 (1983); J.L. Brdas, B. Thmans, J.G.Fripiat, and J.M. Andr, R.R. Chance, Phys.
Rev. B29, 6761 (1984).
14. see, for example, J.L. Brdas, D. Beljonne, V. Coropceanu, and J. Cornil, Chem. Rev. 104, 4971 (2004).
15. see, for example, J.M. Andr, Chaos and chemistry: simple models to understand chaos in chemistry, in the
series Theoretical and Computational Chemistry, Vol. 15: Computational Materials Science, J. Leszczynski,
Ed., Elsevier (2004); J.M. Andr, In Silico Chemistry, past, Present and Future, in Fundamental World of
Quantum Chemistry, A Tribute to the Memory of P.O. Lwdin, Vol. 3, E. Brands and E. Kryachko, Eds.,
Kluwer (2004).

113
 Beyond NICS
Stefano Pellonia, Guglielmo Monacob, Riccardo Zanasib, and Paolo Lazzerettia
a
Dipartimento di Chimica dell'Universit degli Studi
di Modena e Reggio Emilia
via G. Campi 183, 41100 Modena, Italy
email: stefano.pelloni@unimore.it, lazzeret@unimore.it

b
Dipartimento di Chimica dell'Universit degli Studi di Salerno
via Ponte don Melillo, 84084 Fisciano (SA), Italy
email: gmonaco@unisa.it, rzanasi@unisa.it

Abstract. A ring current model describing the flow of delocalized electrons, induced in unsaturated molecules by a
magnetic field perpendicular to the molecular plane, has been developed to define simple and practical indices of
current strength, which provide a reliable measure of aromaticity on the magnetic criterion. Comparison with
corresponding ab initio estimates of current strength for a series of aromatic and antiaromatic systems is used to assess
the quality of the proposed indices, which are shown to be preferable to others currently used, e.g., out-of-plane
components of magnetizability, , and NICS. It is also shown that these quantities are both biased by spurious
geometrical parameters, which limit their practicality. In particular, NICS depends on the inverse of the ring radius and
it does not provide acceptable magnetotropicity scales.
Keywords: magnetotropicity criteria, ring current models, magnetizability, nucleus-independent chemical shift, current
susceptibility.
PACS: 33.15.-e; 33.15.Kr;82.56.-b

INTRODUCTION
The precise definition of an indisputable yardstick of aromaticity, based on a limited number of essential
features, and universally accepted by the chemical community, is not yet available. A number of quantitative
aromaticity indices have been proposed: aromatic stabilization energies (ASE),1 harmonic oscillator model of
aromaticity (HOMA),2 unified index,3 topological resonance energy (TRE),4 etc.
Many chemists prefer magnetic criteria. Definitions of magnetic aromaticity, or diatropicity, are related to the
ability of an unsaturated ring to sustain a diamagnetic -electron ring current in the presence of a uniform magnetic
field perpendicular to the molecular plane. The basic inference is that aromaticity is equivalent to cyclic
delocalization and mobility of -electrons. Currently used magnetotropicity quantifiers are magnetic susceptibility
exaltation,5 out-of-plane magnetizability and magnetizability anisotropy,6 and nucleus-independent chemical shift
(NICS)7. Connections between the various aromaticity benchmarks have been established8 and the possibility that
aromaticity is a multidimensional phenomenon has also been contemplated.9
Failure to recognize the tensor character of magnetic response properties has caused widespread
misunderstanding. All that one actually need is a ring current model to rationalize the out-of-plane component of
magnetic tensors, as shown hereafter. Only this component is affected by currents of delocalized - and -electrons,
induced in planar unsaturated systems by a magnetic field orthogonal to the molecular plane.
A crucial computer experiment which demonstrates that isotropic properties are unsafe measures of
magnetotropicity was made in the cyclopropane molecule,10,11 sometimes considered a strongly -aromatic system
on the basis of huge calculated average NICS(0) at the center of mass.12 In fact, the trace of the NICS tensor is
mainly biased by very large in-plane components xx=yy., as big as 50.9 ppm. The out-of-plane zz=, that is, the
unique tensor component affected by delocalized -ring currents induced by a magnetic field at right angles to the
molecular plane, is much smaller, 32.7 ppm. Then the huge isotropic value NICS(0) = av, with av=
(1/3)(xx+yy+zz) = (1/3)(50.92+32.7)=44.9 ppm, depends on mechanisms different from ring currents, as shown
later.11
The conclusion arrived at from this example is unequivocal: the isotropic NICS(0) cannot be used as a reliable
index of magnetotropicity in general. One could possibly adopt only the out-of-plane NICS as a measure of

Theory and Applications in Computational Chemistry: The First Decade of the Second Millennium
AIP Conf. Proc. 1456, 114-118 (2012); doi: 10.1063/1.4730650
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114
magnetotropicity.13 Nonetheless, most recent findings prove that also NICS is unsafe. It does not work as a
reliable magnetotropicity measure, either for planar conjugated hydrocarbons CnHn with Dnh symmetry, or inorganic
unsaturated cyclic molecules.14,15
The present study adds further evidence on the inadequacy of NICS, on the basis of an extended comparison
with current susceptibilities calculated ab initio.15-19 More practical and easy-to-evaluate indices of - and -current
strength, deduced from a simple ring current model (RCM), are proposed as magnetotropicity quantifiers.

dB
90

h
uR
ur

ur X uR

FIGURE 1. On the left: the element of magnetic field induced by an element of diatropic current density, i.e., flowing
clockwise in a circular loop. On the right: the paratropic -ring currents above and below the molecular plane of flattened C8H8.
Red(blue) arrows denote ascending (descending) currents.

RING CURRENT MODEL

We consider an infinitely thin and perfectly circular conducting loop with radius s and area A= s2, supporting a
current with intensity I=IBBext, induced by an external magnetic field Bext orthogonal to the loop, see Fig. 1. The
magnetic dipole at right angles to the loop is given by
m = Bext = I B Bext A, (1)
B
where the current susceptibility I is positive/negative for clockwise/anticlockwise flow. The element of magnetic
field, generated via a feed-back effect by an element of electronic current density induced by Bext, is calculated by
the RCM represented in Fig. 1, relying on the Biot-Savart law of classical electrodynamics.14,15 The out-of-plane
component of the central shielding tensor, for any point P at distance h from the plane of a cyclic unsaturated
molecule sustaining a current flowing through the thin circular loop with radius s, is given by14,15
0 0 I Bs2
(h) = = . (2)
2 ( s 2 + h 2 ) 3 / 2 2 ( s 2 + h 2 )3 / 2

Quite remarkably, eqs. (1) and (2) show that and (h) both depend on the loop radius s. Eqs. (1) and (2) can
be used to obtain two different estimates of the current susceptibility:

I sB = (3)
s 2
and
2 (0) s
I sB NICS = . (4)
0

115
The current susceptibility is a measure of the strength of the ring current flowing in the delocalized electrons of a
cyclic unsaturated molecule. Although such a quantity is not experimentally accessible, it can possibly be used as a
quantitative index of aromaticity/anti-aromaticity on the magnetic criterion with higher confidence than NICS(0)
and NICS(h). In fact, it is independent of molecular geometrical parameters, whereas , as shown by eq. (1),
depends on the area A of the current loop,14 and NICS(0)= (0) at the ring center depends on the inverse of the
loop radius s according to eq. (2). The RCM in Fig. 1 can be empirically checked by a logarithmic plot of (h)
values calculated ab initio14
3
log (h) = log( s 2 + h 2 ) + log K (5)
2
for h >> s, where the intercept
0
K = (6)
2
is negative for diatropic compounds. An analogous relationship is used for paratropic systems. For a series of neutral
and charged unsaturated cyclic hydrocarbons CnHn one finds a virtually linear behavior (i.e., Bravais correlation
coefficient very close to 1), with the correct slope 3/2, for points P at h within a certain hmin-hmax range of values.
In most cases good agreement was observed between ab initio (calc) values and corresponding (graph) from
the intercept in eq. (6), see Table 1.
Eqs. (3) and (4) are exact for a single loop of radius s. In the presence of many concentric loops of different
radii, and placed at different heights, they can only be heuristically accepted. The existence of several loops makes
the effective average radius sav different from the geometric radius s, and in a different way for different properties.
If one imposes equality of Eqs. (3) and (4), it is possible to define an effective average loop radius
1
3
s av = 0 , (7)
2 (0)

which can be expected to provide an improved definition of current susceptibility,

1
2sav (0) 4 2 (0) 3
IB NICS = = = . (8)
sav2 0 02

RESULTS OF THE CALCULATIONS

The practicality of the simple RCM in Fig. 1, based on the classical Biot-Savart law, was tested for -electron flow
in aromatic and anti-aromatic CnHn hydrocarbons with Dnh symmetry, and in a few inorganic cyclic molecules, P6 ,
N6 , Si6H6, B3H6N3, and B3H3O3. The H6 ring was studied for -ring currents. Large basis sets of gaugeless Gaussian
functions were used, within the continuous-translation-of-the-origin-of-the-current-density-diamagnetic-zero
(CTOCD-DZ) procedure.14,15 The results of the calculations are reported in Table 1. For CnHn hydrocarbons, the
RCM in Fig. 1 was tested at the coupled Hartree-Fock (CHF) level of accuracy, employing a (13s10p5d2f/8s4p1d)
basis set to optimize molecular geometries and to evaluate via the SYSMO package20 the -contribution to the out-
of-plane magnetizability and to the out-of-plane component of the central shielding for points P at distance h from
the origin.
As can be seen in Table 1, the estimates of the current susceptibility I sB and I sB NICS , both defined within the
common assumption of current flow along a single circle of radius s containing the ring atoms, are quite far from
the ab initio values. However it is interesting to note that they give upper and lower bounds,respectively, to the ab
B
initio values. Therefore, it is not surprising that the estimate I NICS gives a significantly better fit, with a decrease
of more than ten percent points in the average deviation from I(ab initio).

116
 TABLE 1. Results of the calculations in SI units.

molecule (0) (calc) sgeo sav (graph) I sB I sB NICS IB NICS I ( abinitio)

C3H3+ 14.6 9.4 0.78 1.09 11.8 4.9 1.8 2.5 4.0
C4H42+ 14.1 13.7 1.02 1.25 16.3 4.2 2.3 2.8 4.0
C4 H 4 55.8 33.3 1.02 1.06 45.9 10.2 9.1 9.4 15.6
C4H42 31.8 62.9 1.02 1.58 68.9 19.2 5.2 8.0 10.4
C5H5 36.9 77.2 1.20 1.61 71.2 17.1 7.0 9.5 11.6
C6 H 6 37.2 89.8 1.40 1.69 98.7 14.6 8.3 10.0 11.7
C7H7+ 36.0 111.0 1.61 1.83 108.7 13.6 9.2 10.5 12.1
C8H82+ 34.6 135.0 1.81 1.98 130.3 13.1 10.0 10.9 12.3
C8 H 8 27.4 163.0 1.83 2.28 155.4 15.5 8.0 10.0 18.3
C8H82 50.8 267.0 1.85 2.19 243.0 24.8 15.0 17.7 19.5
C9H9 50.5 306.0 2.03 2.30 305.3 23.6 16.3 18.5 19.9
C10H10 47.7 358.0 2.24 2.47 350.4 22.7 17.0 18.7 20.1
B3H6N3 4.5 28.2 1.42 2.32 19.0 4.5 1.0 1.7 1.9
B3H3O3 1.4 16.8 1.36 2.88 11.0 2.9 0.3 0.6 1.6
P6 26.7 170.5 2.08 2.34 170.5 12.5 8.8 9.9 11.7
N6 41.4 63.0 1.28 1.45 65.9 12.2 8.4 9.5 10.6
N42 35.1 41.2 0.95 1.33 41.1 14.5 5.3 7.4 9.4
2
Al4 7.7 55.3 1.82 2.44 73.0 5.3 2.2 3.0 4.6
Si6H6 24.5 209.0 2.21 2.57 222.1 13.6 8.6 10.0 11.8
H6 68.2 59.6 0.98 1.20 48.1 19.8 10.6 13.1 12.6
%Av. 35 36 21
Error

(0), in ppm, is the -electron (-electron for H6) contribution to the out-of-plane component of the magnetic shielding at the
center of mass, calculated ab initio. The loop radii s, and sav from eq. (7), are in m 1010. For all the compounds except H6,
sustaining -electron currents, (calc), in JT2 1029 , is the contribution of the -electrons to the out-of-plane component of
the magnetizability, calculated ab initio. (graph) is obtained from the logarithmic plot, eqs. (5) and (6). Estimates of in nA/T,
calculated via eqs. (3), (4) and (8) are compared with IB(ab initio) in the last column.

CONCLUSIONS

The practicality of a simple -ring- current model based on the classical Biot-Savart law was proven for neutral
and charged aromatic and anti-aromatic CnHn hydrocarbons and a few inorganic cyclic molecules with Dnh
symmetry, in the presence of a magnetic field orthogonal to the molecular plane. The same classical tool can be used
to explain the effects of delocalized -electron currents in H6, the cyclic arrangement of three hydrogen molecules.
The RCM proposed in Fig. 1 shows that (h), the out-of- plane component of the magnetic shielding at points
along the circuit axis, at large distance h from its center, is linearly related to , the out-of-plane component of the
magnetizability tensor. This result can be used to rationalize NICS scan profiles by eq. (2). The current

117
susceptibility IBNICS defined by eq. (8) gives a simple and reliable magnetic criterion for aromaticity and antia-
aromaticity, much easier to evaluate than the corresponding quantity obtained ab initio. Satisfactory, and sometimes
good, agreement between IBNICS and IB(ab-initio) estimates has been found for the molecules studied. These quantities,
measured in nA/T, are independent of geometrical structure, whereas other popular magnetic indicators of
aromaticity are strongly biased by molecular geometry, which severely limits their ability to define quantitative
scales. In particular, depends on the loop area, whereas NICS is an inverse function of the loop radius.
The failure of NICS to provide a realistic description of magnetotropicity is demonstrated by comparing results
reported in Table 1. For instance, on the basis of NICS, aromaticity would increase in the series C8H82+, C7H7+,
C6H6 , whereas IBNICS and IB(ab-initio) increase in the opposite order. Other inconsistencies between NICS and current
susceptibility scales are observed for CnHn hydrocarbons.
Quite surprisingly, on the NICS criterion, P6 and Si6H6 would be less -diatropic than benzene. In effect, they are
only bigger than C6H6, whereas the current strength measured by IBNICS and IB(ab-initio) is comparable in the three
cyclic systems. An analogous comparison of N6 with benzene documents a further failure. The -contribution to the
central shielding (0)=41.4 ppm of N6 is bigger than that of C6H6, 37.2 ppm, then, on the NICS criterion, the
former would be more -diatropic than the latter. But this only a geometrical effect, since, as shown by eq. (2), (0)
values are inversely proportional to the ring radii sgeo and sav reported in Table 1, which are smaller for N6. As a
matter of fact, both IBNICS and IB(ab-initio) current strengths are bigger for benzene. Therefore, we are fully confident
that the current susceptibility is the most reliable quantifier of magnetotropicity available so far, and believe that the
unsafe NICS indicator should be abandoned.

ACKNOWLEDGMENTS
Financial support to the present research by the Italian MIUR via PRIN funds is gratefully acknowledged.

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6. W. H. Flygare, Chem. Rev. 1974, 74, 653-687 (1974).
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6317-6318 (1996).
8. M. Cyraski, T. M. Krygowski, A. R. Katrizky and P. von Ragu Schleyer, J. Org. Chem. 67, 1333-1338 (2002).
9. K. Jug and A. M. Kster, J. Phys. Org. Chem. 4, 163-169 (1991).
10. S. Pelloni, P. Lazzeretti, and R. Zanasi, J. Phys. Chem. A 2007, 111, 8163-8169 (2007).
11. R. Carion, B. Champagne, G. Monaco, R. Zanasi, S. Pelloni, and P. Lazzeretti, J. Chem. Theory Comput. 6, 2002-2018
(2010).
12. D. Moran, M. Manoharan, T. Heine, and P. von Ragu Schleyer, Org. Lett. 5, 23 (2003).
13. P. Lazzeretti, Phys. Chem. Chem. Phys. 6, 217-223 (2004).
14 S. Pelloni and P. Lazzeretti, J. Phys. Chem. A 115, 4553-4557 (2011).
15. S. Pelloni, G. Monaco, P. Lazzeretti, and R. Zanasi, Phys. Chem. Chem. Phys.13, 20666-20672 (2011).
16. H. Fliegl, D. Sundholm, S. Taubert, J. Juslius and W. Klopper, J. Phys. Chem. A, 113, 86688676 (2009).
17. G. Monaco and R. Zanasi, AIP Conf. Proc., 2009, 1148, 425428 (2009).
18. G. Monaco, R. Zanasi, S. Pelloni and P. Lazzeretti, J. Chem. Theor. Comput. 6, 33433351 (2010).
19. H. Fliegl , S. Taubert , O. Lehtonen and D. Sundholm, Phys. Chem. Chem. Phys. 13, 20500-20518 (2011).
20. P.Lazzeretti, M. Malagoli, and R. Zanasi, Technical Report on Project Sistemi Informatici e Calcolo Parallelo, Research
report 1/67, CNR, Rome (1991).

118
 Semiclassical Instanton Theory of Nonadiabatic
Reaction Rate Constant. I. Formulation
Yoshiaki Teranishia , Hiroki Nakamurab and Sheng H. Linb
a
Institute of Physics, National Chiao Tung University,
1001 Ta Hsueh Rd., Hsinchu, 30010 Taiwan,
b
Institute of Molecular Science, National Chiao Tung University,
1001 Ta Hsueh Rd., Hsinchu, 30010 Taiwan,

Abstract
The reaction rate constant of electronically nonadiabatic chemical reactions is for-
mulated by extending the semiclassical instanton theory of adiabatic chemical reaction
with use of the Zhu-Nakamura theory of nonadiabatic transition. The instanton tra-
jectory at a given temperature can be searched eciently by the method used for
multi-dimensional tunneling splitting. A compact expression of the rate constant ap-
plicable to multi-dimensional systems is derived.

Keywords: nonadiabatic transition, reaction rate, semiclassical theory, instanton.

PACS: 02,33,34,82

1 INTRODUCTION
The thermal reaction rate constant is an important quantity in chemistry, and there is a
long history of theoretical investigation of the direct evaluation of the rate constant since
the pioneering works done by Eyring and Wigner [1, 2]. This kind of classical transition
state theory (TST) based on the thermal activation has been tried to be improved by many
investigators by including the recrossing and quantum mechanical tunneling eects. See,
for instance, the following review articles [3, 4, 5, 6]. The importance of the periodic orbit
or the instanton trajectory in the formulation of rate constant was recognized and the
semiclassical instanton approach was developed in chemical physics [7] and quantum eld
theory [8]. This semiclassical instanton approximation has been employed in various elds
such as tunneling splitting in polyatomic molecules and decay of metastable states, etc
(see [5, 9] and literatures therein). A certain generalization was discussed by Cao and Voth
to smoothly connect the low- and high-temperature regimes and to include the eects of
bath by using the path integral centroid approach [10, 11]. Quantum instanton theory has
also been formulated by Miller and coworkers and various applications to practical systems
have been performed [12, 13]. Furthermore, recently, the semiclassical instanton approach
has been revisited by Kryvohuz and a compact analytical expression of the reaction rate
constant has been derived [14].

e-mail:nakamura-1624@kba.biglobe.ne.jp
Theory and Applications in Computational Chemistry: The First Decade of the Second Millennium
AIP Conf. Proc. 1456, 119-130 (2012); doi: 10.1063/1.4730651
2012 American Institute of Physics 978-0-7354-1057-2/$30.00

119
 It should be noted that the above mentioned theories are valid for electronically adi-
abatic chemical reactions, namely, for chemical reactions on a single adiabatic potential
energy surface. As for electronically nonadiabatic chemical reactions, one typical example
of which is electron transfer process between molecules [15, 16, 17], not many works have
been done so far to formulate a general theory for directly evaluating the reaction rate con-
stants beyond the perturbative treatment of electronic coupling. Voth and coworkers [18]
have developed a computational methodology to evaluate rate constant including the ef-
fects of bath by using the Pechukas type treatment of nonadiabatic transition based on the
diabatic state representation [19]. Okuno and Mashiko formulated an expression of rate
constant by using the Landau-Zener formula at the minimum energy crossing point [20]. A
nonadiabatic version of transition state theory for unimolecular reactions was developed by
Marks and Thompson by using the phase space ensemble and the Landau-Zener formula
in the diabatic state representation [21]. This was applied to bond ssion processes in
bromoacetyl chloride [22]. Topaler and Truhlar studied nonadiabatic decay rate of excited
complex in scope of statistical model [23]. Nakamura and coworkers [24] have formulated a
nonadiabatic transition state theory by using the Millers general formula of the ux-side
correlation function [25] and the Zhu-Nakamura theory of nonadiabatic transition which
gives accurate analytical formulas for nonadiabatic transitions [26]. They have applied it
to electron transfer and are successful to improve the celebrated Marcus formula by uni-
formly covering the whole range of electronic coupling strength [27]. The Zhu-Nakamura
theory is a one-dimensional theory, but can be used usefully in multi-dimensional systems
along classical trajectories.
There have been proposed various simulation methods to deal with nonadiabatic pro-
cesses (see, for instance, [26, 28]). The simplest ones are the trajectory surface hopping
methods such as the fewest switches trajectory surface hopping method [29, 30] and the
ZN-TSH (Zhu-Nakamura trajectory surface hopping) method [31, 32]. A bit more sophis-
ticated ones to include the eects of phases are ZN-HKSCIVR (Zhu-Nakamura Herman-
Kluk Semiclassical Initial Value Representation) method [33] and the spawning method
developed by Martinez and coworkers [34]. It should be noted that these methods are
not for evaluating the rate constants directly. It should also be noted that only the Zhu-
Nakamura theory can treat classically forbidden transitions properly analytically in which
the potential surface crossings are located below the total energy of the system.
In this paper we formulate a compact expression for the nonadiabatic reaction rate con-
stant. Since the nonadiabatic chemical dynamics would open up a new signicant branch
of chemical dynamics not only in the sense to comprehend the dynamics occuring in Nature
but also in the sense to control the dynamics and to manifest new molecular functions [35],
a compact formulation of the nonadiabatic chemical reaction rate constant would be quite
useful. Being stimulated by the semiclassical instanton approach developed by Kryvohuz
[14], we generalize his idea to nonadiabatic processes. The instanton trajectory is dened
by including the eects of nonadiabatic transition and is searched by using the method
devised by Milnikov and Nakamura to treat tunneling splitting in a symmetric double well
potential in general polyatomic molecules [9]. Furthermore, the analytical Zhu-Nakamura
formulas of nonadiabatic transitions are incorporated. This theory can cover a wide range
of energy from deep tunneling to high energy above the crossing point. In this paper the
so called nonadiabatic tunneling type of crossing in which two diabatic potential surfaces
cross with the opposite signs of slopes is treated. This paper is organized as follows. In

120
the next Section 2, the semiclassical instanton theory is reviewed with an application to
nonadiabatic processes kept in mind. Section 3 presents the formulas of Zhu-Nakamura
theory appropriate for the nonadiabatic tunneling type transition. Section 4 describes our
formulation of the nonadiabatic reaction rate constant. This includes the formulation of
the rate constant, the denition of instanton trajectory, and the practical method to nd
it. Concluding remarks are given in Section 5.

2 SEMICLASSICAL INSTANTOIN THEORY

By following the work by Kryvohuz [14], the semiclassical instanton method is explained.
The rate constant k is expressed as follows under the assumption that the imaginary part
of the energy is small,
2 2 ImQ
k = ImF = , (2.1)
h
h ReQ

where = 1/(T ), and F and Q are the Helmholtz free energy and the partition function,
respectively. As usual, by introducing the imaginary time t by
t = i
h i , (2.2)
the partition function Q is rewritten as
  
H H iHt/
h
Q = Tr(e )= dx < x|e |x >= dx < x|e |x >= D[x( )]eS[x( )]/h ,
(2.3)
where D[x( )] represents the path integral and the action S[x( )] is dened in terms of
the inverted upside-down potential V (x) as
 h 
 dxn 
S[x( )] = ( )2 + V [x( )] d, (2.4)
0 2 n d
where is the mass. Here we should note that the potential V (x) is the nonadiabatic
tunneling type as shown in Fig.2.1.
There are two solutions of the stationarity condition of the action, S = 0. One is
the trajectory sitting on the maximum of the inverted potential which gives the partition
function Qr of the reactant which is equal to ReQ, and the second solution provides the
instanton trajectory. Thus we have
1 2
k= Im[Q(xinst )], (2.5)
Qr
h
where xinst is the instanton trajectory. In the case of N dimensional system, the instanton
trajectory X( ) denes one-dimensional path and the transversal displacements along the
instanton dene (N 1)dimensional space Y( ). The action S is thus expressed as
 h 
   h 

dX 2 dYn 2 
S (
) + V [X( )] d + nm ( ) + Vnm [X( )]Yn Ym d (2.6)
0 2 d n,m 0 2 d

The contribution of the transversal mode to the partition function is given by [14]
N 1 1
, (2.7)
n=1 2sinh(n /2)

121
 (x)

E()

(x)

xt xb x

FIGURE 2.1: Nonadiabatic Tunneling type of potential

where exp(n )(n = 1 N 1) are the eigenvalues of the 2N 2N monodromy matrix

R2N (h) which satises the following dierential equation along the instanton trajectory:
d
R2N + F( )R2N = 0 (2.8)
d
with  
0 1/
F( ) = 2V (2.9)
xn xm 0
and
R2N ( = 0) = 1. (2.10)
In the case of harmonic potential, n is explicitly given by

n = hn , (2.11)

where n are the harmonic frequencies of transverse degrees of freedom along the instanton
trajectory. R2N has two more eigenvalues corresponding to the zero stability parameter
= 0. Now, the rate constant k is expressed as

2
k= Im D[x( )] exp[ Sef f [x( )]/
h], (2.12)
hQr
where  h 
dX 2 
Sef f = (
) + V [X( )] d + [X( )] (2.13)
0 2 d

122
with
N
 1
[X( )] = h ln[2sinh(n [X( )]/2)]. (2.14)
n=1
Sef f
The instanton trajectory Xinst ( ) is determined from the condition X = 0 as
  2X V ( )  h  n

+ d + coth(n /2) = 0. (2.15)
0 2 X 2 n X
The last term introduces additional potential and the overall eective one-dimensional
potential is given by
1
Vef f (X) = V (X) + hn [X( )],
(2.16)
2 n
where n [X( )] are harmonic frequencies of the transverse degrees of freedom along the
instanton trajectory. The instanton energy E() is obtained from
Sef f
E() = . (2.17)

This formulation corresponds to the improved second approximation of semiclassical in-
stanton in Ref.[14]. In the actual applications to nonadiabatic processes, we employ the
simpler rst approximation [14] in which the instanton is determined by the rst term of
Eq.(2.15) (Gutzwiller approximation), namely by
2X V ( )
+ = 0. (2.18)
2 X
In this approximation n depends only on the instanton determined by this condition,
n [X( )] = n [Xinst ( )] = n ( ), (2.19)
and thus
[X( )] = ( ). (2.20)
We use this rst approximation, simply because it is much simpler than the second one
and the improvement by the latter was found to be only slight [14]. It should be noted,
however, that in the case of present nonadiabatic process, the eects of nonadiabatic tran-
sition, namely, the nonadiabatic transition probability and the dynamical phase [X( )],
should be added to Sef f (see next section). Once the instanton trajectory Xinst ( ) and
the eective one-dimensional potential Vef f (Xinst ) are determined, the rate constant is
calculated from the one-dimensional transmission ux f through this eective potential
as
kQr = Qtrans f (2.21)
with
N 1 1
Qtrans =  , (2.22)
n=1 1
2sinh 2 n ()

where Qtrans is the contribution from the transverse degrees of freedom (see Eq.(2.7)).
In the case of nonadiabatic process, this transmission ux f is calculated from the Zhu-
Nakamura formula for the nonadiabatic tunneling type transmission probability, as ex-
plained in the next section.

123
3 ZHU-NAKAMURA THEORY OF NONADIABATIC
TUNNELING TYPE TRANSITION
Nonadiabatic tunneling type potential system is the one shown in Fig.2.1 in which the lower
adiabatic potential E1 (x) has a barrier. It should be noted that transmission through
this lower adiabatic potential is aected by the nonadiabatic coupling with the upper
adiabatic potential E2 (x). This potential system corresponds to the Marcuss normal
case in electron transfer. The semiclassical Zhu-Nakamura theory provides a whole set of
analytical formulas of transition amplitude including phases which can be used whatever
the coupling strength is (see Ref.[26]). Here we present the formulas of transmission
probability which can be directly employed in the present instanton approach. All the
formulas are given in terms of adiabatic potentials. The expressions in the adiabatic state
representation are generally more accurate than those given in the diabatic representation.
The basic dimensionless parameters a2 and b2 to characterize the potential crossing are
dened as (see Fig.2.1)
h2
(1 2 )
a2 = , (3.1)
(Rb Rt )2 (Eb Et )
and
E (Eb + Et )/2
b2 = , (3.2)
(Eb Et )/2
where is the mass and
Eb Et
= , (3.3)
E2 ([Rb + Rt ]/2) E1 ([Rb + Rt ]/2)

where Rt (Et ) and Rb (Eb ) are the positions (energies) of the potential top and bottom,
respectively (see Fig.2.1). When Rb = Rt , = 1 and the following denition of a2 should
be used:
h2  2 E (R) 2 E1 (R) 
2
a2 = | R=Rb | R=Rt . (3.4)
4(Eb Et ) R2 R2
When the diabatic potentials are available, then the following expressions, which are a
little bit less accurate than the above but are more convenient, can be used:

2 F (F1 F2 )
h
a2 = (3.5)
2 8VX3

and
F1 F2
b2 = (E EX ) , (3.6)
2F VX

where Fj (j = 1, 2) is the slope of the jth diabatic potential with F = |F1 F2 |, VX and
EX are the diabatic coupling and energy at the crossing point. Without loss of generality
F1 F2 can be assumed to be positive.
(1) At E Et , the overall transmission probability P is given by

B(c /)e2ZN
P (E) =  2 , (3.7)
0.5a 2ZN
1+ a+1 B(c /)e +B(c /)e2ZN

124
where
2
c = ZN (1 0.32 102/a eZN ) (3.8)
 T1r
ZN = |K1 (x)|dx, (3.9)
T1l


6 + 10 1 1/b4
ZN =
, (3.10)
16a|b| 1+ 1 1/b4
2x2x e2x
B(x) = , (3.11)
x2 (x)
and 
2
K1 (x) = [E E1 (x)]. (3.12)
h2

The parameters ZN and ZN represent the eects of tunneling and nonadiabatic tran-
sition, respectively. It should be noted that the factor eZN is equal to that of Gamov
and that the two eects of tunneling and nonadiabatic transition cannot be separated,
as is seen from Eq.(3.7). In the strong diabatic coupling limit, a2 0, the transmission
probability P of Eq.(3.7) goes to
e2ZN
P = , (3.13)
1 + e2ZN
which agrees with the ordinary single potential barrier penetration probability.
(2) At Eb E Et , we have
W2
P (E) = (3.14)
1 + W2
with 
A  t3 b2 B t
W = cos t 2/3 , (3.15)
a2/3 0 3 a2/3 a C + a1/3 t
where
0.38 2
A=1+ (1 + b2 )1.20.4b , (3.16)
a2
a 3b2

B= 1.23 + b2 , (3.17)
a+3
and

C = 0.61 2 + b2 . (3.18)
(3) At E Eb , the transmission probability P is given by
4 cos2 (ZN S )
P (E) = , (3.19)
4 cos2 (ZN S ) + (pZN )2 /(1 pZN )
where
 T2
ZN = K2 (x)dx, (3.20)
T1

0.23 a
S = S + 40ZN , (3.21)
a + 0.75

125
  

S = + ln arg i , (3.22)
4

5 a
= ZN (1 + 10ZN ), (3.23)
a + 0.8


6 + 10 1 1/b4
ZN =
, (3.24)
16ab 1+ 1 1/b4

and 
 2 1/2
pZN = exp
. (3.25)
4ab 1 + 1 b4 (0.72 0.62a1.43 )
Here pZN represents the nonadiabatic transition probability for one passage of avoided
crossing point.

4 RATE CONSTANTS OF NONADIABATIC

CHEMICAL REACTIONS
4.1 Reaction Rate Constant
In the case of the nonadiabatic process of our interest, the eective action Sef f of Eq.(??)
in the rst approximation should be replaced by
  
ND dX 2
Sef f [X( )] = ) + V [X( )] d + ( ) ln(1 pZN ) + D [X( )]
( (4.1)
0 2 d
with
D = 2hS , (4.2)
where ( ) is the contribution from the transverse degrees of freedom as before and
S is given by Eq.(3.22). The potential V (X) here represents the upside-down of E1 (x)
(see Fig.2.1). When the instanton trajectory runs through the avoided crossing along the
upside-down adiabatic potential E1 (x), the phase S called dynamical phase and the factor
ln(1 pZN ) which represents the transferability should be added. Actually, the transition
amplitude I11 for staying on the potential E1 (x) by one passage of the avoided crossing
point is given by (see Ref. [26]).

I11 = 1 pZN eiS , (4.3)

where pZN is given by Eq.(3.25). The instanton trajectory is determined from the condi-
tion,
ND
Sef f
= 0. (4.4)
X
When the instanton trajectory Xinst ( )( = 0 = ) is determined from this condi-
tion, the one-dimensional eective potential Vef f (Xinst ) is obtained for the given temper-
ature . Thus the original multi-dimensional problem is reduced to the one-dimensional
transmission through this eective potential along the instanton trajectory and the rate

126
constant is given by the corresponding transmission ux [14]. In the present nonadia-
batic transition case, this transmission ux is calculated by the Zhu-Nakamura analytical
formula and the rate constant k is nally given by

kQr = Qtrans fN D , (4.5)

where Qtrans is the contribution from the transversal degrees of freedom and is given by
(see Eq.(2.22))
N 1 1
Qtrans =  , (4.6)
n=1 2sinh 1 ()
2 n

and fN D is the nonadiabatic transmission ux as mentioned above and is given by


1
fN D = dEeE P (E). (4.7)
2h
Here we are considering the energy region E Et and thus the transmission probability
P (E) is given by Eq.(3.7). However, since the transmission probability expressions are
available also at higher energies E Et , the rate constant at these energies can be given
by the same expression as Eq.(4.5). Since the instanton trajectory shrinks to a point Xt ,
top of the potential barrier (see Fig.2.1), we have
N 1 1
Qtrans = , (4.8)
n=1 2sinh( 2 n )

where n are transverse frequencies at Xt . The ux fN D is the same as Eq.(4.7) with

P (E) given by Eqs.(3.14) and (3.19) for energies Et E Eb and E Eb , respectively.

4.2 Search of the Instanton Trajectory

There have been proposed several practical methods to search instanton trajectory [14,
36, 37, 38]. Here we employ our own method which was proved to be quite eective in
the applications to tunneling splitting in double well potentials of polyatomic molecules
[9]. The instanton trajectory is a periodic orbit starting from xi at = 0 and coming
back to the same position xi at = . The starting point xi corresponds to the turning
point T1l in Fig.2.1 at energy E(). At the half time = /2 it reaches the other turning
point xf which corresponds to T1r in Fig.2.1. Instead of using the time , we introduce
the following parameter z
1
z = (2 ), (4.9)

where = 0(x = xi ) [ = (x = xi )] corresponds to z = 1[z = 1]. The instanton
trajectory becomes a parametrized path and is expressed as
M

xn = xin + (1 z 2 ) Cln l (z), (4.10)
l=1

where l (z) are taken to be Legendre polynomials. The number M of necessary basis
functions is not large. Actually, in the case of tunneling splitting it was found to be

127
 20 to get 5-6 signicant digits of accuracy in the action even in the 21-dimensional
malonaldehyde. Then the action Sef N D is expressed as a function of {C , x }. It should be
f l i
noted that being dierent from the tunneling splitting case, the initial and nal positions
x ( = i, f ) are unknown and should be determined variationally. Although there is a
symmetry for = 0 /2 and = /2 and what we actually need is the half
period calculation from = 0 to = /2, as mentioned above, we have used the whole
range of from = 0 to = in order to reduce the number of unknown parameters.
The procedure to nd the instanton path for each temperature is as follows.
(1) Assuming certain initial values for D , {Cl }(l = 1, , , , M ) and xi , we calculate
approximate trajectory, instanton energy, nal position xf and avoided crossing point xc .
Then we can compute ( ) and D [X( )], and determine the zero-th order approximate
instanton trajectory.
(2) Using the previous results of {Cl , xi }, we apply the following variational principle.
Namely, for the variation

{Cl } {Cl + Cl } and xi xi + xi , (4.11)

we minimize the action

N D ({C }, x )
Sef f l i
=0 (4.12)
Cl
and
N D ({C }, x )
Sef f l i
= 0. (4.13)
xi
From this improved path, ( ) is calculated and the improved D [X( )] is obtained.
Then the improved instanton trajectory is determined. We repeat this procedure.
(3) If everything is converged within a predetermined accuracy, then the nal solution
is obtained. If not converged, we go back to the process (2).

5 CONCLUDING REMARKS
Considering the importance of nonadiabatic chemical dynamics [35], it is quite useful to for-
mulate a compact expression of the nonadiabatic reaction rate constant. The semiclassical
instanton theory developed by Kryvohuz [14] is extended so as to be applicable to nonadi-
abatic chemical reactions by using the Zhu-Nakamura theory of nonadiabatic transition.
The eects of nonadiabatic transition can be incorporated by using the analytical formulas
of nonadiabatic transition along the instanton path. The instanton-trajectory-searching
method developed before for the multi-dimensional tunneling splitting in symmetric dou-
ble well potential [9] is found to be useful also in the present problem, although extra
eort is required to determine the starting point of the trajectory at a given temperature.
The method was applied to the two-dimensional nonadiabatic tunneling type potential,
but can actually be applied also to the Landau-Zener type [26]. Numerical applications
to low dimensional systems in comparison with exact quantum mechanical calculations
will be reported in a separate paper in order to demonstrate the usefulness of the present
formula.
Since conical intersections of potential energy surfaces are ubiquitous and play im-
portant roles in chemical and biological systems, applications of the present method to

128
multi-dimensional real systems are very important and present a good subject for future
studies.

ACKNOWLEDGMENTS
We thank the support by The Academia Sinica. H. N. would like to express his sincere
thanks to the support by National Chiao Tung University that made him possible to carry
out this research.

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130
 QM/MM studies of gas-liquid collisional energy transfer
Xiaohu Li and George C. Schatza

aDepartment of Chemistry, Northwestern University, Evanston IL 60208-3113

Abstract. In this manuscript we describe a molecular dynamics method that has recently been developed to model
collisional energy transfer in collisions of hyperthermal gas-phase molecules with ionic liquid surfaces. This method is
based on a quantum mechanics/molecular mechanics (QM/MM) partitioning in which electronic structure methods are
used to determine forces for the hyperthermal gaseous molecule and molecules in the liquid which it directly interacts
with during the first 10 ps of the collision process, while empirical potentials are used for atoms in the liquid that are not
directly involved in interacting with the gaseous molecule. Collisions of the gaseous molecule with the liquid surface are
simulated using molecular dynamics methods, and from this it is possible to determine energy transfer associated with the
gas-surface collision, including scattering of the molecule from the liquid that leads to energy and momentum transfer,
and trapping of the gas molecule in the liquid. We illustrate this approach with an application to the collision of
hyperthermal CO2 with two ionic liquid surfaces: [bmim][BF4] and [bmim][Tf2N]. The results are used to model recent
experimental studies, and our analysis includes an examination of rotational and angular distributions associated with the
CO2 scattering, and the translational diffusion and vibrational relaxation of the trapped CO2.
Keywords: Ionic liquid, QM/MM, molecular dynamics, energy transfer, diffusion, hyperthermal, collisional energy
transfer.
PACS: 34.35.+a, 34.50.Ez, 68.03.-g, 68.03.Hj

INTRODUCTION

Molecular beam studies of the collisions of hyper-thermal gaseous atoms and molecules with room temperature
ionic liquids (ILs) have recently emerged as an effective tool for characterizing the structural and chemical
properties of the IL/vacuum interface. ILs are of great interest currently as a result of their many unique properties,
including low vapor pressure, high ionic conductivity, thermal stability, high viscosity, high solubility for many
substances of strategic importance (such as CO2), and they are being considered for applications to synthesis,
catalysis, fuel cells, photo-electrochemical cells, and as propellants. Common room-temperature ionic liquids
contain an organic cation and a weakly coordinating organic or inorganic anion, among which one of the most
investigated combinations is an imidazolium ring with alkyl chains attached to both ring N atoms and an anion
e.g., 1-alkyl-3-methylimidazolium combined with nitrate, tetrafluoroborate, hexafluorophosphate, or bis
(trifluoromethylsulfonyl) imide. FIGURE 1 shows the structures involved for the case of the [bmim] (b=butyl)
cation and [BF4] and [Tf2N] anions. The cations and anions can be substituted to adjust the chemical or physical
properties, and an important feature of ionic liquids is that there is often nano-structuring of the liquid in which the
alkyl portion of the cation form clusters. This extends to the surface of the IL in which the alkyl chain extends
preferentially out from the bulk.
The molecular beam studies of scattering from IL surface are possible because of their low vapor pressure and
because a variety of sources are now available which can prepare atoms and molecules with hyper-thermal (~eV)
energies. It is also convenient to use a rotating wheel structure to continuously refresh the IL as this means that the
molecular beam is always hitting a pristine surface. Recent examples of experimental studies have included
Mintons work on the collisions of hyperthermal Ar and O with the ionic liquid [emim][Tf2N]1 (e=ethyl) and studies
by Nesbitt of CO2 collisions with [bmim][Tf2N], [bmim][BF4] and other ILs.2-3 These studies, in combination with
theoretical interpretation obtained from molecular dynamics calculations with QM/MM (quantum mechanics/
molecular mechanics) methods3-5 have provided new insights concerning the structure of IL interfaces.
In the Ar + [emim][Tf2N] studies (which also included modeling of Ar+[emim][NO3]5), it was found that
complex but understandable chemistry occurs as a result of collisional energy transfer for Ar atom energies of 5 eV,
in which there is significant probability of proton transfer between the cation and anion in the liquid leading to
neutralized cations and then the neutralized anions evaporate from the liquid. When atomic oxygen is used instead of
Ar, the chemistry becomes even richer, including reactions such as hydrogen abstraction that are familiar from
combustion chemistry. In addition some of the reactions under these circumstances are unknown (too endothermic)
even at combustion temperatures, including CC bond cleavage and O atom addition/elimination reactions. And in
some cases hyper-thermal collisions induced reaction between cation and anion, such as nitrate addition to the

Theory and Applications in Computational Chemistry: The First Decade of the Second Millennium
AIP Conf. Proc. 1456, 131-138 (2012); doi: 10.1063/1.4730652
2012 American Institute of Physics 978-0-7354-1057-2/$30.00

131
imidazolium ring. Such a process is of interest in the use of ionic liquids as fuels as it is relatively easy to make the
anion be an oxidant and the cation be a hydrocarbon fuel.6-7.

FIGURE 1. .Chemical structures of the cation and anions of the RTILs studied in this work. To facilitate discussion, the
nomenclature for the different groups is shown. Groups are highlighted in purple and surrounded by enclosed brackets.

The CO2 + IL studies have been concerned with rotational excitation of CO2 in collisions with [bmim][BF4] and
[bmim][Tf2N]. Here it was found that CO2 collisions proceed via both impulsive scattering (IS) and trapping
desorption (TD) mechanisms with the latter being dominant in general. The relative amounts of these mechanisms
and the amount of rotational excitation from these mechanisms depends on ionic liquid, with [BF4] leading to
greater TD and less rotational excitation. Molecular dynamics calculations3 are able to match the observations
accurately, and they demonstrate that key factors governing the results are the strength of the CO2 interaction with
the anion, and the position of the anion relative to the surface of the ionic liquid. In particular, the CO2 interacts
more strongly with the smaller BF4 ion than with [Tf2N] and this leads to greater TD for [BF4]. However the
[Tf2N] ion is present in greater abundance at the surface than the smaller [BF4] and this leads to greater rotational
excitation in the [Tf2N] system.
There have been numerous molecular dynamics studies of the properties of bulk ILs and of IL/vacuum interfaces
(as has been reviewed8-10), and this has demonstrated the usefulness of theory in predicting structural and
thermodynamic properties, and the variation of these properties with the nature of the cation and anion. The use of
molecular dynamics to model IL collision processes provides important challenges that go beyond the study of
equilibrium properties, most importantly the need to use reactive force fields that describe bond formation and
breaking, and the inclusion of polarization and charge transfer effects in the interaction of the colliding species with
the IL. To incorporate these factors we have used QM/MM methods in which the colliding species and nearby
atoms in the IL are described using electronic structure theory and Born-Oppenheimer molecular dynamics, and the
remaining atoms are described using empirical molecular mechanics force fields.
Two different QM/MM methods have been used for these studies. In our initial work we combined the MSINDO
semi-empirical electronic structure method11 with the Tinker molecular dynamics method,12 with the division of
molecules between these two descriptions being determined by proximity of the IL molecules to the colliding
species. Although this method was useful for O,Ar + IL studies at 5 eV, it was too inefficient to be used for studies
that required a large number of trajectories, and there were also some problems with accuracy of the MSINDO
methods in describing ions. In more recent work we have developed a new approach which combines the PM6
electronic structure method with dispersion and hydrogen bonding correction (PM6-DH)14-16 as implemented in
MOPAC200917 with the GROMACS molecular dynamics code.18 This provides a more accurate and faster (using
localized molecular orbitals in MOPAC) electronic structure method than MSINDO for most applications (and
which also avoids the problems with DFT methods for charge transfer processes), and another advantage is that
GROMACS is a fully parallelized code, and provides a broader menu of QM/MM embedding options than in the
earlier work.

132
 In this paper we expand upon our earlier molecular dynamics studies of collisions of hyper-thermal CO2 with
[bmim][BF4] and [bmim][Tf2N] to examine the rotational energy transfer, energy relaxation and diffusion process
in more detail. In particular we examine the rotational polarization and angular distributions associated with the
scattered CO2 and we examine the vibrational energy relaxation and translational diffusion of the trapped CO2
during the first 10 ps after colliding with the IL surface. These studies use our more recent PM6-DH/GROMACS
code, and in the next section we brief review the details that are associated with this calculation. Then in the
following section we present new results which show how the CO2 rotational motions are polarized after scattering
from the IL, the vibrational energy relaxation as CO2 gets trapped on the surface and its surface diffusion
coefficients on both RTILs surfaces.

METHODOLOGY

A detailed description of the QM/MM MD methodology can be found in Ref. 3. An OPLS-AA type force field13
for the RTILs was adopted, and in the initial stage of the calculations, we performed MD simulations for the bulk
liquid using periodic boundary conditions. We then generated RTIL surfaces by applying slab boundary conditions
to the bulk simulation by increasing the box size along the z-axis to effectively eliminate long range electrostatics in
interactions between replicas of the slab. Equilibrated structures of the slab were selected as the starting geometries
for QM/MM MD calculations. The QM region includes the 10 ion pairs that are closest to the impacting CO2(~300
atoms), corresponding to a radius of 15~20 from the impact point The CO2s were launched towards the surfaces
with hyper-thermal energy(15 kcal/mol). The NNDO-type semi-empirical method PM6 with dispersion and
hydrogen bonding(PM6-DH) correction14-16 as implemented in MOPAC200917 was utilized to describe the
interactions between CO2 and the RTILs. In several studies3,14-16 the PM6-DH method was able to produce RMS
errors of 1~2 kcal/mol compared to hybrid DFT B3LYP or even higher level of theory. The MOZYME functionality
in MOPAC2009 was used during our dynamics. MOZYME converges the self-consistent field (SCF) equations
using localized molecular orbitals (MO)14, leading to linear scaling with system size. Because of the relatively large
size of our QM region, the QM and MM regions were partitioned using a mechanical embedding scheme20. The
dynamics were performed using a modified version of GROMACS 4.5.318 which interfaces with MOPAC2009.

RESULTS AND DISCUSSION

Structures of the RTIL Surfaces

In FIGURE 2, partial mass and number density profiles along the surface normal (z axis) as well as the average
second Legendre polynomial P2() for several directional angles from both RTILs are shown. Several comments
are in order. Firstly, both surfaces can be divided into three regions, that is, surface, maximum density and bulk
phases (lightest to darkest gray areas from right to left in FIGURE 2). This is consistent with several experimental
and theoretical studies24-28. Furthermore, while the [bmim][BF4] surface is dominated by the butyl chains (butyl-C3
and butyl-C4), the terminal CF3 groups (anion-CF3) compete with the butyl chains on the [bmim][Tf2N] surface.
Lastly, orientation order parameters as shown in (e) and (f) in FIGURE 2 indicate that the butyl chains protrude from
the [bmim][BF4] surface into the vacuum (large P2() value in the surface region). In stark contrast, the ordering
of ionic species on the [bmim][Tf2N] surface is drastically different. While the relatively shorter terminal anion-CF3
groups point into vacuum, the butyl chains are flattened. Thus, the surface-dominant and protruding butyl chains
make the surface of [bmim][BF4] rougher than that of [bmim][Tf2N], while the latter interface is shared between
the flatter butyl chains and terminal anion-CF3 groups. Hence, the scattering dynamics of gas molecules are
expected to be different on the two surfaces due to the difference in surface topology.

CO2 Scattering Results

In Ref 3, we have characterized in detail the ro-vibrational energy transfer of CO2 on both RTIL surfaces, with
good agreement between QM/MM molecular dynamics results and experiment. It was found that the [bmim][BF4]
surface is more absorptive of CO2 than [bmim][Tf2N], which leads to greater loss in translational energy and less
rotational excitation of CO2s that scatter from [bmim][BF4]. These differences are found to result from an interplay
between structure of the interface and the strength of interactions that depends on anion identity. The results also
suggest that CO2 interacts strongly with ionic species on the RTIL surfaces due to the large induced dipole moments

133
on CO2 during the collisions. The inclusion of electronic polarization is therefore critical in determining the final
rotational excitation of CO2 compared to results from an MM model with fixed charge. In this section, we focus our
study on the angular momentum polarization of CO2 scattered off both surfaces as well as the relaxation and
diffusion of the CO2s that remain trapped at the end of the 10 ps dynamics calculations.

0.80 Cation Ring normal Cation Ring normal

Butyl C3C4 Butyl C3C4
0.60 Anion SC
<P2()>

0.40
0.20
0.00
(e) (f)
Number Density(1023)

0.20
BF4 butylC3 anionCF3 butylC3
0.60 butylC4 Cation ring anionSO2 cationring
butylC4 anionN

0.40

0.20
(c) (d)
0.00
1.60 ([BMIM][BF4]) ([BMIM][Tf2N]
Density(g.cm3)

1.20

0.80

0.40
(a) (b)
0.00
30 20 10 0 10 20 30 30 20 10 0 10 20 30
Distance() Distance()

FIGURE 2 Mass and number density profiles along the surface normal for [bmim][BF4] (a,c) and [bmim][Tf2N] (b,d). Average
second- order Legendre polynomial P2() of various directional angles in [bmim][BF4] (e) and [bmim][Tf2N] (f). Gray areas
depict different regions along the surface normal. From the darkest to lightest: bulk, maximum-density, and surface regions. The
red dashed horizontal lines represent experimental mass density values.

Angular Momentum Polarization of CO2

Stereodynamics at the gas/liquid interface provides insight into the important physical interactions that directly
influence heterogeneous chemistry at the surface and within the bulk liquid. We have investigated the orientation of
CO2 that scatters off RTILs surfaces as a function of total rotational angular momentum. Since the incoming velocity
is in the xz-plane, the component of rotational angular momentum along the y-axis provides information about
polarization. We have plotted the normalized angular momentum component along the y-axis Jy/|J| as a function of
total magnitude of angular momentum in FIGURE 3. This shows that as higher angular momentum values are
reached, the angular momentum of CO2 becomes more and more oriented along the positive y-axis, with Jy/|J| going
from nearly zero (statistical behavior) to close to 1.0 (for the [BF4] liquid) as J varies from 0 to 90. This is consistent
with a recent measurement of the rotational polarization of CO2 scattering from perfluoropolyether(PFPE)
surfaces19. Moreover, the maximum value of Jy/|J| is larger for the [bmim][BF4] surface.
This phenomenon can be explained by the difference in surface topology. CO2s which exit the surface with
higher angular momentum tend to be scattered impulsively. Hence, the rough surface provides greater torque along
the positive y direction. This suggests that the correlation between the orientation and magnitude of the angular
momentum may be used as an indicator of the amount of surface roughness, as has also been noted in experimental
studies19.

134
 To further characterize the angular momentum polarization, we plot the final scattering angle as a function of the
rotational angular momentum in FIGURE 4.

0.90

BF4 inc=45
0.75 Tf2N inc=45
0.60
Jy/|J| 0.45
0.30
0.15
0.00
0.15
0.30
0 10 20 30 40 50 60 70 80 90
J
FIGURE 3 CO2 angular momentum polarization in scattering off both [bmim][BF4] and [bmim][Tf2N] surfaces at 45 incoming
angle. The initial velocity is in the xz-plane along the positive x and negative z directions (with surface normal pointing along the
positive z-axis).

75 BF4 inc= 0 75 Tf2N inc= 0

BF4 inc=45 Tf2N inc=45
65 65
55 55
final(degree)

final(degree)

45 45
35 35
25 25
15 15
0 10 20 30 40 50 60 70 80 90 0 10 20 30 40 50 60 70 80 90
J J

FIGURE 4 Correlation between angular momentum and final scattering angle for both RTIL surfaces. Both normal and 45
incoming trajectories are shown.

The general trend is that the scattering angle is not correlated with J for low values of J, but shows stronger
variation with J for J>60, especially for the [BF4] IL. In particular, we see that for 45 incident angle, the final
scattering angle is close to being normal to the surface, while for 0 incident angle, the CO2s are more parallel to the
surface. Using a similar analysis to that in Ref 3, we find that these trajectories correspond to CO2 interacting most
strongly with the butyl group in [bmim][BF4], resulting in a large momentum transfer that causes the final scattering
angle to be substantially changed from its initial value.

135
 Surface Relaxation of Thermally Trapped CO2

In Ref 3, in more than half of the total trajectories for both RTILs, the CO2s were trapped at the end of the
dynamics (after about 10 ps of simulation time). In this section, we analyze the relaxation process of these trapped
CO2s including both the diffusivity and relaxation time scales. To do this, we define the first collision point
following Ref 3 as the time when the CO2 center-of-mass velocity along the surface normal first changes direction.
Our earlier work demonstrated that when CO2 collides with the surface through multiple collision points, both the

0.16 0.16
<vx(0)vx(t)>(nm /ps )

<vz(0)vz(t)>(nm2/ps2)
BF4 <vx(0)vx(t)> BF4 <vz(0)vz(t)>
2

0.12 Tf2N <vx(0)vx(t)> 0.12 Tf2N <vz(0)vz(t)>

2

0.08 0.08

0.04 0.04

0 0

0.04 0.04
0 0.5 1 1.5 2 2.5 0 0.5 1 1.5 2 2.5
t(ps) t(ps)

FIGURE 5 Velocity autocorrelation function after CO2 gets trapped for the [bmim][BF4] and [bmim][Tf2N] IL surfaces. Both x
(left) and z (right) directions are shown, as the x and y directions are almost isotropic.

exiting translational and rotational energies are rapidly equilibrated with the surface temperature(298K). This
analysis was only applied to the scattered CO2s, but it is of great interest to examine the trapped CO2s as well,
since these trajectories could eventually lead to dissolution of CO2 into the bulk. We have analyzed these properties
using the velocities after the first collision (setting the time of the first collision to t=0). The CO2 diffusion
coefficient was evaluated using the Green-Kubo equation22,

BF4 C(t)/C(0)
Tf2N C(t)/C(0)
C(t)/C(0)

0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0

t(ps)

FIGURE 6 Vibrational relaxation of CO2 as a function of time for the two RTILs. It can be seen that after the first
collision point, CO2 loses memory of its initial condition within 1ps.

D= 0
v (0)v (t)dt

The vibrational energy relaxation of CO2 on the surface can be probed using Onsagers principle23,

136
 C(t) Ev (0)Ev (t)Ev 2
C(0)
= Ev
2 E 2
v
= exp (t/ )

where is a vibrational cooling time, and Ev(t) is the CO2 vibrational energy. To define this energy, we use a
procedure outlined in Ref 3 for decomposing the total energy into COM translational, rigid-body rotational and
vibrational motions. Only the vibrational energy relaxation is considered here as the other energy components have
similar time scales.
Typical velocity autocorrelation functions (VACs) from our calculations are shown in FIGURE 5 and the
vibrational energy relaxation is plotted as a function of time in FIGURE 6. The calculated diffusion coefficients and
relaxation time constants are presented in TABLE 1. In TABLE 1, we first note that vibrational energy relaxation
occurs on both surfaces in a relatively short time scale, on the order of 1 ps. Relaxation in [bmim][BF4] occurs on a
slightly longer time scale than in [bmim][Tf2N]. The Table also shows that CO2 diffuses ~4 times slower on [bmim]
[BF4] than on [bmim][Tf2N], both perpendicular and parallel to the surface. Also, the transverse diffusion
coefficient is about 4 times the normal diffusion coefficient, as might be expected given the strong vertical
stratification of the liquids. Note that a diffusion coefficient of 10x10-5cm2/s leads to (Dt) of 1~3 for the 10 ps
simulations that we have done, which means that the trapped CO2s are localized in the surface layer. This is
consistent with results from a recent MD simulation, where a dense layer of CO2 was found at the surface21. The
picture that emerges from these results is that the trapped CO2s lose most of their initial translational energy in
about a ps, while still being localized in the surface region of the IL. For [bmim][BF4], this is where the butyl
groups reside, so relaxation is a little slower than on [bmim][Tf2N] where the heavier CF3 groups cause more
efficient energy transfer.
TABLE 1 Surface diffusion and relaxation time constants for trapped CO2 in the
RTILs (uncertainties are in parenthesis)

RTILs Transverse Normal diffusion Vibrational

diffusion coefficient coefficient(10-5cm2/ relaxation time(ps)
(10-5cm2/s) s)

[bmim][BF4] 12.1(1.3) 3.0(0.3) 1.0(0.2)

[bmim][Tf2N] 45.9(3.6) 10.5(0.3) 0.7(0.0)

CONCLUSIONS

In this paper, we have explored the angular momentum polarization of CO2 that scatters off RTIL surfaces, and
we have also studied energy relaxation and diffusion in CO2s that become trapped. It is concluded that especially
for the [bmim][BF4] liquid at high angular momentum (quantum number J over 60), the angular momentum is
highly orientated along the positive y axis, meaning that the CO2s are cartwheeling as they come off the surface.
Furthermore, we also found correlation between high J and final scattering angle for this liquid which is consistent
with high momentum transfer in these collisions. Careful scrutiny has found that the high J CO2s are mostly
scattered by protruding groups such as the butyl group of bmim that is preferentially located at the IL/vacuum
interface. Our studies of diffusion have revealed that CO2 favors horizontal diffusion on both surfaces. In addition,
CO2 diffuses about 4 times slower on [bmim][BF4] than on the denser [bmim][Tf2N]. Finally, the vibrational
relaxation on both surfaces occurs within 1ps, with a slightly faster time scale on [bmim][Tf2N].

ACKNOWLEDGMENTS

X.L and G.C.S were supported by AFOSR grant FA9550-10-1-0205. G.C.S. also acknowledges support from the
NSF Center for Non-equilibrium Chemistry at Interfaces (CENECI). Computations were done using the
Northwestern University Quest computer system

137
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138
 Design of Modified Proteins using Knowledge-based
Approaches
Yves Dehouck, Dimitri Gilis, Marianne Rooman

Genomic and structural Bioinformatics, Universit Libre de Bruxelles, CP 165/61, Av. F. Roosevelt 50, 1050
Brussels, Belgium

Abstract. PoPMuSiC (http://babylone.ulb.ac.be/popmusic) is a program that has been developed to predict rapidly
changes in protein thermodynamic stability upon single-site mutations. We describe in this paper the theoretical model
that underlies the PoPMuSiC software, and present a few applications to various issues of biological interest. In
particular, we investigate the possible use of PoPMuSiC for the prediction of changes in protein-protein binding affinity
upon mutation. We also summarize previous studies where PoPMuSiC has been used to modulate the relative stability of
different protein structural states, to help the identification of mutations that stabilize and solubilize the Tobacco Etch
Virus protease (TEV) and to detect structural weaknesses in proteins that are subject to domain swapping.
Keywords: mutagenesis, protein stability, protein solubility, protein-protein binding affinity, conformational changes,
domain swapping, in silico approach.
PACS: 87.15.-v, 87.15.A, 87.15.

INTRODUCTION
The availability of bioinformatics tools that provide estimations of the impact of mutations on the
thermodynamic stability, thermal stability, interactions, solubility or function of proteins is of crucial importance in
the design of modified proteins. Such tools have the potential to support protein engineering projects aiming at
creating mutant proteins that, for example, remain active in non-physiological conditions or present enhanced
functional properties, with important applications in biotechnology [1,2]. They can also help the rationalization of
the effect of naturally occurring amino acid variants and their relationship to disease, and thus possess interesting
applications in medicine. In particular, they are expected to lead to significant improvements in the understanding of
the mechanisms of various diseases, to the development of enhanced diagnostics, new therapeutic approaches, and
more personalized treatments [3,4]. Although approaches based on multiple sequence alignments remain for now
predominant in this context, predictions of stability changes upon mutation have been recognized as a relevant input
in the identification of deleterious and disease-causing mutations [4-7]. On a more fundamental level, the analysis of
the predicted distributions of stabilizing or destabilizing mutations in sets of natural or engineered proteins may be
extremely valuable to refine our understanding of the relationships between protein sequence, structure, and function
[8-11], or to investigate the evolutionary dynamics of protein sequences [11-14].
Several methods have been developed to predict the effects of mutations on the thermodynamic stability of
proteins [15-27], and a few methods are devoted to predict changes in thermal stability [26,28], solubility [29-31], or
binding properties [e.g. 32-35] upon mutations. Many of these methods rely on a simplified structural representation
in which not all atoms are taken into account explicitly, on statistical potentials extracted from datasets of protein
structures, and machine learning technologies. Some others rather use empirical potentials built from optimized
combinations of various physical energy terms. Note that most of these methods are quite fast with respect to more
detailed approaches, such as free energy perturbation [36] or thermodynamic integration [37].
Recently, three studies compared the performances of methods predicting thermodynamic stability changes upon
point mutations, using experimentally characterized mutants that had not been used to train any of these methods
[27,38,39]. They showed a correct trend in the predictions, and moderate to good accuracy levels. The PoPMuSiC
program shows a fair accuracy and is moreover extremely fast: it estimates the stability changes resulting from all
possible point mutations in an average-sized protein in seconds. Moreover, a unique feature of PoPMuSiC is that it
yields the estimation of the optimality of each residue in the sequence with respect to the stability of its structure, a
powerful tool for the design of rationally modified proteins.
We present in this paper how PoPMuSiC functions, and in particular the statistical potentials and machine
learning techniques on which it is based. We then present several applications of PoPMuSiC for designing proteins

Theory and Applications in Computational Chemistry: The First Decade of the Second Millennium
AIP Conf. Proc. 1456, 139-147 (2012); doi: 10.1063/1.4730653
2012 American Institute of Physics 978-0-7354-1057-2/$30.00

139
of modified thermodynamic stability or solubility, and for predicting protein-protein binding affinity changes upon
mutation.

DESCRIPTION OF POPMUSIC

Prediction of protein stability changes upon mutations

The thermodynamic stability change of a protein caused by the mutation of a residue of type sw at position q
along the sequence into a residue of type sm is estimated on the basis of the structure of the wild-type protein and
energy functions. More precisely, the folding free energy change upon mutation, noted GP, is expressed as a
linear combination of 13 statistical potentials (Wi, i=1, 13), two terms that depend on the difference in volume
between the wild-type and mutant amino acids (V), and an independent term [27]:
13
GP = i (A)Wi + 14 (A)V+ + 15 (A)V + 16 (A) , (1)
i=1
where the coefficients i depend on the solvent accessibility A of the wild-type residue sw, V=(Vm-Vw) H((Vm-
Vw)) with H the Heaviside function, and Vw and Vw are the volume of the wild type and mutant amino acids,
respectively. The potentials Wi are derived from the joint frequencies of various sequence or structure descriptors
of the same residue or of neighbouring residues, computed in a dataset of known protein structures. They describe
correlations between various sequence or structure descriptors of the same amino acids or of neighbouring ones,
following a previously described formalism [40]. The descriptors considered are the amino acid type s, the torsion
angles defining the backbone conformation t of a given residue, its solvent accessibility a, and the spatial distance d
between the average geometric centers of the side chains of every pair of residues. The 13 potentials Wi are
denoted in terms of these descriptors as Wst, Was, Wsd, Wsds, Wstt, Wsst, Waas, Wass, Wast, Wasd, Wstd,
Wasdas, Wstdst. The terms of the type Wvw and Wvwx and are defined as:

P(v, w) P(v, w, x) P(v)P(w)P(x)

Wvw = kT ln ; Wvwx = kT ln , (2)
P(v)P(w) P(v, w)P(w, x)P(x, v)

where v, w, x are any of the descriptors s, t, a and d, P are joint frequencies observed in the protein structure dataset,
k is the Boltzmann constant and T the absolute temperature. The terms Wasdas and Wstdst are defined in a similar
way [40]. Higher order coupling terms, linking more than four descriptors, are not taken into account, since they
were shown to yield no improvement in the prediction of stability changes upon mutation [27]. In addition to the
statistical potentials, the two terms V in eq. (1) account for the volume difference between the mutant and wild-
type amino acid and hence provide a coarse description of the impact of creating of a cavity (if Vm<Vw) or
accommodating a larger side-chain within the protein structure (if Vm>Vw). Statistical potentials cannot be expected
to describe correctly such effects, since they are derived from a dataset of native structures of wild-type proteins,
with very few packing defects.
The weighting coefficients i(A) (i=1, 16) were chosen to be sigmoid functions of the solvent accessibility A of
the mutated residue:
1
i (A) = fi ri ( Aci )
+ bi , (3)
1+ e
where ci is the inflection point of sigmoid i, ri its slope, fi its scaling factor and bi its vertical shift. The reason for this
choice is that it enables the description of a smooth transition between two different environments: the protein core
and the protein surface. Indeed, it was shown previously that the relative weight of the different types of interactions
varies according to whether they concern residues at the surface or in the core [41].
Our model thus involves 64 different parameters (i.e.16 (cj, rj, fi, bi)). The values of these parameters were
estimated with the help of a neural network model minimizing the mean square error () on the G predictions for
a dataset of N experimentally characterized protein mutants [27]:
1 N
= (GM ,n GP,n )2
N n=1
, (4)

140
where GM,n is the experimentally measured folding free energy change of mutant n and GP,n its predicted
value, obtained with eqs. (1)-(3). The training and validation dataset contains altogether 2648 different single-site
mutations, in 131 proteins of known structure, whose folding free energy change has been experimentally
determined [27]. The data was originally extracted from the ProTherm database [42], and then thoroughly checked
to correct or eliminate erroneous inputs. Mutations introduced in heme proteins or in pseudo-wild type constructs
were not considered. Mutations that involve a proline or destabilize the structure by more than 5 kcal/mol were also
rejected, since they are likely to induce structural modifications that are not taken into account by the program.

Estimation of protein sequence optimality

The program for predicting the stability change upon mutation is fast enough to estimate within seconds the
changes resulting from all possible mutations in an average-sized protein. It is therefore possible to estimate how
robust the structure of a given protein is against all possible in silico mutations in its sequence. It is also possible to
identify positions that are particularly poorly optimized with respect to protein stability, for which several mutations
are predicted to improve stability. The ability to identify such positions in a protein sequence may be of substantial
interest, as they constitute attractive targets for protein engineering applications. They may also be involved in the
mechanisms of protein function [43,44], the occurrence of structural switches or the development of conformational
diseases [15,45].
For each position q in the sequence of a protein, we define a score q that quantifies the degree of non-optimality
of the amino acid at that position, with respect to the overall stability of the protein:
19
q = GP (sw,q sm,q ) H ( GP (sw,q sm,q )) , (5)
m=1
where m is one of the 19 possibilities of mutation of the amino acid sw in position q, and GP (sw,q sm,q ) is the
corresponding predicted stability change. The score is thus the sum of the predicted stability changes of all
stabilizing mutations at a given position in the sequence. Since most mutations have a destabilizing effect on the
protein, can be expected to be almost vanishing for many positions. Therefore, very negative values of point out
particularly interesting positions, where many mutations are stabilizing or a few mutations are strongly stabilizing.

Web interface
PoPMuSiCs web interface allows the users to compute the stability change upon a specific point mutation, or all
possible point mutations in a protein sequence to estimate the sequence optimality with respect to the structures
stability [46]. All queries require a protein structure to be specified, either in the form of a Protein DataBank (PDB)
code (in which case the structure is automatically retrieved from the PDB server [47]), or the user can upload his
own structure file or select a file that he has previously uploaded. The user may provide a structure file generated by
a modelling approach, as long as it complies with the PDB format. Note, however, that the performances of
PoPMuSiC were evaluated on the basis of experimentally resolved protein structures and are likely to be lower for
modelled structures; the accuracy of the predictions will depend on the quality of the model.
Three types of queries may be performed:
- The prediction of the stability change resulting from one given mutation, specified by the user, in the protein of
interest.
- The prediction of the stability change of a list of single-site mutations in a protein of interest. In this case, a file
containing the list of mutations must be uploaded. The server outputs a file containing the predicted stability
change resulting from each mutation.
- The prediction of the stability changes resulting from all possible single-site mutations in the protein of interest.
The server outputs a file containing the predicted stability change resulting from each mutation. A second file,
containing the sequence optimality scores for each position in the sequence is also given as output. In addition,
an interactive figure is created, which allows the user to view the distribution of -values along the sequence,
and to easily identify the individual contribution of each mutation (Figure 1).

141
FIGURE 1. Example of the distribution of the -values along the sequence. The first line is the residue sequence number in the
PDB file, the second line is the secondary structure computed with DSSP [48],[ ], the third line is the sequence.
sequence The helix regions
are coloured in red and the coils in green. The size of the peaks is proportional to the -value,
value, which is given below the peaks (in
kcal/mol).

APPLICATION TO THE P
PREDICTION OF CHANGES IN PROTEIN-PROTEIN
PROTEIN
BINDING AFFINITY
Protein-protein
protein interactions play a crucial role in numerous biological processes and represent therefore an
important target for medical research and drug design applications. Several methods have been designed to conduct
computational alanine scanning mutagenesis experiments [e.g. 32-35], in order to identify
dentify hot spots i.e. positions
that play a major role in the interaction between the two partners and are therefore interesting targets for
mutagenesis. Fast and accurate methods allowing the estimation of the effect of all possible mutations on the
binding
nding affinity between two proteins are however still missing.

Even though PoPMuSiC has not been designed and optimized to address this issue, it can easily be applied to
complex
com
estimate the effect of mutations on the stability of the complex as a whole (G ( P ), and of each partner
partner
partners
considered independently (GP ). As a first approximation, we may consider that only mutations of residues
located in, or in the proximity of, the interface between the two partners can potentially affect the binding affinity.
affi
The predicted change in binding affinity resulting from any given mutationmutation, GPbind,1, is then be expressed as
follows:

GPbind,1 = GPcomplex GPpartners . (6)

In this case, a mutation that equally (de)stabilizes the individual partner in which it is introduced and the complex as
a whole would thus be predicted to have no effect on the binding affinity. This is however not always the case. For
example, mutations that destabilize one partner without being directly involved in the interactions with the other o
partner have been observed to lower the binding affinity. This may result, for instance, from an increased overall
flexibility of the folded partner. A different approximation would thus be to focus on the (de)stabilizing effect of the
partner G
mutation on the complex as whole, independently of its effect on the individual partner, Pbind,2:

GPbind,2 = GPcomplex . (7)

GPbind,1 corresponds to the actual measurement of the change in binding aff.inity.

aff inity. But since theoretical
approaches are limited when it comes to the model range cooperative effects, GPbind,2
modelling of flexibility or of long-range
may still contain useful information for the prediction of changes in binding affinity upon mutation. Predictions
obtaine through a linear combination of G
based on an intermediate model can easily be obtained Pbind,1 and GPbind,2 :

GPbind = w G
GPbind,1 + (1 w) GPbind,2 = GPcomplex w GPpartners
p
. (8)

We compared the performances of this predictive model, with different values of w,, on a dataset of mutations to
alanine
lanine for which the impact on the binding affinity has been experimentally measured (Table 1). The corresponding
results obtained with the prediction method previously described by Kortemme and Baker (KB) [32] are given as a
reference. It should however bee noted that the comparison of this method with PoPMuSiC is not absolutely relevant,
for two reasons. The first is that PoPMuSiC relies on a coarse-grained
coarse grained representation of protein structures, whereas
the KB method is based on a more detailed and computat
computationally
ionally expensive model and includes a modelling
model of side-
chain rearrangements. The second reason is that the KB method has been optimized using experimental data on the

142
folding free energy changes induced by mutations to alanine in various proteins, whereas the training of PoPMuSiC
was performed in view of assessing any type of mutation, and is thus not restricted to mutations to alanine.

The performances of our predictive models were assessed by measuring the Pearson correlation coefficient (R)
between predicted and measured Gbind values, as well the ability to correctly identify deleterious mutations
(GMbind > 0.5 kcal/mol). For each model, the cut-off value on GMbind was defined so that the number of
mutations predicted as being deleterious is equal to the actual number of deleterious mutations. Unsurprisingly, the
model described by GPbind,1 (equations 6 and 8, w=1.0) shows better predictive abilities than GPbind,2 (equations
7 and 8, w=0.0). There is however a clear improvement that results from using a combination of these two models.
Indeed, R tops at 0.55 when w is set to 0.75, which compares favourably to R=0.51 and R=0.47 for w=1.0 and
w=0.0, respectively. It also suggests a small improvement over the more detailed KB method (R=0.54), even though
this method retains slightly better results for the binary identification of deleterious mutations.

If we focus on mutations at positions that are part of the interface between the two partners (Table 1), we observe
that all methods display a good true positive rate and a relatively poor true negative rate for the identification of
deleterious mutations. The opposite goes for mutations in other sites. In the latter case, both the KB method and the
model described by equation 6 (GPbind,1) appear completely unable to identify deleterious mutations. This is not
surprising since for these mutations GPpartner is either equal or very close to GPcomplex. In contrast, GPbind,2
(equation 7 and 8, w=0.0) allows the correct identification of about half of the non-interface deleterious mutations,
while keeping a very reasonable true negative rate.

In conclusion, our results show that the models described by equations 6 and 7 both have limitations, but can be
combined to improve the overall performances of the prediction of changes in binding affinity. Further
developments will be directed towards the definition of a more efficient way of combining these two models. In
particular, it appears that mutations at the interface and mutations in other locations should probably be evaluated
differently.

TABLE (1). Comparison of the performances of different approaches to the prediction of changes in protein-protein binding
affinity upon mutation to alanine. The True Positive Rate (TPR) and True Negative Rate (TNR) for the identification of
mutations that have a deleterious effect on the binding affinity (GMbind > 0.5 kcal/mol) are given for either: a all 376
mutations (out of which 191 are deleterious), b the 230 mutations of residues directly involved in the interface between the two
partners (out of which 156 are deleterious), or c the 146 mutations of residues that are not directly involved in the interface
(out of which 35 are deleterious). d Pearson correlation coefficient between predicted and measured values of Gbind,
measured on a subset of 362 mutations, after exclusion of mutations that affect the binding affinity by more than 5 kcal/mol.
Method TPRa TNRa TPRb TNRb TPRc TNRc Rd
(all) (all) (interface) (interface) (other) (other)
GPbind (w=1.00) 0.67 0.66 0.81 0.30 0.06 0.91 0.51
GPbind (w =0.75) 0.70 0.69 0.82 0.39 0.14 0.88 0.55
GPbind (w =0.50) 0.68 0.67 0.76 0.46 0.31 0.81 0.54
GPbind (w =0.25) 0.66 0.66 0.73 0.49 0.37 0.77 0.51
GPbind (w =0.00) 0.66 0.65 0.71 0.50 0.46 0.75 0.47
KB method 0.73 0.74 0.88 0.42 0.09 0.95 0.54

APPLICATION OF POPMUSIC TO SPECIFIC PROTEINS OF INTEREST

We present in this section some applications of PoPMuSiC to systems of biological or biotechnological interest.
A first series of examples focuses on the rational selection of mutations in view of modulating the relative stability
of different structural states of proteins. We have studied with PoPMuSiC 1-antitrypsin (1-AT) and the Josephin
domain of ataxin-3, two proteins involved in diseases provoked by aggregation [49,50]. 1-AT is an inhibitor of
serine protease that belongs to the serpin family. It presents a reactive center loop (RCL) that is recognized by serine
proteases. After cleavage of the RCL by the protease, 1-AT undergoes a conformational change where the RCL
inserts into the A -sheet of the protein to form an additional -strand and carries the protease to the opposite site of
1-AT. This move provokes structural changes in the active site of the protease, leading to its inactivation. Serpins
can also present an abnormal behaviour where the RCL of one serpin inserts into the A -sheet of another serpin,

143
forming disease-causing polymers [51]. The possibility to modulate the polymerization propensity of 1-AT
[49] The Protein DataBank contains the structure of the active form of 1-AT
through mutations was investigated [49].
(PDB code 1QLP) and of a complex between trypsin and 1-AT AT with a RCL that is cleaved and inserted into the A
-sheet (the inserted form, PDB code 1EZX).1EZX) All the possible single-site
site mutations have been introduced in the
active and in the inserted forms,, and their GP has been computed with PoPMuSiC. We have used the structure of
the inserted 1-AT
AT to model the environment of the RCL in a polymerized form of the protein. We have identified
tions that both stabilize the active state of 1-AT and destabilize its inserted form, assuming that such
the mutations
mutations could decrease the polymerization propensity of 1-AT. We have also considered mutations that both
destabilize the active state and stabilize
stabiliz the inserted one, to verify if such mutations promote polymerization. A
subset of these mutations has been experimentally characterized and 80% of these mutations presented the expected
behaviour (Table 2) [49].

redicted and measured stability of 1-AT

TABLE (2). Predicted AT variants and their polymerization propensity. (a) and (b): GP
computed with PoPMuSiC in the active and inserted forms, respectively. (c) Measured melting temperature. (d) The proteins werwere
incubated at 60 C, aliquots
uots were removed at different time points and subjected to non denaturing
denaturing PAGE. Polymerized forms
not penetrate the gel. The polymerization time is the time required to monomeric 1-AT
cannot AT to disappear from the PAGE.
Mutant GP(active) GP(inserted) Tm Polymerization
(kcal/mol)a (kcal/mol)b (C)c time (min)d
Wild-type / / 58 10
K331F -0.6 1.7 64 30
K331I -1.3 1.5 61 20
K331V -1.1 1.4 62 20
K331T -0.6 1.1 57 10
S330R 1.3 -0.7 52 5

Ataxin-33 is another protein whose aggregation causes disease, in particular Spinocerebellar

Spinoc Ataxia Type 3.
Ataxin-3 contains a N-terminal
terminal Josephin domain and a polyglutamine (polyQ) C-terminal
terminal tail. The length of the
polyQ modulates its pathogenicity [52]. We have investigated the assumption that the stability of the Josephin Jo
domain is also related to the aggregation
aggreg propensity of ataxin-3 [50]. First, we have predicted with PoPMuSiC the
mutations that (de)stabilize the Josephin domain. Then, some selected mutations were introduced in the Josephin
domain in its isolated form and in ataxin
ataxin-3. The stability and the aggregation propensity of these variants were
characterized. The experimental results showed that the stability of the Josephin variants agrees with the predictions,
and that the aggregation of ataxin-33 is modulated
modula by the stability of Josephin. The in silico pre-study has guided our
quest to identify rapidly a subset of interesting mutations that could impact the stability of the Josephin domain and
that could be tested experimentally.

In a second series of examples,, we show how the PoPMuSiC sequence optimality scores for each sequence
position (equation
equation 5) can be used to analyze regions that could be involved in structural changes. 3D domain
swapping is a structural modification that occurs when identical proteins exchange identical domains or regions to
form an oligomer. Three regions are involved in domain swapping: the closed and open interfaces, and an the hinge
loop (see Figure 2 for a definition). The open interface connects the swapped regions. The interactions
inte at this
interface
face are expected to be weaker in the monomeric form, to allow the opening of the structure leading to the
swapped oligomer. The hinge loop is the only part of the protein that has a different structure in the monomer and in
the oligomer.

FIGURE 2. Schematic
chematic representation of a swapped dimer. Each monomer is coloured in light and dark grey. The hinge loop, the
closed interface and the open interface are represented in red on the first, second and third picture, respectively.

We have used PoPMuSiC,, and other in silico methods, to identify structural weaknesses in 13 proteins that have
been observed in a swapped conformation [53].. Structural weaknesses are defined as regions whose sequence is not

144
optimal according to the structure. It is possible to use PoPMuSiC to introduce systematically all the single-site
mutations, to compute their GP and the sum of the GPs of all the stabilizing mutations at each sequence
position, . A very negative value of reveals a region that is not optimal according to the
thermodynamic stability. We have found negative peaks in the closed interface and in regions that are in contact
with the hinge loop in nine out of the 13 proteins. Mutations that could modulate the swapping propensity of the
proteins have also been proposed.

Controlling the stability and solubility of proteins of biotechnological interest through mutagenesis is another
goal of protein design. The Tobacco Etch Virus Protease (TEV) is used in biotechnology to remove solubility tags
from the N- or C- terminal part of a recombinant protein. The TEV protease exhibits a low solubility (about 1
mg/ml), which could provoke production and storage problems. In a first step, we have selected with PoPMuSiC
eight mutations among the most stabilizing ones [54]. Then, we have proposed the five mutations that were the most
likely to improve the solubility. For that purpose, we have chosen the mutations that optimize the interactions with
the solvent, i.e. surface mutations that stabilize the protein and increase the polarity of the surface. The physico-
chemical properties of these mutations have been characterized experimentally (Table 3).

TABLE (3). Predicted and measured stability TEV variants and their solubility. (a) and (b): G calculated with PoPMuSiC and
measured, respectively. (c) Measured solubility.
Mutant GP GM Solubility
(kcal/mol)a (kcal/mol)b (mg/ml)c
Wild-type / / 1.5
K45F -2.63 -0.43 1.54
L56V -1.06 0.0 6.2
Q58F -1.27 -0.60 1.56
E106G -1.64 -1.40 1.7
S135G -1.07 0.0 5.77
L56V/S135G / -0.1 >40

The measured thermodynamic stabilities are in agreement with the predictions: the mutants are either more stable
or neutral. Interestingly, two mutations have been shown to improve the solubility. Moreover, the solubility of the
double mutant L56V/S135G increases up to 40 mg/ml, and the activity of TEV is not affected by all these mutations.

CONCLUSIONS
The PoPMuSiC program is a powerful tool for the prediction of stability changes upon mutation. Its performances
were shown to be in line or superior to other comparable algorithms, and it has also the advantage of being extremely
fast, which allows the assessment of all possible single-site mutations in any given protein. Several research groups
have used PoPMuSiC to successfully design improved proteins for various applications [e.g. 55-57] or clarify the
mechanisms of disease-causing mutations [e.g. 58-60]. In addition, the predictions of PoPMuSiC also provide
valuable information with respect to the analysis of protein-protein binding affinity, protein solubility, as well as the
propensity of proteins to undergo conformational changes.

ACKNOWLEDGEMENTS

This work was supported by the Belgian State Science Policy Office through an Interuniversity Attraction Pole
Program (DYSCO), the Belgian Fund for Scientific Research (F.R.S.-FNRS) through an FRFC project. YD and MR
are Postdoctoral Researcher and Research Director, respectively, at the F.R.S.-FNRS.

145
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 On the Fundamental Processes in Molecular Electrical
Doping of Organic Semiconductors
Georg Heimel, Ingo Salzmann, and Norbert Koch

Institut fr Physik, Humboldt-Universitt zu Berlin, Brook-Taylor-Strae 6, D-12489 Berlin, Germany

Abstract. Integer electron transfer between organic semiconductors (OSCs) and strong donor/acceptor molecules has
been regarded as the fundamental mechanism of molecular electrical doping. However, this process entails a number of
consequences that are in conflict with well-established concepts of organic-semiconductor physics such as the charge-
induced appearance of polaronic states within the fundamental gap of the OSC. Here, from the results of (time-
dependent) density-functional theory calculations on prototypical OSC/dopant pairs, we derive a new and different
picture for the mechanism of molecular electrical doping, which resolves these inconsistencies. Common doping-related
observations are rationalized through intermolecular hybridization of OSC and dopant frontier molecular orbitals.
Controlling the degree of this hybridization thus naturally emerges as a strategy for the design of improved molecular
dopants in future high-performance organic electronic devices.
Keywords: Organic semiconductor, pentacene, molecular electrical doping, density functional theory.
PACS: 81.05.Fb, 72.80.Le, 73.61.Ph, 31.15.es, 31.70.Ks

INTRODUCTION
Doping of semiconductors permits tuning their conductivity as well as the alignment of their electronic bands at
interfaces with other materials. In the case of inorganic semiconductors, it is thus the development of processes for
controlled doping of high-purity intrinsic starting materials that paved the way for the multitude of microelectronic
devices that pervade information society. In contrast, the majority of todays organic (opto-)electronic devices, such
as organic field-effect transistors, organic light-emitting diodes (OLEDs), or organic photovoltaic cells (OPVCs), is
based on intrinsic organic semiconductors (OSCs). This is insofar remarkable as, in fact, the entire field of organic
electronics originates in the discovery of strongly increasing electrical conductivity in poly(acetylene) upon doping
with iodine [1-3]. However, it was found that employing halides or alkali metal as dopants for OSCs detrimentally
affects both their processability and their long-term stability [4]. With the goal of overcoming these technological
hurdles, appreciable effort is currently invested into the development of strong, environmentally stable organic
donors and acceptors that can assume the role of molecular electrical dopants. Indeed, this approach has allowed
further pushing the performance of OLEDs [5-13] and OPVCs [13-18]. Despite its initial success, however,
persistent inconsistencies in the prevailing models for the fundamental processes in molecular electrical doping of
OSCs appear to impede further progress. Here, we summarize our recent advances [19] in understanding the
microscopic mechanisms that give rise to a range of macroscopic phenomena, which are commonly observed in
molecularly doped OSCs but, so far, were not fully understood. In contrast to the predominantly experimental
Ref. [19] we will focus more on conceptual and computational aspects in the present contribution.
In particular, after briefly revisiting doping in inorganic semiconductors, we will describe the standard model
of molecular electrical doping in OSCs prevalent in literature and highlight the inconsistencies therein. In the
following section, we will then discuss some conceptual aspects prior to providing computational results obtained
with density-functional theory (DFT) and time-dependent density-functional theory (TDDFT). On the basis of these
results, we will subsequently expound a new and different picture for the fundamental process in molecularly doped
OSCs, which resolves the inconsistencies in the standard model. Lastly, we will discuss the implications of our
findings for the future chemical design of improved molecular dopants.

Theory and Applications in Computational Chemistry: The First Decade of the Second Millennium
AIP Conf. Proc. 1456, 148-156 (2012); doi: 10.1063/1.4730654
2012 American Institute of Physics 978-0-7354-1057-2/$30.00

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FIGURE 1. (a) Evolution of the relative energetic alignment of the valence band (VB), conduction band (CB), and the Fermi
level (EF) for an inorganic semiconductor upon increasing p-dopant concentration; short horizontal lines above the VB edge
indicate shallow acceptor states introduced by dopant atoms. (b) Fundamental process of molecular electrical p-doping in organic
semiconductors (OSCs) according to widely accepted perceptions: one electron hops from the highest occupied molecular orbital
(H) of the OSC into the lowest unoccupied molecular orbital (L) of the dopant. (c) Scenario after mutual OSC/p-dopant
ionization: a static electron (-) remains on the dopant while a mobile hole (+) in the surrounding OSC matrix eventually escapes
the Coulomb attraction by hopping beyond the Onsager radius (dashed circle).

Standard Models for the Doping of Semiconductors

Starting with an intrinsic inorganic semiconductor (Fig. 1a, left panel), we recall that, by introducing impurity
atoms in a controlled manner, defect states are introduced in the semiconductors fundamental gap. In the case of
p-type doping, these are empty (or acceptor) states lying typically only a few meV above the edge of the valence
band (VB) as indicated by the short horizontal line in the center panel of Fig. 1a. Because all available states are
occupied following Fermi-Dirac statistics, essentially all acceptors sites are ionized at room temperature and the
number of thusly generated free charge carriers (holes in the case of p-doping) equals the number of dopant atoms.
As a consequence, the Fermi level (EF), located in the middle of the gap prior to doping, continually shifts towards
the VB upon increasing doping concentration. At higher doping levels (on the order of per mille), the semiconductor
can be degenerately doped and EF lies within the VB in that regime (right panel in Fig. 1a). The process for
n-doping is analogous: shallow donor states are introduced just below the conduction band (CB) edge leading to a
continuous upward shift of the Fermi level upon increasing dopant concentration until, in the degenerate regime, EF
comes to lie within the CB.
In contrast, the standard approach for molecular electrical doping of organic semiconductors is the admixture of
a few mole-percent of a molecular species with an electron affinity (EA) in the range of the ionization energy (IE) of
the OSC for p-type doping [13, 20-22]. One electron is thought to hop from the highest occupied molecular orbital
(the HOMO, further abbreviated by H in the Figures) of the OSC to the lowest unoccupied molecular orbital (the
LUMO, further abbreviated by L in the Figures) of the p-dopant, as indicated in Fig. 1b. This integer charge
transfer is generally assumed to subsequently lead to a static electron on the p-dopant and an itinerant hole in the
OSC (Fig. 1c) [13, 17, 20, 21, 23-30]. Those holes that escape the Coulomb attraction of the remaining charge on
the dopant molecule, i.e., those that make it beyond the Onsager radius (dashed circle in Fig. 1c), then contribute to
an overall increase in the density of mobile charge carriers and, therefore, to the observed increase in sample
conductivity [19, 30, 31].
The most obvious consequence of molecular electrical doping via mutual ionization of OSC and dopant would
be the emergence of singly occupied states, i.e., positive polarons (P+), in the fundamental gap of the OSC, which,
according to long-established understanding of charge carriers in organic materials [32-35], exhibit a lower IE than
neutral OSC molecules (Fig. 2a). Therefore, this doping-induced density of occupied states should, in principle, be
well detectable experimentally, e.g., by ultraviolet photoelectron spectroscopy (UPS). Most strikingly, however, no
such polaronic states with a reduced IE have ever been directly observed in OSCs doped with organic acceptors.
What has been observed in numerous UPS studies on molecularly p-doped OSCs is a continuous shift of the HOMO
level towards EF upon increasing dopant concentration, while retaining a constant IE (Fig. 2a) [5, 20, 24, 26, 29, 31,
36]. However, in contrast to expectations based on inorganic semiconductors (Fig. 1a), both this shift and the
independently measured doping-induced increase in sample conductivity was found to saturate at doping levels of a
few mole-percent [19, 30, 31]. In fact, the HOMO always remained significantly below EF even at doping ratios of
tens of percent [19, 31, 37], which is well within the regime of degenerate doping in the case of inorganic
semiconductors (Fig. 1a). This lead to the suggestion of Fermi-level pinning at the P+ states in p-doped OSCs at high

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FIGURE 2. (a) Experimentally observed evolution of the relevant energy levels upon increasing p-dopant concentration in
molecularly doped organic semiconductors (OSCs). H, L, EF, and Evac denote the HOMO, LUMO, Fermi level, and vacuum
level, respectively. A constant ionization energy (IE) is retained and singly occupied positive polarons (P+) with a reduced IE are
thought to emerge in the fundamental gap of the OSC until, at a saturation doping level of a few percent, EF is suggested to get
pinned by P+. (b) Current perception of the relative energetic position of relevant energy levels in the saturated regime.

doping concentrations [20, 31]. Again, however, the alignment of the relevant energy levels expected in the
saturation regime (Fig. 2b), which should manifest, e.g., in measurable UPS intensity at [32-35] or close to EF [29],
could never be experimentally confirmed. Also for OSCs molecularly n-doped with strong organic donors, no
doping induced density of occupied states at EF (arising from negative polarons in the OSC matrix in this case)
could ever be observed in the saturated doping regime. Interestingly, however, some UPS studies reported the
emergence of new states within the fundamental gap of the neutral OSC entirely below EF, which were designated as
gap states but not further assigned [14, 37].

RESULTS AND DISCUSSION

Conceptual Considerations

Having highlighted several inconsistencies in the commonly accepted mechanism for molecular electrical doping
of OSCs, we now proceed to expound an alternative picture that resolves these inconsistencies. In doing so, we first
recall that, to enable charge transport through OSCs in general, its constituent molecules are designed to expose their
delocalized S-electron systems so as to promote S-orbital overlap with adjacent molecules. In order to achieve the
desired energy-level alignment (Fig. 1b), also the dopant species generally exhibit a more or less delocalized
S-electron system, which is thus available for intimate contact with adjacent OSC molecules. With the aim of
developing the important consequences of close contact between the frontier S-orbitals of OSC and dopant, we take
a step back and first re-examine the situation of covalent bonding between two hydrogen atoms in a H2 molecule
(Fig. 3a): Electronic interaction between the individual atoms gives rise to the emergence of two energetically split
molecular orbitals (MOs), a symmetric (and thus bonding) linear combination of the two atomic 1s orbitals at lower
energy and an antisymmetric (and thus antibonding) linear combination at higher energy. As only the former is
(doubly) occupied in the ground state, the overall interaction between the two H atoms is evidently bonding;
minimizing the total energy by further increasing the energy splitting between bonding and antibonding MO
(thereby lowering the energy of the former) provides a strong driving force for the formation of a covalent bond.
When approaching two He atoms (Fig. 3b), the same orbital splitting occurs. In contrast to the H2 molecule,
however, a total of four electrons now needs to be accommodated in the two available MOs and, thus, both the
lower-energy bonding and the higher-energy antibonding levels are occupied. Consequently, the overall interaction
between two He atoms is nonbonding and the dimer is only weakly held together by van der Waals forces. This
situation is quite similar to that encountered in common OSCs, which are generally composed of closed-shell
molecules (Fig. 3c). Also there, a total of four electrons, two from each molecular HOMO, need to be
accommodated in the two supramolecular hybrid orbitals (SMHOs), which arise from symmetric (i.e., bonding) and
antisymmetric (i.e., antibonding) linear combinations of the single-molecule HOMOs. We note that the energy

150
FIGURE 3. (a) Familiar molecular-orbital picture of a hydrogen molecule. (b) Schematic of the energy splitting between
bonding and antibonding MOs in a He dimer. (c) Energy splitting between the HOMO levels (H) of two OSC molecules upon
formation of bonding and antibonding supramolecular hybrid orbitals. (d) Schematic of a mutual orientation where the energy
splitting between supramolecular hybrid orbitals formed by the HOMOs of two adjacent OSC molecules is suppressed. Arrows
indicate electrons occupying the respective atomic, molecular, and supramolecular hybrid orbitals.

splitting between these two SMHOs can, in principle, be quite significant (on the order of 1 eV), provided the
molecules are favorably arranged with respect to each other, e.g., in a fully symmetric, perfectly eclipsed, coplanar
dimer [38, 39]. As with the two He atoms, however, the overall interaction between two OSC molecules is
nonbonding and, therefore, the distance and relative orientation of two OSC molecules is determined by a
competition between dispersive and electrostatic (mostly quadrupole-quadrupole) interactions [40-42] and,
therefore, the overall intermolecular bonding is rather weak compared to the covalent case. With no incentive to
maximize the energy splitting between bonding and antibonding SMHOs, the acting forces tend to favor relative
molecular orientations, where this HOMO-HOMO splitting is greatly suppressed; such a scenario is depicted in
Fig. 3d, where the nodal structure of the single-molecule HOMOs forbids their intermolecular hybridization in a
slightly slipped configuration [38, 39]. We note on the side that this (unfortunate) tendency is closely connected
to the notoriously low charge-carrier mobility in OSCs, as a small HOMO-HOMO splitting is essentially equivalent
to a small hopping integral [38].
The preliminaries just discussed set the stage for considering the natural consequence of electronic interaction
between the HOMO of an OSC and the LUMO of a p-dopant (Fig. 4). By design, these two single-molecule frontier
orbitals are close in energy (cf. Fig. 1b) and, orbital symmetry permitting, the electronic interaction between the two
molecular species will equally lead to the formation and energetic splitting of bonding and antibonding SMHOs
composed of symmetric and antisymmetric linear combinations of the doubly occupied OSC HOMO and the empty
dopant LUMO, respectively (Fig. 4a). As a total of two electrons (from the OSC HOMO) need to be accommodated
in the two SMHOs, only the lower-energy bonding level is (doubly) occupied and the higher-energy antibonding
SMHO is empty. This leads us to the following important conclusions: (i) Instead of one electron hopping from the
OSC HOMO into the p-dopant LUMO (cf. Fig. 1b), both electrons from the OSC HOMO are now in the bonding
hybrid SMHO. (ii) In contrast to the situation for two OSC molecules (Fig. 3c), its occupation, as with the H2
molecule (Fig. 3a), leads to an overall bonding interaction between OSC and dopant and, thus, presents an
appreciable driving force for the formation of such supramolecular complexes; increasing the energy splitting
between bonding and antibonding SMHOs, thus lowering the energy of the former, only serves to further stabilize
OSC/dopant complexes with mutual molecular orientations that maximize intermolecular frontier-orbital overlap.

Frontier-Orbital Hybridization for Prototypical OSC/dopant Material Combinations

With a general conceptual framework in place, we consider next the prototypical example of pentacene (PEN) as
an OSC and one of the strongest organic acceptors, 2,3,5,6-tetrafluoro-7,7,8,8-tetracyanoquinodimethane
(F4-TCNQ), as the p-dopant (Fig. 4b). In attempting to computationally access the properties of the corresponding
OSC/dopant complex proposed above, it has to be borne in mind that all pertinent experiments were performed on
thin solid films [17, 19, 30]. There, even if the pure OSC is highly crystalline, admixture of the typical amount of a
few mole-percent of F4-TCNQ renders the films amorphous [19, 43]. As the solid-state structure is thus inaccessible
on the molecular level, one is left with considering gas-phase dimers of PEN and F4-TCNQ instead. Examining the
relevant frontier MOs of OSC and dopant (Fig. 4c), it becomes apparent that in a perfectly symmetric, eclipsed
coplanar dimer with the long molecular axes aligned, they cannot mix and hybridize for symmetry reasons: the

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FIGURE 4. (a) Schematic of hybridization, energy splitting, and occupation of OSC HOMO and p-dopant LUMO through
formation of bonding and antibonding supramolecular orbitals. (b) Chemical structures of OSC pentacene (PEN) and p-dopant
F4-TCNQ. (c) Calculated PEN HOMO and F4-TCNQ LUMO. (d) Representative local-minimum complex structure. (e)
Calculated bonding and antibonding supramolecular hybrid orbitals. (f) Calculated bonding hybrid orbital of complex between
the p-dopant F4-TCNQ and the alternative OSC, D-NPD. (g) Calculated bonding hybrid orbital between the OSC PEN and the
alternative p-dopant Mo(tfd)3.

HOMO of PEN exhibits a nodal plane along the long molecular axis perpendicular to the molecular plane, while the
LUMO of F4-TCNQ does not. However, by laterally translating and azimuthally rotating the coplanar molecules,
one easily arrives at several configurations with significant in-phase and out-of-phase orbital overlap needed for the
hybridization of the involved single-molecule frontier orbitals into bonding and antibonding SMHOs, respectively.
Having thusly identified promising starting configurations for subsequent DFT geometry optimizations, one is
next faced with choosing an appropriate exchange-correlation (XC) functional: the local-density approximation can
be expected to produce spurious overbinding between OSC and dopant, and the generalized-gradient approximation
(GGA) might not be well-suited to accurately describe potential (long-range) charge transfer between OSC and
dopant due to the so-called self-interaction error (SIE) [44]. This calls at least for a hybrid GGA functional that
contains a certain amount of Hartree-Fock exchange to mitigate the SIE.
Using such functionals, specifically B3LYP [45, 46], mPW1PW [47], and PBE0 [48] in conjunction with a
6-31G** contracted-gaussian atomic-orbital basis set [49, 50], we indeed found four local-minimum structures for
PEN/F4-TCNQ complexes with minimal variance between different XC functionals; one representative structure is
shown in Fig. 4d (see also Ref. [19]). Notably, while GGA should not produce any binding at all in purely van der
Waals bonded molecular dimers, we obtain an intermolecular binding energy of around 0.3 eV (counter-poise
corrected for the basis-set superposition error), which suggest that, as anticipated from the discussion above,
occupation of the bonding SMHO indeed leads to OSC-dopant attraction. To estimate its magnitude relative to van
der Waals interaction, we further optimized all four local-minimum geometries using the ZB97X-D range-split
hybrid GGA functional [51], which contains semi-empirical Grimme-type [52] van der Waals corrections. Upon
doing so, we observed that (a) two previously distinct local-minimum structures converged to a single one, that (b)
the average intermolecular distance, not surprisingly, decreased by 0.1-0.2 , and that (c) the intermolecular binding
energy increased to a0.9 eV, which points towards a van der Waals contribution of ca. 0.9 - 0.3 = 0.6 eV.
More importantly, all methods and local-minimum structures lead to the hybridization between PEN HOMO and
F4-TCNQ LUMO suggested in Fig. 4a. Regardless of the choice for the XC functional, the energy mismatch
between the respective frontier MOs of the isolated molecules is substantially smaller than the energetic splitting
between bonding and antibonding SMHOs [19]. For the structure in Fig. 4d, these are depicted in Fig. 4e. Additional
results shown in Figs. 4f and 4g for F4-TCNQ as p-dopant with a different OSC, D-NPD [20, 29] , as well as PEN as
OSC with a different p-dopant, Mo(tfd)3 [53-55] lend further credence to the generality of frontier-orbital
hybridization and energetic splitting of the resulting SMHOs in molecularly doped OSCs (see also Ref. [19]).

Comparison to Experiment: Assessing a New Model for Molecular Electrical Doping of OSCs

Prior to further discussing computational results on OSC/dopant complexes, it is worthwhile to evaluate the
consequences of the microscopic picture developed so far for the general mechanism of molecular electrical doping

152
FIGURE 5. (a) Schematic energy-level diagram illustrating the microscopic mechanism for molecular electrical p-doping of an
organic semiconductors (OSC) with ionization energy IE. The doping concentration increases from left to right: (far left) pristine
OSC, (left center) weakly p-doped OSC, (right center) saturated p-doping regime, and (far right) 1:1 OSC/p-dopant blend. (b)
same as in (a) for n-type doping. See text for details.

(Fig. 5a, from left to right). Starting with an intrinsic OSC, the formation of SMHOs leads to the emergence of
doubly occupied bonding hybrid states, Hhyb, below the HOMO of the intrinsic OSC. At typical doping ratios of a
few mole-percent, these are masked by the occupied density of states of the OSC molecules not involved in complex
formation (whose constant IE is measured) and, therefore, they cannot be easily detected by UPS (cf. Ref. [29]).
Furthermore, empty antibonding hybrid states, Lhyb, appear within the gap of the intrinsic OSC. As all available
states are occupied according to Fermi-Dirac statistic, the presence of these leads to the observed shift of the HOMO
towards EF [5, 20, 24, 26, 29, 31, 36]. Importantly, this shift saturates, when the Fermi level is pinned between the
empty hybrid states and the HOMO of the OSC molecules not involved in complex formation. Evidently, the reason
why no polaronic states with a reduced IE were ever observed at EF is that there simply are no such states. In
contrast, the bonding hybrid states with their increased IEhyb can be directly observed by UPS in 1:1 mixed films of
PEN and F4-TCNQ [19].
As a further consequence of Fermi-Dirac occupation, not all antibonding hybrid states are occupied at room
temperature, which rationalizes the relatively high doping ratios (compared to inorganic semiconductors) needed in
practical applications [5-18]. In contrast to the standard model for molecular electrical doping (Fig. 1c), it is thus
ionized complexes and not ionized OSC molecules that counterbalance mobile holes. Together with the decreased
barrier for hole injection from metallic electrodes, i.e., a decreased energy difference between EF and the OSC
HOMO, the scenario just described is also in line with the observation of an overall increasing device conductivity.
N-type doping proceeds in full analogy (Fig. 5b). The formation of SMHOs leads to the emergence of doubly
occupied, bonding hybrid states within the fundamental gap of the intrinsic OSC. Upon increasing doping
concentration, EF thus continually moves up in energy until, in the saturation regime, it gets pinned between the
LUMO of the intrinsic OSC and the bonding hybrid states, which now lie entirely below the Fermi level and provide
a natural explanation for the observed gap states [14, 37].

Magnitude of the Energy Splitting between Bonding and Antibonding Supramolecular Hybrid Orbitals

So far, our new model for molecular electrical doping of OSCs can fully explain all common doping-related
observations and, in addition, resolves the inconsistencies in the broadly accepted model prevalent in literature.
However, one rather unsatisfactory detail remains and that is, in the case of p-doping, the postulation of empty, anti-
bonding SMHOs within the OSC gap, which, naturally, are not directly accessible by UPS. In order to
experimentally probe these states, and thereby assessing the magnitude of the energy splitting between bonding and
antibonding SMHOs, different techniques are thus needed. One possibility is ultraviolet-visible (UV-VIS)
absorption spectroscopy that could reveal the according fingerprint optical transitions. In order to facilitate the
assignment of the spectral features expected in such experiments, we performed (previously unpublished) TDDFT
calculations at the PBE0/6-31G** level on single PEN and F4-TCNQ molecules as well as the three local-minimum
structures found for their complexes with the ZB97X-D functional (see Ref. [19]). The results are shown in Table 1.
Notably, the PEN/F4-TCNQ complexes exhibit optical gaps that are substantial, but still considerably smaller than

153
 TABLE 1. Energies (in eV) and oscillator strengths of the lowest
optically allowed transitions calculated with time-dependent density-
functional theory at the PBE0/6-31G** level for isolated PEN and
F4-TCNQ molecules, their respective ions, and supramolecular
PEN/F4TCNQ complexes obtained with ZB97X-D/6-31G**
geometry optimizations.
System Transition Energy / eV Oscillator Strength
PEN 2.0762 0.0469
F4-TCNQ 3.0758 1.1439
Complex I a 1.0059 0.0961
Complex II b 1.0668 0.1375
Complex III c 0.9255 0.1037
PEN+ (cation) 1.2540 0.0131
F4-TCNQ- (anion) 1.7513 0.3065
a
shown in Ref. [19]
b
shown in the supporting material to Ref. [19]
c
shown in Fig. 4d

those of the individual constituent molecules, as expected from the rough sketch in Fig. 4a. As the local structure of
such complexes in (amorphous) thin-films [19] is unknown and as solid-state effects on transition energies are,
naturally, not included in our present calculations, comparison with experiment must remain somewhat qualitative.
It is remarkable, however, that new absorption features indeed arise well within the optical gap of PEN upon p-
doping with F4-TCNQ [19]. Prior to their assignment, one needs to take into account that also charged individual
molecules give rise to characteristic sub-gap absorption features (Table 1), which could be erroneously assigned to
those of the complexes. Only affirmative comparison with additional paramagnetic electron-spin resonance
measurements, sensitive to unpaired electrons in the sample, finally allowed assigning these features to bonding-to-
antibonding SMHO optical transitions [19].

SUMMARY AND OUTLOOK

To summarize, we developed a conceptual framework and presented computational evidence for intermolecular
frontier-orbital hybridization between OSCs and molecular dopants. In contrast to the integer charge transfer picture
prevalent in literature, this model, and the supramolecular hybrid orbitals within the fundamental gap of the intrinsic
OSC that it predicts, provide a microscopic explanation for commonly observed phenomena in molecularly doped
OSCs. Moreover, our new model resolves persistent inconsistencies that plagued previously accepted perceptions.
Most importantly, our view on molecular electrical doping OSCs also reveals the limitations in the efficiency of
presently used dopant molecules: At typical doping concentrations of a few mole percent, the structural integrity
(i.e., the crystallinity) of the OSC host matrix is severely compromised and, with it, also the charge-carrier
mobility [43]. Therefore, one would like to work with far lower doping concentrations than presently used, ideally in
the range of that employed in inorganic semiconductor technology. This necessitates that every dopant is ionized,
i.e., that every dopant actually provides one free charge carrier, as in inorganic semiconductors. However, in
contrast to inorganic semiconductors, where doping-induced defect states are typically only a few meV away from
the band edge (Fig. 1a), the SMHOs formed in OSCs doped with standard molecular acceptors (p-type) or donors
(n-type), lie several tenths of an eV within the gap of the intrinsic semiconductor (Fig. 5). Clearly, in order to
increase the efficiency of molecular electrical doping, this energy offset needs to be minimized. As it arises from
electronic coupling between OSC and dopant frontier molecular orbitals, this coupling must be suppressed.
Shielding the functional core of sufficiently strong donor and acceptor molecules through the attachment of bulky
insulating side groups thus emerges as strategy for the chemical design of improved molecular dopants for future
high-performance organic electronic devices.

ACKNOWLEDGMENTS
The authors would like to thank S. Duhm, M. Oehzelt, P. Pingel, B. M. George, A. Schnegg, K. Lips, R.-P.
Blum, A. Vollmer, D. Neher, A. Elschner, and W. Caliebe for their invaluable contributions to the experimental part
of this work and J. P. Rabe for fruitful discussions. Financing through the DFG (Germany), the JSPS (Japan), and
the Austrian Science Fund (FWF) Project No. P21094 is gratefully acknowledged.

154
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 Computational Approaches to Target Fishing and
Ligand Profiling
Didier Rognan

Laboratoire d'Innovation thrapeutique, UMR

UMR7200 Universit de Strasbourg/CNRS,, 67400 Illkirch, France

Abstract. The explosion of publicly available bioactivity data has fostered the development of computational methods to
predict target-ligand
ligand interactions at a very large scale. This survey will review all possible approaches from ligand
ligand-centric
methods to target-ligand
ligand structural methods. Depending on the target and the context, strengths and limitations of herein
present approaches are critically discussed.
Keywords: chemogenomics, drug design, ligand, selectivity
PACS: 87.15.A- , 87.15.B-

INTRODUCTION

Computational
omputational and medicinal chemists have traditionally been focusing their efforts in designing and synthesizing
compounds targeting a single protein. Significant advances in miniaturizing chemical and biological experiments led
the pharmaceutical industry to massively invest in high-throughput
high screening robots able to screen several million
compounds. Since this key information was obviously not publicly available, drug designers have been in the
paradoxical situation where academic scientists had enough time time to mine a huge amount of data that they were
lacking, whereas their industrial colleagues were in possession of the data but not of the intellectual freedom to
efficiently analyze it. Public initiatives to release previously hidden data [1, 2],, archive published information [3] or
even to generate them [4] have significantly changed the situation. Million of bioactivity data points are now
available for learning and prediction. Scientific and economic pressure to design drugs with controlled selectivity
profiles as well as the recent boost of drug repurposing led to the development of in silico ligand profiling methods
aimed at (i) predicting potential targets (and thus a mechanism of action) for orphan bioactive bioacti ligands, (ii)
identifying off-targets
targets responsible for side effects and adverse reactions, (iii) propose novel targets for existing
drugs. From a conceptual point of view, three main approaches with different starting points are possible. They will
be reviewed
viewed from here on with an emphasis on success stories.
Ligand-Centric Methods
Ligand-based
based methods follow the simple assumption that similar ligands bind to similar targets. Considering that
pair-wise ligand similarity measurements are very fast, it is therefore relatively easy to prioritize a few targets for
potential binding to a query ligand (FIGURE 1).

FIGURE 1.
1 Ligand-based approach to predict target-ligand
ligand interactions
From a technical
nical point of view, one just needs a database of target-annotated
annotated compounds, a chemical descriptor and
a similarity metric. Many bioactivity databases are available. Interestingly, two independent reviews found that
academic and commercial databases do no nott overlap very much and that merging them while removing data
d

Theory and Applications in Computational Chemistry: The First Decade of the Second Millennium
AIP Conf. Proc. 1456, 157-164 (2012); doi: 10.1063/1.4730655
2012 American Institute of Physics 978-0-7354-1057-2/$30.00

157
redundancy is desirable [3, 5].
Three research groups have mainly contributed to establish the proof-of-concept
proof concept that pairwise ligand similarity
searches is an efficient way of identifying novel targets forr known ligands. The NIBR (Novartis Institute for
Biomolecular Research) has pioneered the usage of ligand circular fingerprints to establish target-specific
target QSAR
models by training machine learning algorithms (Nave Bayes, Support Vector Machines) to discriminate disc true
actives from inactive compounds [6-8].
[6 . On average, the correct target was found 77% of the time when a multiple
category Bayesian model was applied to external test sets [8].
Shoichet's group at UCSF has developed the Similarity Ensemble Approach (FIGURE (FIGURE 2)[9]
2 in which a query
ligand is compared to 246 target-specific
specific ensemble of compounds (activity classes) by means of a simple Tanimoto
coefficient measurement on Daylight topological finge
fingerprints. The approach was successfully applied to predict the
possible binding of 3,665 FDA-approved
approved drugs to 246 MDL Drug Data Report (MDDR) targets [10]. Among all
possible combinations,, 30 were prioritized based on the statistical significance of the computed similarity scores. 23
associations could be confirmed experimentally, out of which 5 were very potent (Ki < 100 nM) [10]. The SEA
approach could later be applied to predict the possible binding of 746 commercial drugs to the protein
farnesyltransferase (PFTase), a major target enzyme for developing antitumoral drugs [11]. Among investigated
drugs, the antiallergic drug Loratidine (H1 histamine antagonist) and the antifungal agent Miconazole (14-
demethylase inhibitor) were successfully predicted to bind to PFTase with low micromolar affinities [11].

A B

FIGURE 2. Two strategies of ligand-based

ligand target fishing. A) Similarity Ensemble (SEA) Approach. A query ligand is
systematically compared to sets of target-annotated
target annotated ligands. Similarity is expressed by a Tanimoto coefficient to multiple ligands
and annotated by an expectation value by analogy to amino acid sequence alignments. B) Interpolating the affinity (F) of a query
ligand (triangle) from weighted distances (wifi) of its nearest neighbors (A,B,C,D) in the chemical
hemical descriptor space. pKi values of
the neighbors are indicated in brackets.

Mestres et al. uses a conceptually similar but technically different approach based on Shannon Entropy
Descriptors (SHED) computed from the distribution of atom-centered
atom centered pharmacophoric feature pairs [12]. This
structural
tural descriptor was used to annotate a library of 2,0000 nuclear hormone receptor (NHR) ligands covering 25
receptors, and to predict potential off-target
off target NHR binding by a set of 3,000 current drugs [13]. The approach was
later extended to a larger er set of ca. 700 therapeutically relevant targets [14] and appliedappl to predict the
polypharmacological profile of 482 novel heterocyclic compounds against a restricted set of 86 GPCRs [15]. 23 of
these target-orphan
orphan compounds received an annotation for at least one receptor, according to the corresponding pair-
pair
wise similarity to known GPCR ligands. Since the four adenosine receptors (A1, A2A, A2B, A3) were frequent hitters,
10 ligands were screened in vitro for binding to the four adenosine receptors. 2 of them were confirmed to be
micromolar antagonists of the A2B and A3 receptors, respectively [15].. Chemical similarity to both ligands led to 282
additional commercially-available
available compounds which were then virtually profiled against the four adenosine a
receptors. Of particular interest were eight compounds predicted to target the previously unreached A1 and A2A
adenosine receptors. Three of them were conformed to be relatively selective micromolar antagonists of the later 2

158
receptor subtypes [15]. All above reported studies make use of 2-D 2 D topological fingerprints to describe ligands.
Interestingly,
ly, a recent report comparing the merits of 2-D2 and 3-D D ligand descriptors suggests that 2-D2 descriptors
are better suited to predict main targets whereas 3-D D descriptors are better to identify off-targets
off [16]. Due to the
lack of exhaustive and public profiling data, the accuracy of ligand
ligand-based profiling methods
thods is still unknown. A first
answer was recently given by Vidal et al. [17] who tried to recover er a recently published binding data matrix of 13
known antipsychotics on 34 targets [18].. Relying on a reference set of 21,100 compounds with known binding
affinities for the 34 targets, inhibition constants of the 13 drugs to the 34 targets were predicted from drug neighbors
in the reference set close in chemical descriptor space by an inverse
inverse distance weighting interpolation. The scope of
predictability as well as the recall was shown to rise with the binding affinity range whereas the precision was
following the inverse relationships. Promisingly, 65% of all affinities could be predicted withwi a log unit error with a
precision of 92% [17].
Binding Site
Site-Centric Methods
The second group of method assumes that similar binding sites recognize similar ligands. Any novel binding site
close enough to binding sites with known ligands is therefore likely to bind the latter ligands (FIGURE 3).

FIGURE 3.Binding
3 site-based approach to predict target-ligand
ligand interactions

Sequenced-Based Approaches

4) The simplest possible description of a binding site is its amino acid sequence. This representation is however
limited to targets of the same family for which the full sequence alignment is usually unambiguous. When applied to
a set of 372 non olfactory G Protein-coupled
Protein receptors (GPCRs), a binding site-biased
biased phylogenetic tree was almost
identical to that derived from full sequence alignments[19],
alignments , with the advantage that its interpretation
interp is much easier
since it is restricted to a fixed and limited number of residues. Receptors close in this focused tree, whatever their
full sequence identity (sometimes below 20%) are therefore likely to share very similar ligands, as exemplified in
many recent reports (FIGURE 4)

O F
N N N
O
N
OEt NH
N N
N O
H
N N

O OH N N
N
H OMe

Candesartan cpd 3 Astemizole

Ki (AT1) = 0.17 nM Ki (GPRC6A) = 18 M pIC50 (H1) = 7.4
Ki (CRTH2) = 2.1 M Ki (mGluR5) = 56 M pIC50 (SST5R) = 5.4

FIGURE 4. Crossreactivity of GPCR ligands inferred from binding site sequence similarities [20-22].
[20 The substructure
responsible for cross recognition (binding theme) is displayed in bold.

159
 Structure-Based Approaches
Comparing binding site sequences is however restricted to protein subsets and cannot be extended to a large
array of targets. Structural approaches to binding site similarity detection, notably in absence of fold conservation,
are necessary to decipher
ecipher subtle relationships among unrelated targets [23, 24].
The SOIPPA algorithm [25] was designed and applied to detect similarity between unrelated proteins. Starting
from a graph representation of protein C C atoms with a geometric potential and position-specific
position amino acid score
assigned to each graph node [26],, a maximum common subgraph is detected to align two proteins. The SOIPPA
method was successfully used to predict the crossreaction of catechol-O-methyltransferase
methyltransferase inhibitors (entacapone,
tolcapone) with the M.tuberculosis enoyl-acyl carrier protein reductase [27]. The SOIPPA site comparison method
was recently embedded in a flowchart involving subsequent docking to potential off off-targets
targets to remove potential false
positives and integration of remaining off-targets
off in drug-target
target networks and metabolic pathways [28, 29].
Systematic pair-wise
wise comparison of the staurosporine-binding site of the proto-oncogene
oncogene Pim-1
Pim kinase with
6,415 druggable protein-ligand
ligand binding sites [30] using the SiteAlign algorithm [31] suggested that the ATP-binding
ATP
site of synapsin I (an ATP-binding
binding protein regulating neurotransmitter release in the synapse) may recognize the
pan-kinase
kinase inhibitor staurosporine [32]. Biochemical validation of this hypothesis was realized by competition
ATP 35S for binding
experiments of staurosporine with ATP- inding to synapsin I. Staurosporine, as well as three other inhibitors
of protein kinases (cdk2, Pim-11 and casein kinase type 2), effectively bound to synapsin I with nanomolar affinities
and promoted synapsin-induced F-actinactin bundling. The selective Pim-1
Pim kinase inhibitor quercetagetin was shown to
be the most potent synapsin I binder (IC50 = 0.15 M), M), in agreement with the predicted binding site similarities
between synapsin I and various protein kinases. Other protein kinase inhibitors and ATP--competitors did not bind to
synapsin I, as predicted from a lower similarity of their respective ATP
ATP-binding
binding sites to that of synapsin I.
I Cavity
comparisons can even lead to pocket deorphanization. The chemogenomic analysis is not restricted to comparing co
druggable-ligand
ligand binding sites. Davis et al. reported an exhaustive alignment of overlapping protein-protein
protein and
protein-ligand
ligand binding sites to select cavities amenable to modulate protein-protein
protein protein interaction with drug-like
drug
compounds [33].. The analysis was able to recover known protein
protein-protein
protein interaction inhibitors and to propose novel
interfaces that may be targeted by small molecular-weight
molecular compounds.

Protein-Ligand-Centric Methods
Protein-ligand-centric
tric methods use information from both targets and their cognate ligands to predict novel data
(FIGURE 5).

FIGURE 5. Integrated protein-ligand

ligand approaches to chemogenomic in silico screening. Ligands can be retrieved from public
databases (e.g. PubChem, ChEMBL) and docked to protein 33-D D structures of interest (PDB: X X-ray and NMR structures;
ModBase: 3-D D comparative models) to yield protein
protein-ligand docking matrices. Alternatively, protein
tein-ligand complexes or models
can be used as starting points to generate 3-D
3 D pharmacophore databases and subsequently pharmacophore-ligand
pharmacophore fitness matrices.
Last, machine learning methods can be trained to discriminate true protein
protein-ligand
ligand complexes (even of unknown 3-D structures)

160
using simple fingerprints embedding protein (or active site) and ligand structural information, and finally to yield binary protein-
ligand association matrices.

Parallel Docking of Ligands to Multiple Proteins

Despite docking is a slow computational procedure amenable to serious errors in estimating binding free energies
[34], it is the method which has the most successfully be used to discover new targets for existing ligands (TABLE
1). The main reasons for this observation is that (i) molecular docking is probably considered as the most logical
approach to predict protein-ligand interactions, (ii) many docking programs of almost comparable accuracy are
available. The most critical issue is probably to set-up a collection of interesting binding sites from protein-ligand X-
ray structures. Among the few possible options, the sc-PDB dataset of druggable protein-ligand binding sites is the
current largest collection offering nearly 10,000 binding sites suitable for molecular docking [35].

TABLE 1. Target-ligand interactions predicted by reverse docking.

Docking Nr. of targets Ligand Novel target Reference
program
FlexX 400 -winiferin PDE4 [36]
FlexX 400 meranzerin COX1, COX2, PPAR- [37]
TarFisDock 698 HTS hit Peptide deformylase [38]
Gold 2100 1,3,5-triazepan-2,6-diones sPLA2 [39]
GlamDock 6000 6-bromo-indirubin-3oxime PDK1 [40]
Dock 845 sulfonamides HLA-Cw*4 [41]
Dock 384 clozapine HSPA1A [42]
ICM 252 nilotinib MAPK14 [43]

Reverse docking was successfully applied to identify the main targets of bioactive natural compounds [36-38]
and of a diversity set of compounds from a scaffold focussed combinatorial library [39]. It was also applied to
identify secondary targets for known protein kinase inhibitors [40, 43] and to discover unintended off-targets for
known drugs thereby proposing a molecular explanation to observed side effects [41, 42]. Interestingly, success was
neither restricted to a particular docking algorithm nor to particular protein classes suggesting that the method can be
broadly used. The major problem with the method is the difficulty to rank order, by increasing binding energy,
proteins exhibiting very heterogeneous properties of their binding cavities [44]. Statistical and topological
approaches to post-process docking results clearly enhance the accuracy of docking-based target screening. Usage of
docking scores in consensus with rank information [43], normalizing the docking score matrix [41] and scoring by
interaction fingerprint similarity[45] are possible approaches to overcome the inaccuracy of scoring functions.

Pharmacophore-based parallel screening

Instead of docking compounds to protein-ligand binding sites, it is faster to just check whether the ligand fulfils
pharmacophore features derived from protein-ligand complexes. This concept was brought first by Langer et al. [46]
for profiling bioactive ligands against a small collection of structure-based pharmacophores. Starting from protein-
ligand complexes of known X-ray structure, pharmacophore hypotheses are generated by an automated
pharmacophore perception algorithm [47] and converted into pharmacophore queries. The protocol was validated
on set of known protein-ligand complexes [46] spanning various activity classes, embedded into an automated
workflow and successfully used to assign three targets to two secondary metabolites from the medicinal plant Ruta
graveolens [48]. Currently, more than 2,500 pharmacophore models are available for parallel virtual screening as
part of the Inte:Ligand Pharmacophore database. It covers 300 unique clinically relevant pharmacological targets
originating from major therapeutical classes as well as antitargets such as the human Ether--go-go Related Gene
(hERG), and members of the cytochrome P450 family. The PharmMapper server [49] offers a free resource to fish
targets by a reverse pharmacophore search. It encompasses a database of 7,000 protein-ligand-derived
pharmacophores (PharmTargetDB) and a fast ligand-to-pharmacophore fitting tool enabling a full screening within
1-2 h. The method was only validated on the classical examples of tamoxifen and methotrexate and permits to
retrieve true targets of those two drugs among the top scorers. Complex-based pharmacophore models may be
complemented by classical ligand-based pharmacophores to augment the scope of applicability, notably to protein
classes (e.g. membrane proteins) for which few experimental structures but numerous ligands are available.

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 Protein-ligand fingerprint similarity searches

Contrarily to reverse docking and pharmacophore searches, protein-ligand fingerprints can be encoded in very
simple bit strings or vectors describing ligand and protein properties [50]. Ligand and protein fingerprints can be
either concatenated [51, 52] or compared using separate kernels [53]. Machine learning algorithms (Support Vector
Machines, Random Forest, Naive Bayes) are trained on known positives (true complexes) and negatives (false
complexes) to discriminate attributes of true and false complexes and further predict novel associations with a
precision close to 80 % [52]. Binary predictions (true or false complex) are easier to implement than inhibition
constant predictions for the simple reason that training datasets are larger. State-of-the art prediction of 542
inhibition constants (pKi values) using such a method reaches an acceptable accuracy (r2 =0.53, root-mean square
error of prediction of 1.50)[54] considering the very heterogeneity of the training data. Interestingly, the most
precise protein kernel (based on binding site similarities for example) is not necessarily the most reliable. Bajorath
and colleagues [55] suggested that simplified strategies for designing target-ligand SVM kernels should be used
since varying the complexity of the target kernel does not influence much the identification of ligands for virtually
deorphanized. In agreement with a previous work [53] on three target classes (GPCRs, enzymes, ion channels), our
own experience with 7,000 druggable protein-ligand complexes from the Protein Data Bank suggests using
chemogenomic models (ligand + target descriptors) only if less than 30-50 ligands are available for each target [56].
Moreover, 3-D binding site descriptors did not outperform simple sequence-based descriptors when a
chemogenomic model was usable [56]. Due to their novelty, there are rather few successful applications of
chemogenomic models in the literature. Weill et al reported the use of concatenated protein and ligand fingerprints
(PLFP) to find nonpeptide oxytocin receptor ligands among a database of 336,000 commercially available drug-like
compounds [57]. Interestingly, the chemogenomic method provided more validated hits than other virtual screening
methods (2-D and 3-D similarity search) used in parallel. Using a sequence-based protein descriptor and structural
ligand features, a SVM model was trained on 626 proteins and 10,000 active compounds to discover, among a
library of 85,000 drug-like compounds, nine novel active compounds for four pharmaceutical targets (GPR40,
SIRT1, p38, GSK-3) [58]. A similar approach was reported to predict the binding affinity of non nucleoside
inhibitors to 14 HIV-1 reverse transcriptase mutants and therefore prioritizing the most interesting lead compound
with respect to known and still unknown protein mutant sequences [59].

Pros and Cons of Ligand Profiling Methods

Many computational methods are available for screening target libraries. On the one hand side, ligand-centric
methods are very fast but rely on the existence of prior knowledge (bioactivity data) and target-specific QSAR
models. These methods can be applied to the most interesting pharmaceutical targets but not to those for which
ligands remain to discover (orphan targets for example). On the other side, target-based approaches (binding site
similarity, pharmacophore search, docking) are restricted to the few macromolecules for which a high-resolution 3-
D structure is available. These methods are slow but provide a plausible binding mode to each selected target. Last,
a category of emerging computational methods (chemogenomic or proteochemometric methods) relies on both
ligand and target information to predict novel associations or binding data. The main development in the field of
ligand profiling will be the design of intelligent workflows utilizing the best possible method for the target of
interest depending on the local context (ligand knowledge, protein structure, binding site properties). Such hybrid
workflows could be applied to a very large protein set (> 5000 targets) with reasonable accuracy to prioritize the
most likely targets for experimental validation. Having a list of putative targets in hands, a logical follow-up will be
next the prediction of possible side effects for the query compound.

ACKNOWLEDGMENTS
The author thanks many former and current collaborators (Esther Kellenberger, Jean-Sbastien Surgand, Pascal
Mller, Claire Schalon, Jamel Meslamani) for their invaluable contribution to the in-house development of novel
chemogenomic methods.

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 Accelerated Molecular Dynamics: Theory, Implementation
and Applications
Yi Wang and J. Andrew McCammon
Center for Theoretical Biological Physics, Howard Hughes Medical Institute, Department of Chemistry and
Biochemistry, Department of Pharmacology, University of California, San Diego, La Jolla, 92093, USA

Abstract. Accelerated molecular dynamics (aMD) is an enhanced-sampling method that improves the conformational space
sampling by reducing energy barriers separating different states of a system. Since it was rst proposed by Hamelberg et al. (J.
Chem. Phys., 120:11919, 2004), the method has been applied to study a variety of biological and chemical problems. AMD is
now available in several major molecular dynamics programs and its applications range from protein and lipid conformational
sampling to ab initio and free energy calculations. Here we briey review the development of the aMD method, focusing on its
theory, implementation and applications. Through discussions of several examples, we also comment on potential directions
of future development of the aMD method.
Keywords: Accelerated molecular dynamics, enhanced sampling, free energy calculation, conformational sampling

PACS: 82.20.W, 87.15.A-, 87.15.ap

INTRODUCTION
Molecular dynamics (MD) has become one of the most widely used computational techniques in theoretical biology
research. MD trajectories, obtained from integration of the Newtonian equations of motion, offer a microscopic
picture of the system under study. Based on the principles of statistical mechanics, these trajectories are then used
to calculate macroscopic thermodynamic properties. In recent years, the rapid improvement in computational software
and hardware has allowed MD studies of a wide range of biological and chemical problems [1, 2, 3, 4, 5, 6]. However,
despite these successful applications, there remains a substantial gap between the timescale of current MD simulations
and that of typical biological processes, the former of which is usually on the order of tens to hundreds of nanoseconds,
while the latter may be many microseconds, milliseconds, or even longer. To bridge this gap, various enhanced
sampling techniques have been proposed to expedite the sampling of an MD simulation, such as conformational
ooding [7, 8], hyperdynamics [9, 10], metadynamics [11, 12], and the adaptive biasing force method [13, 14, 15] (to
name only a few). Accelerated molecular dynamics (aMD) [16], inspired by earlier work of Voter [9, 10], also belongs
to this class of enhanced sampling methods.
Since it was rst proposed by Hamelberg et al. [16], the aMD method has been applied to study a variety of
protein and lipid systems. The theory of aMD has also been further extended and various forms of the algorithm,
including replica-exchange aMD [17] and selective aMD [18], have been proposed to address specic biological or
chemical questions. In addition, while the aMD implementation was originally limited to in-house modications of
MD programs, it has recently been added to several major simulation softwares that are free of charge to academic
users. In this article, we will review the development of the aMD method in the past few years, discuss the choice of
aMD parameters and then comment on the advantages and limitations of the method.

AMD: THE THEORY

In the original form of aMD [16], when the systems potential energy falls below a threshold, E, a bias potential is
added, such that the modied potential, V (r), is related to the original potential, V (r), via

V (r) = V (r) + V (r), (1)

Theory and Applications in Computational Chemistry: The First Decade of the Second Millennium
AIP Conf. Proc. 1456, 165-172 (2012); doi: 10.1063/1.4730656
2012 American Institute of Physics 978-0-7354-1057-2/$30.00

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FIGURE 1. Schematics of the aMD algorithm. The parameter E determines the portion of the energy surface boosted in aMD,
while determines the shape of the modied potential.

where the boost potential V (r) is given by,


0 V (r) E
V (r) = (EV (r))2 (2)
+EV (r) V (r) < E.

Here, E is a user-specied threshold that determines the portion of the energy surface affected by the boost potential,
and determines the shape of the modied potential: the smaller , the more attened the energy surface becomes
(gure 1). As increases, the modied potential asymptotically approaches the original potential; as decreases,
the energy surface below E begins to resemble a constant potential. A key feature distinguishing aMD from the
hyperdynamics method by Voter [9, 10] is that the Hessian matrix is no longer diagonalized at every step, which
is needed in hyperdynamics to identify the transition state. Such an expensive calculation is also avoided in the
method proposed by Rahman and Tully [19]. However, their method completely attens the potential surface near
an energy well, thereby, introducing a discontinuity in the derivative of the potential. As a result, a special integration
technique is adopted to traverse points where V (r) = E. In aMD, since the boost potential has a quadratic form, the
corresponding derivative is always continuous, thereby, allowing the method to be readily implemented in classical
molecular dynamics (cMD) programs. Nevertheless, as pointed out by Hamelberg et al. [16], it is important to choose
an value that is much greater than zero in order to avoid the theoretical issue described here.
From an aMD simulation, the ensemble average of an observable can be calculated using the following reweighting
procedure: 
dr A(r) exp(V (r))
A =  (3)
dr exp(V (r))
 
dr A(r) exp(V (r))  dr exp(V (r))
=   (4)
dr exp(V (r)) dr exp(V (r))
 
dr A(r) exp( V (r))exp(V (r))  dr exp( V (r))exp(V (r))
=   (5)
dr exp(V (r)) dr exp(V (r))
A(r) exp( V (r))
= , (6)
exp( V (r))
where =1/kB T , with kB standing for the Boltzmann constant and T standing for the temperature. ... and ...
represent the ensemble average in the original (unbiased) and the aMD (biased) ensembles, respectively.
In a nutshell, the enhanced sampling in aMD is achieved by reducing energy barriers separating various states of the
system. Take a somewhat extreme example, when becomes very small, the modied potential below E approaches a
constant energy surface, in which case all the enthalpic barriers are removed and sampling is only limited by entropic
contributions as well as diffusion in the conformational space. In practice, however, using a very small not only
pushes the theoretical limit of the method as described above, but also generates signicant noise in the reconstructed
ensemble average (Eq 6). As detailed in Shen et al. [20], the reweighted average can be dominated by a few data
points with large values of V in highly accelerated simulations. Therefore, optimal aMD parameters must ensure
enhanced sampling while maintaining a reasonably low statistical noise in the reweighted results. Before we discuss

166
the choice of parameters, below we rst review the theoretical development of the aMD method in the past few years.
Each of the newly developed aMD algorithms, such as replica-exchange aMD [17] and selective aMD [18], was aimed
at improving the sampling performance of the method and/or statistical quality of the results with a focus on specic
biological or chemical applications.

Dual-boost aMD
Since protein conformational changes tend to be governed by changes in the torsional degrees of freedom, the aMD
method was originally applied to only boost the dihedral potential [16]. The follow-up study by de Oliveira et al.
extended the method to boost the total potential of the system [21]. The authors performed extensive analysis on a
box of TIP3P water molecules and identied a set of optimal acceleration parameters that increase solvent diffusion
while maintaining the structural features of liquid water. Based on these parameters, a dual-boost aMD method was
tested, where separate boost potentials are applied to the dihedral and the total potential, respectively [22]. This method
revealed enhanced protein conformational sampling compared with only boosting one type of potential. The reduced
viscosity of water is suggested to play a key role in this speedup. Following these results, the dual-boost aMD has
been applied to study a variety of protein systems [23, 24, 25, 26].

Replica-exchange aMD
Given the statistical noise in aMD reweighting, Fajer et al. [17] set out to explore the use of replica exchange
method to address this issue. Similar to the work by Xu et al. [27], their REXAMD belongs to the class of Hamil-
tonian replica-exchange methods, where a number of aMD simulations are performed at various acceleration levels.
Because ensemble average can be obtained directly from the ground replica with zero acceleration, statistical noise is
signicantly reduced. Meanwhile, enhanced sampling is achieved through the exchange with replicas at high acceler-
ation levels. The efciency and performance of REXAMD in free energy calculations were rst tested on a zero-sum
chemical transition, ethane-to-ethane, and then on a more challenging case involving a halogenated butane. Both tests
clearly revealed the faster convergence of REXAMD than cMD and demonstrated decent acceptance ratio for replica
exchange [17].
While REXAMD improves the statistical quality of aMD reweighting, the computational efciency is limited in
the original algorithm, since only information from the ground replica is used to generate the free energy data.
Employing the multistate Bennett acceptance ratio (MBAR) method, Fajer et al. [28] further extended REXAMD
and used MBAR to combine information from simulations at all acceleration levels. Their study indicates that the
MBAR approach provides better performance than weighted histogram, a traditionally used multistate method [28].
Combining MBAR and REXAMD signicantly improves the computational efciency of the latter method, while
maintaining its advantage in statistical reweighting over the original aMD approach. Initially implemented in AMBER,
REXAMD is now being added into the program NAMD (personal communication with Mikolai Fajer).

Selective aMD
Since the statistical noise in aMD results is directly related to the boost potential applied in the simulation, another
direction to improve the quality of reweighting is to reduce the boost potential V . However, reducing V via
lowering the acceleration level will also diminish the advantage of enhanced sampling. After all, when the boost
potential approaches zero, aMD becomes comparable to classical MD simulations. Using the cyclophilin A system
as a test case, Hamelberg and McCammon [29] showed that enhanced sampling can still be achieved by applying the
boost potential to a selected number of atoms in the system. Wereszczynski and McCammon further demonstrated
the superior performance of selective aMD than the original, boosting-all-dihedral aMD. Through evaluation of the
binding free energy of the clinically approved drug oseltamivir and the N1 u protein neuraminidase, they showed that
the computational cost of the latter method could be reduced by as much as 70% in selective aMD. Selective aMD
therefore offers an efcient approach to lower the statistical noise in reweighting while maintaining the performance
of enhanced sampling. This method is implemented as an in-house modication of the highly parallel MD program
DESMOND (version 2.2) [18].

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 Other development
One of the latest additions to the family of aMD algorithms is the adaptive aMD method (Ad-AMD), where the
threshold energy E is adjusted based on the history of the simulation. As detailed in Markwick et al. [30], the method
denes an adaptive threshold energy E based on the rst two principal components obtained from analysis of available
X-ray crystal structures of the target protein. The adaptive nature of E arises from a history-dependent, Gaussian-
shaped potential that is added to E every 500 ps. As suggested by the authors, Ad-AMD only samples low-energy wells,
thereby, avoiding the statistical noise introduced by attening the entire potential energy surface. This method has been
applied to study the conformational plasticity of the protein P450cam [30] and to perform ab initio calculations on the
double proton transfer reaction in a formic acid dimer [31]. We will describe the latter application in more detail in the
following sections.
Apart from the aMD algorithms described above, which all involve raising energy wells in the potential surface, de
Oliveira et al. [32] proposed an alternative lowering-barrier version of aMD, where the boost potential is dened as:
(E V (r))2
V b = (7)
+V (r) E
In contrast to the original aMD method, V b is only applied when the potential V (r) is above the threshold energy E.
This implementation reduces the statistical noise in reweighting by allowing much of the simulation to remain in the
original potential surface. However, a drawback is that the system may sample states that are originally inaccessible
due to large energy barriers. Recently, Sinko et al. [33] extended the lowering-barrier aMD method and modied the
form of the boost potential:
(V (r) E1 )2
V c = (8)
(1 +V (r) E1 )(1 + e(E2 V (r))/2 )
where the parameters E1 and 1 represent the original aMD parameters, while E2 and 2 are used to protect the high
energy barriers. Through three test cases, the authors demonstrated that the new boost potential prevents the system
from visiting highly unfavorable states while maintaining the enhanced sampling performance of aMD.

IMPLEMENTATION
Despite its relatively simple algorithm, implementation of the aMD method into a molecular dynamics program
requires careful design to avoid signicant performance hit. This issue is especially pertinent to highly parallel
programs, such as NAMD [34]. The NAMD implementation of aMD [35] requires the addition of a new reduction
class to access the systems potential energy right after the force evaluation at each timestep. This design guarantees
minimal interference between the aMD module and the regular MD workow, where energy reduction is performed at
the end of each timestep. As a result, no performance hit is seen when the aMD option is turned off, and benchmark
simulations have shown that aMD runs using NAMD gives performance similar to cMD simulations, with a 7%-12%
slowdown depending on the specic algorithms used [35].
Since its rst implementation, the aMD method has been primarily developed within the framework of the sander
module in the program AMBER [16]. However, nearly all these implementations are based on in-house modications
of the program, making it difcult for other users to access the aMD method. Apart from the recent NAMD implemen-
tation described above, aMD has also been added into PMEMD, the highly parallel module of the AMBER program,
and is scheduled for release in 2012 (personal communication with Levi Pierce, Romelia Salomon-Ferrer and Ross
Walker). Additionally, taking advantage of the rapid development of graphical processing units (GPUs), the PMEMD-
aMD implementation has been ported to GPUs and has demonstrated superior performance: Benchmark simulation
performed on a single GPU is faster than the same simulation performed on 96 CPUs (personal communication with
Levi Pierce, Romelia Salomon-Ferrer and Ross Walker). As these software and hardware developments continue, the
various aMD methods described above will become increasingly accessible to expert and novice users alike.

APPLICATIONS
Since its rst application on the alanine dipeptide [16], the aMD method has been used to study a variety of biological
and chemical problems, ranging from protein and lipid conformational sampling to quantum mechanical and free

168
energy calculations. Below we focus on a few examples of these applications and direct the readers to a couple of
recent reviews [36, 37] for more details.

Free energy calculation

As described in the previous section, the aMD method should reproduce the correct ensemble average of an
observable, such as the free energy prole, or, potential of mean force (PMF) of the system along certain reaction
coordinate. As a result, free energy calculation is often used as a test to evaluate the performance of various aMD
algorithms. For instance, as a canonical representation of protein backbone conformations, the - dihedrals of
alanine dipeptide have been studied extensively using aMD [16, 22, 18, 35, 33]. The PMF of the - dihedrals is
obtained through post-processing an aMD trajectory to generate a reweighted 2D histogram [35],
K
Hi j = ki j exp( Vk ), (9)
k=1
where K is the total number of snapshots in the simulation, Vk is the boost potential at snapshot k, and ki j is an
indicator function that denotes whether the - dihedrals at snapshot k fall within the bin (i , j ),

1 (, )k (i , j )
ki j = (10)
0 otherwise.
The - free energy prole is then determined by
Wi j = kB T lnHi j +W0 , (11)
where W0 is an arbitrary constant.
Following the above protocol, the - free energy proles of alanine dipeptide in both gas-phase and bulk water
have been obtained and compared with the results of umbrella sampling or metadynamics [16, 18, 35]. These tests
consistently indicated that aMD reproduced the correct ensemble average. Based on these results, aMD has been
applied to calculate free energy proles for more complex biomolecular systems [38, 22, 18]. A recent example is
the calculation of decalanine folding using the new lowering-barrier aMD described earlier. In this study, Sinko et
al. [33] used the rst two low-frequency principal components as reaction coordinates and calculated the folding free
energy prole of decalanine. Interestingly, apart from reproducing the result of a 350-ns cMD run, their 50-ns aMD
simulation revealed the fully-folded, -helical conformation of the peptide, which was not observed in the cMD run.

Protein conformational changes

Following its initial test on small peptide systems [38, 39], the aMD method has been widely applied to enhance the
sampling of protein conformations [40, 23, 41]. For instance, Grant et al. [24] used aMD to characterize the nucleotide-
dependent conformational transition of the protein Ras, an important signalling molecule that switches between active
and inactive states upon GTP- and GDP-binding, respectively. Their aMD simulations revealed a dynamic linkage
between the nucleotide-binding site and the C-terminus of the protein, the latter of which is critical for its signaling
function. Recent aMD studies of the maltose binding protein [26] and the proline racemase enzyme [25] also revealed
large structural transitions in these proteins that are not observed using cMD simulations. Of particular interest is
the latter system, which represents a novel target for chemotherapeutic intervention for Chagas disease. The aMD
simulations revealed for the rst time a model of the enzyme in the open form, which may expose critical residues that
are related to parasite persistence [25]. The structural information obtained from aMD simulations thereby provides
new insights for structure-based drug design against the Chagas disease.

Lipid diffusion and mixing

Apart from protein systems, Wang et al. [42] applied the aMD method to study lipid diffusion and mixing with
altogether 1.5 s simulations. Using three systems, a pure POPC bilayer, a pure DMPC bilayer, and a mixed

169
FIGURE 2. Enhanced lipid mixing in aMD simulations. A DMPC:POPC mixture is simulated for 70 ns using both cMD and
aMD methods. Figure made using data from Wang et al. [42].

POPC:DMPC bilayer, the authors examined the trans-gauche isomerization, lateral diffusion, and mixing of the lipid
molecules. AMD is found to signicantly enhance the lipid tail trans-gauche isomerization (up to 7.7 times speedup)
and lateral diffusion (up to 3.5 times speedup) for both lipid species. Furthermore, comparison with cMD simulations
revealed a signicant speedup in lipid mixing in the aMD simulation of the POPC:DMPC bilayer (gure 2). These
results demonstrate that apart from proteins, the aMD method is also an efcient approach to study lipid bilayers and
can be further extended to systems involving membrane proteins.

Estimation of kinetic rates

In recent years, major efforts have been devoted to the calculation of kinetic rates from aMD simulations [43,
44, 45, 46]. For instance, Hamelberg et al. [43] related the local roughness of the potential energy surface with the
effective diffusion coefcient of the system. Using the cis-trans-isomerization of Ser-Pro motifs as a test case, they
recaptured the kinetic rate of the system from multiple aMD simulations. Later, de Oliveira et al. [44] performed similar
calculations to estimate the rate of escaping from an -helical to a -sheet conformation of the alanine dipeptide.
More recently, Xin et al. [45] and Doshi and Hamelberg [46] further extended these methods. By assuming a constant
diffusion coefcient, they suggested that the kinetic rate on the unmodied potential surface could be obtained by
extrapolation of results from aMD simulations performed at multiple acceleration levels.

ab initio calculations
By far, the applications described above all involve classical molecular dynamics simulations. Recent studies have
also demonstrated the application of aMD in ab initio calculations to obtain free energy proles from rst principles.
Bucher et al. [47] described such an application of the ab initio aMD (A-AIMD) using the Car-Parrinello scheme.
Their rst test case is the gas-phase cyclohexane molecule. Using A-AIMD, the potential energy surface of this small
system is explored and various molecular conformers are identied, which also yielded accurate free energy statistics.
In a separate study, Pierce et al. [31] focused on the application of the adaptive aMD approach described earlier. Their
studies of the formic acid dimer and the methylene-cyclopropane revealed the advantage of using an adaptive threshold
energy in ab initio aMD simulations.

Other applications
Apart from the applications described above, aMD has also been used in entropy estimation [48], constant pH
simulations [49], as well as the calculation of NMR chemical shift [50]. For instance, in close collaboration with
experimentalists, Markwick et al. reported that the NMR chemical shift was best approximated by an ensemble of
structures obtained from aMD rather than a single, static crystal structure [50]. To this end, they performed twenty aMD
simulations on the ankyrin repeat protein I B. After extracting representative snapshots from the aMD trajectories,

170
cMD simulations and MM/PBSA analysis were performed to obtain free-energy-weighted molecular ensembles.
Chemical shifts calculated based on these ensembles provided substantial improvement over results obtained from
single crystal structures.

FUTURE DIRECTIONS
Compared with metadynamics [11, 12] and many other enhanced sampling methods, an advantage of aMD is the lack
of a pre-dened reaction coordinate: With no need to dene a reaction coordinate a priori, the method requires minimal
knowledge of the system being studied. As a result, aMD can be used to explore a system with little prior knowledge
of its conformational space and transition states. However, while the enhanced sampling performance of aMD has
been demonstrated as described above, several aspects of the method require further improvement. As mentioned
earlier, the exponential averages involved in the reweighting process tend to introduce large statistical uncertainties in
the aMD results. This issue has been found to be particularly problematic for large proteins, where high acceleration
levels may be required to facilitate the systems escape from the initial state. While methods such as REXAMD [17],
selective aMD [18] and the lowering-barrier aMD [32, 33] provide promising directions to resolve this issue, their
performance remains to be further examined through systematic studies of biomolecular systems larger than those
used in the initial tests. The implementation of REXAMD in the widely used program NAMD should signicantly
expedite such studies.
Although the aMD method has only two free parameters, E and (Eq 2), choosing proper values for these
parameters is highly non-trivial. Early aMD studies often included a parameter scan to select optimal values of E
and . For instance, Hamelberg et al. [16] suggested to set E to V , the average potential energy obtained from a
cMD simulation, and then set to E V . Later, de Oliveira et al. surveyed a series of parameters in their study of a
TIP3P water box using the total-boost aMD algorithm [21]. Based on these empirical formulas, Wang et al. [35] set
E to V  + cN, where N stands for the total number of atoms being accelerated and c is a constant set to 0.2 kcal/mol to
2.0 kcal/mol. While these empirical formula provide valuable starting points for future aMD simulations, the optimal
choice of E and has proven to be highly system-dependent. Therefore, new parameter scan needs to be conducted
for every new study, which can quickly become very expensive for certain systems. For this reason, a more robust
and systematic parameter selection protocol is needed to help researchers apply the aMD method on studies of large
biomolecular systems.

CONCLUSIONS
Sampling of the conformational space remains a challenge for MD simulations of most biologically relevant systems.
The aMD method tackles this problem by modifying the systems potential energy landscape and reducing barriers
separating different states. In this article, we reviewed the development of aMD in the past few years, with a focus on its
various algorithms, implementation, and applications. The aMD method, originally proposed by Hamelberg et al. [16],
has been adopted to study a broad range of systems, resulting in new algorithms such as selective aMD, replica-
exchange aMD, as well as ab initio aMD. These continued theoretical developments along with the implementation
of aMD in several major simulation programs now provide the basis for users to tackle a variety of biological and
chemical problems.

ACKNOWLEDGMENTS
This work is supported in part by the National Science Foundation, the National Institutes of Health, Howard Hughes
Medical Institute, Center for Theoretical Biological Physics and the National Biomedical Computation Resource.

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 Sampling and Statistics in Biomolecular Simulations
Hoon Sim , Karthikeyan Diraviyam , Akansha Saxena and David Sept,

Department of Biomedical Engineering and Center for Computational Medicine and Bioinformatics,
University of Michigan, Ann Arbor, MI 48103, USA

Department of Physics, Applied Physics and Astronomy, Rensselaer Polytechnic University, Troy, NY, 12180,
USA

dsept@umich.edu

Abstract. Biomolecular simulations typically produce data in the form of a trajectory where the structure and dynamics are
captured as a function of time. These data typically have inherent temporal correlations, however the many of the analysis
methods we use are developed for sets of independent data. Here we present some ideas and methods for analyzing simulation
data using bootstrapping techniques. Examples using molecular dynamics simulations are provided as illustrations.
Keywords: molecular dynamics, correlation, bootstrap, statistics
PACS: 02.70.Ns, 02.70.Rr

INTRODUCTION
The goal of nearly all biomolecular simulations is to sample the conformational space for the molecule(s) of interest.
The techniques used to carry out this sampling include molecular dynamics (MD), Monte Carlo (MC) and Brownian
dynamics (BD) simulations, and as one might expect each technique has particular advantages and drawbacks. The
objective of this manuscript is not to advocate for or against any particular simulation protocol but instead to address
issues related to how the resulting set of conformations is analyzed. In particular cases the interest may simply lie
in the observation of a singular event (i.e. opening of a binding cleft) but more commonly the objective is to make a
broader statement about conformational dynamics, often summarized using techniques such as principal component
analysis (PCA) or calculating measures like the root-mean square uctuations (RMSF). Both of these methods can
offer signicant insight and are immensely useful, however they are statistical techniques that are designed to work
with samples of independent data points. MC techniques produce conformations that are linked by reversible move
sets while both MD and BD produce a time series of conformations, and the correlation that is inherent in each of
these sampling methods violates the independent data assumption.
Fortunately, statistics is equally well equipped to deal with correlated data, and here we present some relatively
simple ideas on how to measure correlation in data sets (i.e. trajectories), how to sample these data sets based on this
correlation, and how use these metrics to ascertain how fast the sampling of conformational space is converging.

THE BOOTSTRAP
Statistical techniques are largely based on the idea of taking independent samples from a (large) population and making
an inferential statement based on this sample. From the Central Limit Theorem we know the sampling distribution
resulting from many random samples had particular properties: it is Normal, its mean converges to the population
mean, and the variance decreases as the inverse of the sample size. However, in the case where we only have a limited
set of data and, as in our case, that data has inherent correlations, we need to instead make use of the bootstrap.
The bootstrap is a method of approximating the sampling distribution from a single sample of the population [1]. It
is based on the concept of resampling where the single sample is treated like the population, and the resamples from
this population parallel what we would get with multiple, independent samples from a real population. The basic
steps in the procedure we present here are:
1. Determining how many independent data points (frames or structures) we have in the data set (trajectory).
2. Resampling of the data set based on the number of independent points
3. Repeating this resampling to create a bootstrap distribution

Theory and Applications in Computational Chemistry: The First Decade of the Second Millennium
AIP Conf. Proc. 1456, 173-179 (2012); doi: 10.1063/1.4730657
2012 American Institute of Physics 978-0-7354-1057-2/$30.00

173
Much along the lines of the Central Limit Theorem, the bootstrap distribution is largely Normal, it is centered close
to the population mean, and the spread of the distribution or the standard error of the mean is equal to the standard
deviation of our sample divided by the square root of the number of independent data points. We will discuss methods
to determine the number of independent data points in the following sections, but it should be emphasized that although
we can determine how many independent point we have, they are not evenly spaced through the trajectory and there
is not a unique set of independent points. For these reasons, the bootstrap brings additional advantages since the
distribution it creates is comprised of different samples of independent points.

FINDING INDEPENDENT POINTS

The rst step in the bootstrap method detailed above was to determine the number of independent data points we have
in our data set. Our focus here will be on MD and BD trajectories since these have a clear temporal correlation, but
the same types of methods could be applied to MC simulations. Having said that, there is no singular, unique method
of determining independence so the reader is encouraged to think of what might apply best to their own particular
situation. The methods outlined below are simply ones that we have tried and tested. All of the results shown here
were calculated in R [2] using the bio3d package [3].

Autocorrelation of RMSD
The root mean square deviation or RMSD is a common measure of the structural similarity of two proteins. It is
calculated using the simple formula 
atoms di2
RMSD = (1)
Natoms
where di is the distance between atom i in the two structures. As the time difference between two structures increases,
the RMSD increases as well. Another way of thinking of this is that the two structures begin highly correlated, but this
correlation decays with time and eventually the proteins forget about where they were at some previous time point.
We can measure this rate of decay using autocorrelation. If we write the RMSD at a time t as R(t) with a mean value
R and variance 2 , we can write the autocorrelation function as
(R(t) R)(R(t
+ ) R)

ACF() = . (2)
2
We can simply apply Eq. 2 to our data, however we face potential issues with convergence of the simulation. Our
goal here is not to address this problem or even suggest some method to x it since that is better discussed by others,
however one needs to ensure that the length of the simulation is many multiples of the longest observed correlation
time. In some cases the autocorrelation function may decay along a simple exponential, but for many of the problem
we will discuss here prefer a two-term exponential of the form

ACF() (1 ) exp(/s ) + exp(/l ) (3)

where we have two characteristic correlation times s and l .

Figure 1 shows RMSD plots and their autocorrelation analysis for three independent MD simulations of the protein
crambin, each simulation run for a total of 3 s. The RMSD was calculated using the nal structure at 3 s as the
reference point, but the results are largely equivalent whatever the chosen reference is. The short time constants s
we nd range of 0.27-2.9 ns for the three simulations. This time should correspond to the time between independent
structures within the trajectory, and the difference in values relates to the underlying potential energy surface. More
restrictive conformations have shorter correlation times since the proteins interaction with the local energy well leads
to faster dissipation. For crambin, a small 46 residue protein with multiple disulde bonds, these time constants
are reasonable. For larger proteins, we nd s values that approach 600 ps to 1 ns, but it is obvious that individual
trajectories can show signicant differences. The l values show a similar spread, and these time constants in the 25 to
80 ns range and would seem to correspond to the rate at which conformational space is being sampled.
The short correlation time s tells us that two structures separated by this time (or number of frames) have an average
correlation of 1/e  0.37. This may be sufciently independent for a given application, but in practice we tend to

174
 0.5
s = 0.75 ns, l = 40.9 ns

1.0
0.4
s = 2.9 ns, l = 80.3 ns
s = 0.27 ns, l = 24.5 ns

RMSD
0.3
0.2

0.8
0.1
0.0
0.0 0.5 1.0 1.5 2.0 2.5 3.0

Time (s)

0.6
0.5

ACF of RMSD
0.4
RMSD
0.3
0.2

0.4
0.1
0.0

0.0 0.5 1.0 1.5 2.0 2.5 3.0

Time (s)
0.5
0.4
RMSD
0.3
0.2
0.1

0.2
0.0

0.0 0.5 1.0 1.5 2.0 2.5 3.0 0 5 10 15 20

Time (s) Time (ns)

FIGURE 1. (Left) Backbone RMSD plots for 3 independent 3 s MD simulations of crambin. (Right) Autocorrelation plots of
the RMSD using the nal structure as the reference. The time constants are from tting the ACF plots using Eq. 3.

double this quantity so the average correlation is 1/e2  0.14. Since the trajectory is stored as a series of frames, it
is typically most useful to use the correlation times in units of frames as well. Using this, we can then calculate the
number of independent frames as
N f rames Ttotal
Nind = = . (4)
2s ( f ) 2s (t)
where s ( f ) and s (t) are the correlation times in units of frames or time respectively. In a later section we will discuss
how to use this quantity in the bootstrap formalism.

Principal Component Analysis

Principal component analysis or PCA is often used on trajectories to extract the large-scale motions of the
biomolecule and remove the high frequency, low amplitude uctuations of the protein. The method is based on di-
agonalizing the covariance matrix and rank ordering the Eigenvectors based on the Eigenvalues. The mass-weighted
covariance matrix is found by
1/2 1/2
Ci j = Mii (xi xi )M j j (x j x j ) (5)
where the vectors xi and x j represent the atomic coordinates of the molecule, M is the matrix of particle masses, and
the principal components are the set of Eigenvectors that diagonolize the covariance matrix. The largest Eigenvalue
of the covariance matrix is the rst PCA mode and represents the largest scale motion of the protein. It is also the
slowest motion and as we will see later its convergence dominates the convergence of the covariance matrix. Much
like RMSD, the projection of our trajectory on to this rst PCA mode exhibits correlations, and since this is the slowest
PCA mode, this will by denition have the longest correlation time.
Figure 2 shows the projection of our three crambin MD simulations on the rst PCA mode. In this case, the
covariance matrix was calculated using the combined set of trajectories. Interestingly, the time constants we nd
in this case are largely comparable with our earlier results using RMSD, particularly for the short correlation time s .
The long correlation times l are also within 10-20% of the values found from the autocorrelation of RMSD.

175
 3
s = 0.91 ns, l = 35.6 ns

1.0
2
s = 3.24 ns, l = 102.3 ns

1
s = 0.43 ns, l = 71.6 ns

PCA 1

0.9
0
-1
-2

0.8
-3

0.0 1.0 2.0 3.0

0.7
Time (s)
3

0.6
ACF of PCA1
2
1
PCA 1
0
-1

0.5
-2
-3

0.0 1.0 2.0 3.0

Time (s)
0.4
3
2
1
PCA 1
0
-1

0.3
-2
-3

0.0 1.0 2.0 3.0 0 5 10 15 20

Time (s) Time (ns)

FIGURE 2. (Left) Projection of our three crambin simulations on to the rst PCA mode, determine using the covariance matrix
for all three simulations combined. (Right) Autocorrelation of the PCA projections with best-t lines from Eq. 3.

One complication that we face with this approach is that the calculation of the covariance matrix in Eq. 5 again
assumes that the individual data points xi are independent. Since we know this is not true, we really need to develop
a self-consistent method where the covariance matrix is calculated by sampling based on some correlation time, and
then have the projection on to the rst PCA mode recover that same correlation time. A second problem is more
challenging, namely the PCA vectors and indeed the covariance matrix itself converge very slowly, and for short MD
trajectories the primary PCA modes are dominated by a strong cosine content that corresponds to diffusive motion.
Our crambin simulations are long enough that they do not exhibit this cosine behavior, however the three simulations
still are not completely equivalent and are not fully converged.

APPLYING THE BOOTSTRAP

Once we have an estimate of the number of independent frames in a trajectory, we are ready to apply the bootstrap.
Any measure that is calculated by averaging over a trajectory can essentially be recast using the bootstrap formalism.
We will discuss two applications: RMSF and covariance analysis.

Root Mean Square Fluctuations

One of the more common analysis methods is root mean square uctuations or RMSF. This is found using the
formula 
f rames (ri ri )2
RMSF = (6)
N f rames

176
RMSF is a time averaged quantity calculated for over all the frames of a trajectory where we calculate the mean square
uctuations of atomic positions ri from their average value ri . For our purposes, a more useful form of the equation is
  1/2
RMSF = E (ri E[r])2 (7)

where we have introduced operator E, the expectation value. When we apply the bootstrap we are simply calculating
the expectation value E using repeated bootstrap sampling instead of simply averaging over all observations. We have
two expectation values to calculate in Eq. 7. The rst quantity E[r] is the mean structure from the trajectory, and in
this case applying the bootstrap does not change anything since it simply returns the arithmetic mean, i.e. the same
average structure that would always be used for RMSF. Once we have E[r], we can calculate the outer expectation
value in Eq. 7 but now we need to sample the structures ri from the trajectory. Since we have determined that we have
Nind frames in our trajectory, we will randomly sample with replacement from our trajectory and use this set of frames
to calculate a bootstrap estimate of the RMSF. By repeating this procedure hundreds to thousands of times we will
get a (Normal) distribution of RMSF values where the mean of the distribution is our estimate for the RMSF and the
standard deviation of the distribution is the standard error of our estimate.
7

2.0
RMSF
6

1.0
5

0.0
RMSF
4

50 60 70 80 90 100
Residue
3
2
1

0 100 200 300

Residue

FIGURE 3. Bootstrap RMSF results for three independent 100 ns MD simulations of the protein actin (375 AA). The shaded
bands represent a 95% condence interval for each RMSF curve.

Figure 3 shows bootstrap RMSF results for three independent simulations of the protein actin, each 100 ns in length.
The short correlation time was s  840 ps giving us 100 ns/(2 0.84 ns)  65 independent points. The shaded bands
around each curve in Fig. 3 denote the 95% condence intervals for each RMSF estimate. For the most part the three
curves agree across the length of the protein and a Students t-test would show only a few areas where the RMSF
difference is signicant. In our use of this technique we often question if a deviation across only one or two amino
acids is truly signicant or whether this is part of the 5% missed in our statistical test. A more signicant concern is
the lack of overall convergence of the simulation, and as shown by the PCA projections for the crambin simulations in
Fig. 2, even small proteins can show signicant differences over multiple microseconds.

177
 Covariance Analysis
The PCA analysis that we discussed earlier is based on determining the Eigenvalues and Eigenvectors of the
covariance matrix. In looking at the rst few PCA modes we gained some sense of the large-scale motions of the
protein, however the covariance matrix as a whole is a measure of the full conformational space sampled by the
simulation. As the protein explores new regions of conformational space, the covariance matrix continues to be
redened, however once it converges we are arguably nished with the simulation. We can monitor this rate of
convergence by looking at the trace of the covariance matrix. The rate at which the trace increases will be variable
over the course of the simulation, however we can again use the bootstrap to determine this quantity.
In this case we do not want to disrupt the temporal correlation inherent in the data, so we adopt a block bootstrap
procedure [1]. With this method, instead of sampling individual snapshots from the trajectory, we now sample
independent blocks of contiguous snapshots from the trajectory, again using replacement procedure where the block
of data is put back. By sampling blocks of increasing size, we can determine at the increase in the covariance trace as
shown in Figure 4. What is interesting to note is that the time constants for the growth of Tr(Cov) are very close
3.0
2.5
Tr(Cov)

2.0
1.5

 56 ns
 117 ns
 87 ns
1.0

0 100 200 300 400 500

Time (ns)

FIGURE 4. Trace of the covariance matrix for the three crambin simulations determined using the block bootstrapping procedure.
The time constants were determined using single exponential ts to the curves.
to the l values we found with the autocorrelation analysis. The ordering of the time constants is the same, i.e.
the smallest/largest l values from the RMSD or PCA analysis are the smallest/largest values here, and the time
constants for convergence of the covariance matrix are only slightly larger than those found using autocorrelation.
Since the convergence of the rst PCA mode dominates the convergence of the covariance matrix this correspondence
should be expected, and given that the PCA autocorrelation in Fig. 2 was found using the combined trajectories and
Fig. 4 is for the individual trajectories, the small difference in time constants is understandable.

CONCLUSIONS
In this manuscript we have outlined some general methods for the statistical analysis of simulation data that takes into
account the temporal correlations that exist in a trajectory. We saw from the limited set of examples that we obtain

178
consistent results using different metrics, but underlying all of this analysis was the fact that our individual trajectories
still exhibit statistically signicant differences and show a general lack of convergence. Several enhanced sampling
techniques have been developed in recent years (e.g. see the manuscript by Yang and McCammon in this volume and
references therein) and all of these methods improve the sampling and convergence limitations of standard MD. Since
most of these techniques destroy the time progression in a simulation, basic autocorrelation may not be the correct
tool for determining independent structures. However other correlation or clustering techniques could be employed,
and then the bootstrap applied as before.
One issue we did not discuss relates to the selection of atoms for analysis. In all of our crambin calculations we
used the backbone atoms, but we could have equally well selected only the C positions or gone further and selected
all heavy atoms in the backbone and sidechains. As one would expect, more atoms equals more degrees of freedom,
and although the short correlation times s do not change signicantly, the long correlation times l increase since
the number of covariance pairs increases as the square of the number of atoms. With more theoretical work we may
eventually be able to develop more general methods for assessing independence in molecular trajectories, but until that
time each case needs to be analyzed on its own.

ACKNOWLEDGMENTS
This work was supported in part by grant CMMI-0928540 to DS from the National Science Foundation. We thank
Barry Grant for useful discussions and advice on implementing our calculations in bio3d.

REFERENCES
1. B. Efron, and R. Tibshirani, An introduction to the bootstrap, Chapman & Hall, New York, 1993.
2. http://www.r-project.org.
3. B. J. Grant, A. P. Rodrigues, K. M. ElSawy, J. A. McCammon, and L. S. Caves, Bioinformatics 22, 26956 (2006).

179
Narrowing the Gap in Understanding Protein Structure and
Function through Computer Simulations.
Hong Guo

Department of Biochemistry and Cellular and Molecular Biology, University of Tennessee, Knoxville, TN 37996,
United States of America and University of Tennessee/Oak Ridge National Laboratory Center for Molecular
Biophysics, Oak Ridge National Laboratory, Oak Ridge, TN 37830, United States of America,

Abstract. Quantum mechanical/molecular mechanical (QM/MM) free energy simulations are applied for understanding
mechanisms of different enzyme-catalyzed reactions and for determining some of the key factors in transition state (TS)
stabilization and substrate specificity, two of the most important properties of enzymes. It is demonstrated here based on
the results of computer simulations on kumamolisin-As, a member of sedolisin family, and DIM-5 and SET7/9, two of
protein lysine methyltransferases, that transition state stabilization may be achieved in part through the general acid/base
mechanism or the binding of the substrate in the TS-like configuration. Moreover, it is shown that dynamic substrate
assisted catalysis may play an important role in the substrate specificity of enzymes.
Keywords: Quantum mechanical/molecular mechanical; molecular dynamics; enzyme catalysis; transition state
stabilization; substrate specificity

PACS: 80

Introduction

There has been an unprecedented development of powerful computational methods and techniques for
understanding protein structure and function in the past decades. This development along with the dramatic increase
of computing powers makes detailed characterizations of enzymes possible. Nevertheless, applications of these
methods and techniques for understanding enzymes still lag behind. For instance, much of current textbook
materials on enzyme mechanisms are still based on experimental work as well as some insightful ideas developed
many decades ago when quantitative and sophisticated modern computational methods were not available. A large
number of challenging questions in the area of enzyme catalysis, including the origin of transition state (TS)
stabilization and substrate discrimination, may be addressed through detailed computer simulations, and the novel
mechanistic principles revealed from such simulations can benefit the general biochemistry community in the
understanding of enzymes and their function. In this paper, the results
on two types of enzymes, kumamolisin-As and DIM-5/SET7/9, are
discussed and some factors that may be used by these enzymes for TS
stabilization and substrate discrimination are suggested.

Kumamolisin-As
kumamolisin-As belongs to the sedolisin family, a recently
characterized family of proteolytic enzymes.1, 2 It was previously
believed that subtilisin-like serine peptidases (subtilases) had their
three catalytic residues (Ser, His and Asp) totally conserved. The
crystal structure determination of enzymes including sedolisin and
kumamolisin/kumamolisin-As has changed this view.2 It is now known
that there are different subtilisin-like serine-carboxyl peptidases called
sedolisins that have altered catalytic triads and oxyanion holes.
Sedolisins themselves share a number of common properties, including Figure 1. X-ray structure of kumamolisin-As
maximum activity at low pH, the lack of inhibition by pepstatin, determined by Wlodawer et al. (Ref. 7)

Theory and Applications in Computational Chemistry: The First Decade of the Second Millennium
AIP Conf. Proc. 1456, 180-186 (2012); doi: 10.1063/1.4730658
2012 American Institute of Physics 978-0-7354-1057-2/$30.00

180
stabilization by a Ca2+, and presence of conserved acidic residues
required for activity.1, 2 Although sedolisins are still poorly understood,
there is no question about their importance in biology. Indeed, a fatal
neurodegenerative disease, classical late-infantile neuronal ceroid
lipofuscinosis, is caused by a variety of mutations in the TPP1 gene and
the loss of the activity of the lysosomal enzyme TPP1, a member of the
sedolisin family.3 The typical Ser-His-Asp catalytic triad of classical
serine peptidases is substituted by a Ser-Glu-Asp triad in sedolisins,
defining a new family (Figure 1). The catalytic mechanism of sedolisins
and the exact relationship between this family and the families of serine
and aspartic peptidase are still not very clear, and the computational
studies of this enzyme have helped to answer some of the important
questions in this regards (Figure 2).
The X-ray structures of the sedolisin complexes4-12 support the
suggestion that the serine residue (S278 in kumamolisin-As) is the
catalytic nucleophile, while the nearby Glu (e.g., Glu78) is likely to act
as the general base to accept the proton from Ser and assist in the
nucleophilic attack. Consistent with this suggestion, the substitution of
either of these residues was found to lead to a complete loss of
proteolytic activity for some members of the family. Asn155 in
subtilisin (which creates the oxyanion hole and plays an important role
in the stabilization of tetrahedral intermediate) is replaced by an aspartic
acid residue in sedolisins (e.g., D164 in kumamolisin-As). The
importance of this Asp residue for the catalysis has also been
demonstrated by mutagenesis studies. There are two important questions
for understanding sedolisins. One is the exact role of the aspartic acid
residue (e.g., D164 in kumamolisin-As) that replaces Asn155 in
subtilisin and the other is how to explain the substrate specificity of the
enzymes. Computational studies13-18 on the members of this family
provided important insights into these questions. Figure 2. Proposed catalytic mechanism for
The average active site structures for the kumamolisin-As-substrate the acylation reaction based on the
simulations (see below).
(GPH*FF) complex (ES), tetrahedral intermediate (TI), and acyl-
enzyme (AE) from the acylation reaction determined from the QM(SCC-DFTB)/MM MD and free energy (potential
of mean force) simulations are given in Figure 3. Figure 3 shows that Ser278 is the nucleophile that attacks the
carbonyl carbon atom, as expected. Glu78 and Asp164 act as the general base and acid catalysts to accept a proton
from Ser278 and donate a proton to the substrate, respectively, during the TI formation. It was found that preventing
the proton transfer from Asp164 to the substrate increases the free energy for the formation of the tetrahedral
intermediate significantly, supporting the role of Asp164 as the general acid catalyst. Figure 3 also shows that Glu78
gives up its proton to the nitrogen atom (N) of Phe at P 1, leading to the breaking of the C-N peptide bond and the
formation of the acyl-enzyme. Asp164 becomes protonated again and thus acted as a general base during the
acylenzyme formation. The free energy barrier determined for the acylation reaction (Figure 3) was found to be
about 15 kcal/mol from the QM/MM simulations, and this barrier inceased by as much as 10 kcal/mol when the
proton on Asp164 was fixed by the SHAKE algorithm (to prevent Asp164 acting as the general acid and base
catalyst for the nucleophilic attack and acyl-enzyme formation, respectively). This result highlighted the importance
of the role of Asp164 as the general acid/base catalyst during the acylation.13, 14
It has been observed that kumamolisin-As tends to have a higher specificity for the substrates with a positively
charged residue (such as His or Arg) at the P1 site than for those they do not have the positive charged residue at P1.7
Figure 3 shows that the His side chain at P1 rotated significantly during the transition from the substrate to
tetrahedral intermediate. This movement seems to be triggered, at least in part, by the deprotonation/protonation
events and resulted in the interaction of His at P1 with the unprotonated Asp164. Such interaction is likely to
contribute the stabilization of the tetrahedral intermediate and transition state. It was suggested that the dynamics
involving the His residue at the P1 site may play an important role in the catalysis and lead to the higher specificity
for the substrates with His at P1.15, 16 Interestingly, His at P1 moves back to its original position (i.e., to that found in
the substrate complex) to interact with the C=O group of Pro at P 2 in the acyl-enzyme (see also Figure 3). Thus, the
back and forth movements of the His side chain between the C=O group of Pro at P 2 and Asp164 and the formation
of the corresponding hydrogen bonds may effectively lower the free energy barriers for both nucleophilic attack and

181
the acyl-enzyme formation and lead to a relatively high activity
for the substrate with His at P1, as observed experimentally. A
This mechanism was termed as dynamic substrate-assisted
catalysis (DSAC) to distinguish it from the standard substrate-
assisted catalysis (SAC) for which the conformational change
may not be necessary. The importance of DSAC or similar
types of catalytic processes involving the conformational
changes of substrate or/and protein groups triggered by the
bond breaking and -making events might have been overlooked
for some other enzymes, due in part to the dynamic nature of
the effects that may not be well reflected in the X-ray
structures.

DIM-5 and SET7/9: Understanding the Energetic

Origin of Product Specificity
Methyl groups stand beside phosphate groups as major
controlling elements in biology. The modifications of the
methylation states by the enzymes generate distinct sets of
chemical interactions and properties that play roles in a
multitude of regulatory pathways. However, our understanding
of how the methylation/demethylation events are controlled at
molecular level of detail is still lacking. One of the methylation
events is histone lysine methylation, and the enzymes that
catalyze such modification are protein lysine
methyltransferases (PKMTs).19-22 The importance of PKMTs
was first identified about ten years ago. Since then, histone
lysine methylation has been found to play an important role in
controlling many important biological processes with several
lysine residues being identified to be the sites of methylation on
histones.19-22 In addition to the methylation of lysine residues at
different sites (substrate specificity), PKMTs may also transfer
one to three methyl groups from AdoMet to the -amino group
of the target lysine. The ability of different PKMTs to direct
different degrees of methylation is called the product
specificity,23, 24 and the enzymes can therefore be classified as
mono-methylases, di-methylases or tri-methylases. Because B
biological consequences of lysine methylation may differ
depending on whether the lysine residue is mono-, di- or tri-
methylated, the product specificity of PKMTs adds more
complexity to the histone code and provides an additional layer
of regulatory control. Understanding the origin of the product
specificity is therefore of considerable importance.
DIM-5 is a SUV39-type H3K9 tri-methylase from N. crassa
that is essential for DNA methlation in vivo,25, 26 while SET7/9
is mono-methylase that only adds one methyl group to the
target lysine (H3-K4).27, 28 One observation that is of
considerable interest is the existence of the Tyr/Phe switch
position at the active site. For instance, it has been observed
that the mutation of Phe281 of DIM-5 to Tyr alters the tri- Figure 3. (A) Average active site structures of the
methylase into mono- or di-methylase26 and that SET7/9 may kumamolsin-As-substrate (GPH*FF) complex (ES),
tetrahedral intermediate (TI), and acyl-enzyme (AE)
be changed to di-methylases through the corresponding
obtained from the QM/MM MD free energy
TyrPhe mutation (e.g., Y305F mutation).26, 29 In other simulations. The enzyme is in ball and stick and the
words, the PheTyr mutation at this Tyr/Phe switch position substrate in stick. (B) Superposition of the X-ray
tends to decrease the ability of the enzyme to add more methyl structure (purple), ES (Orange) and AE (Green).

182
group(s) to the target lysine.
Although the target lysine might be able to receive three
methyl groups, the methylation process seems to stop at different
stages in different PKMTs (i.e., leading to different product
specificity). It has been proposed based on systematic
investigations of the energetics for the first, second, and third
methyl transfers in some PKMTs that the reason for the stop of
methylation process at certain stage for some PKMTs (i.e., before
the completion of all the three methyl additions) was probably due
to a significant increase of the activation barrier for some later
methyl-transfer reactions.30-33 Therefore, the relative efficiencies
of the chemical steps involving the three methyl transfers from
AdoMet to the -amino group of the target lysine/methyl lysine in
PKMTs may control, at least in some cases, how the epigenetic Figure 4. Comparison of the free energy profiles
marks of lysine methylation are written. One would expect for the third methyl transfer in SET7/9 (Blue) and
therefore that the free energy barrier for the third methyl transfer DIM-5 (Green).

A B C

D E F

Figure 5. Structural data from QM/MM MD and free energy simulations for the third methyl transfer in SET7/9 and DIM-5,
respectively. (A) The average active-site structure of the reactant complex of DIM-5. DIM-5 is shown in balls and sticks, and
AdoMet and substrate are in sticks. The hydrogen atoms on the methyl groups of the di-methyl lysine are not shown. (B) Two-
dimensional plot of r(CMN) and distributions based on the MD simulations of the reactant complex of DIM-5. Here CM is
carbon of the transferable methyl group and N is from the target lysine. (C) The average structure near the transition state for
the third methyl transfer in DIM-5 obtained from the free energy simulations. (D) The average active-site structure of the
reactant complex of SET7/9. (E) Two-dimensional plot of r(CMN) and distributions based on the MD simulations of the
reactant complex of SET7/9. (F) The average structure near the transition state for the third methyl transfer in SET7/9 obtained
from the free energy simulations.

183
in mono-methylases would be significantly higher than that in tri-methylases (even though the barriers for the first
methyl transfer in these enzymes may be similar). Indeed, as is shown from Figure 4, the free energy barrier for the
third methyl transfer was calculated to be as much as 7 kcal/mol higher in SET7/9 than that in DIM-5 based on the
QM/MM free energy (potential of mean force) simulations; for the first methyl transfer, the free energy barriers are
about 16 kcal/mol for the both enzymes.32, 33
To determine the origin for the large increase of the free energy barrier for the third methyl transfer from DIM-5
to SET7/9, the average structures for the reactant complexes and near the transition state for the methyl transfer are
plotted in Figure 5 along with the r(CMN) and distributions. Figure 5A shows that the average active-site
structure of the reactant complex has the lone pair of electrons on N of the target lysine well aligned with the
methyl group of AdoMet in DIM-5. Previous simulations already showed that there seemed to be a good correlation
between the alignment of the methyl group with the lone pair of electrons and the efficiency of the methyl transfer.
Consistent with the average structure in Figure 5A, the distribution plot (Figure 5B) shows that there is a large
population of the structures with relative short r(CMN) distances and small values of the angle; the average
r(CMN) distance in the reactant complex of DIM-5 for the third methyl transfer is around 3, and the average
angle is less than 30. Figure 5C shows that the r(CMN) and r(CMS) distances change to around 2 and 2.5 ,
respectively, as the system reaches the structure near the transition state for the methyl transfer. The average active-
site structure of the reactant complex for the third methyl transfer in SET7/9 is shown in Figure 5D; the structure
near the transition state is plotted in Figure 5F. In contrast to the case for DIM-5, the lone pair of electrons on N of
the dimethylated lysine cannot be well aligned with the methyl group of AdoMet in the reactant complex; the
average r(CMN) distance was calculated to be around 5.4 . This is further demonstrated by the distribution plot in
Figure 5E which shows that the r(CMN) distance is generally quite long during the MD simulations with a broad
distribution of around 90. The results of the simulations given in Figure 5A and 5C show that the structure of the
reactant complex for the third methyl transfers in DIM-5 is rather similar to that near transition state. By contrast,
the structure of the reactant complex for the third methyl transfers in SET7/9 (Figure 5D) is very different from that
near transition state (Figure 5F). Therefore, one of the reasons for the existence of the relatively low free energy
barrier for DIM-5 is likely owed to the fact that a part of TS stabilization is already reflected on the reactant state
through the generation of the TS-like conformation. For SET7/9, an extra energy cost would be required to generate
such TS-like configuration, leading to a relative high free energy barrier for the methyl transfer. The similar
discussion can be made for the second methyl transfers in DIM-5 and SET7/9.

Methods
The QM/MM MD and free-energy (potential of mean force) simulations were applied to characterize the reaction
catalyzed by kumamolisin-As and the methyl transfers catalyzed by DIM-5 and SET7/9. A fast semiempirical
density-functional method (SCCDFTB)34 implemented in the CHARMM program35 was used in the present study
for the QM/MM molecular dynamics (MD) and free energy (potential of mean force or PMF) simulations. The
efficiency of the semiempirical QM methods (such as SCC-DFTB) makes possible to sample millions of the
structures and conformations for enzyme systems and to determine the free energy profiles of the enzyme-catalyzed
reactions. These important tasks for understanding enzymes are often not feasible with high-level first principle ab
initio methods. We have compared the performance of the QM(SCC-DFTB)/MM simulations with the calculations
based on the QM(B3LYP/6-31G**)/MM energy minimization for the processes/reactions relevant to the present
studies and introduced corrections (e.g., in the case of the methyl transfers) for the QM(SCC-DFTB)/MM methods
in our studies. 31, 32
For kumamolisin-As catalyzed reaction, the initial coordinates for the enzyme were taken from the crystal
structure (PDB ID 1SIO, resolution 1.8 ) of kumamolisin-As complexed with the inhibitor AcIPF.7 Moreover, the
X-ray structure for the S278A mutant of pro-kumamolisin (PDB ID 1T1E, resolution 1.18 ) 9 that contains an
activation peptide/linker running through the active site cleft was used to generated the kumamolisin-As-GPH*FF
substrate complex used to initiate the computational studies. The side chains of Glu32, Asp82, Glu78, Ser278, and
Asp164, as well as a part of the substrate involved in the bond breaking and making were treated by QM and the rest
of the system by MM. For PKMTs, the X-ray structures of DIM-526 and SET7/929 (1PEG and 3M53, respectively)
were used. AdoMet/AdoHcy and lysine/methyl-lysine side chains were treated by QM and the rest of the system by
MM. The link-atom approach36 was applied to separate the QM and MM regions. The all-hydrogen potential
function (PARAM27)37 was used for the MM atoms. A modified TIP3P water model38, 39 was employed for the
solvent. The stochastic boundary molecular dynamics method was used for the QM/MM MD and free-energy
simulations.40 After 1.5 ns QM/MM MD simulations were carried out for each of the reactant complexes, the

184
umbrella sampling method41 along with the Weighted Histogram Analysis Method (WHAM)42 was applied. For
detailed information, see Refs. 13-18 and 30-33.

ACKNOWLEDGMENTS
This work is supported in part by the National Science Foundation Award (grant no. 0817940 to H.G.) and the
NSF TeraGrid resources provided by University of Texas at Austin. We also thank the support from the National
Institute for Mathematical and Biological Synthesis (NIMBioS), an Institute sponsored by the National Science
Foundation, the U.S. Department of Homeland Security, and the U.S. Department of Agriculture through NSF
Award EF-0832858, with additional support from The University of Tennessee, Knoxville. We are grateful for the
discussions with a number of people, including Dr. Alex Wlodawer, Dr. Kohei Oda, Dr. Toru Nakayama, Dr.
Xiaodong Cheng, Dr. Jeremy Smith, Dr. Haobo Guo, Dr. Qin Xu, Yuzhou Chu, Jianzhuang Yao and Yufei Yue.

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Minimalist Models for Biopolymers: Open Problems, Latest
Advances and Perspectives
Fabio Trovatoa,b,c and Valentina Tozzinia,c
a
NEST- Istituto Nanoscienze, Cnr, bCenter for Nanotechnology and innovation@NEST - iit
c
Scuola Normale superiore
Piazza San Silvestro 12, 56127 Pisa, Italy

Abstract. Simplified models representing biopolymers at less than atomic resolution (Coarse Grained) have recently
become popular due to the need of reaching the -scale (in space and time domains) in simulations. The reduction of the
internal degrees of freedom of the system brings a potentially unlimited saving of computational cost, at the expenses of
the introduction of two main class of problems: (i) those related to the representability of the system and back-mapping to
atomistic representation, (ii) those related to the parameterization of an accurate and predictive, yet simple enough, force
field for the interactions. In this paper we illustrate these two issues focusing on the representative sub-class of the
minimalist models, namely those with a single interacting center for amino-acid or nucleotide. We describe their
features and the different available parameterization methodologies, illustrating their positive and negative aspects, with
the aim of giving guiding lines for a general parameterization strategy.
Keywords: Coarse Grained models. Proteins. Nucleic Acids. Molecular Dynamics Simulations.
PACS: 87.15.ap, 87.14.E, -87.14.G-

INTRODUCTION
Computer simulations are extremely powerful tools to study the behavior of matter at the molecular level,
allowing reaching an insight that is hardly accessible to experiment. However the in silico study of living matter
presents difficulties that do not have a parallel in the non-biological systems. Bio-molecular systems are structurally
very complex and the processes involving them span about 10 orders of magnitude in the space domain and 15 in
the time domain. Consequently, the simulation of such processes requires the use of different modeling techniques,
treating the system at different levels of accuracy and resolution often combined in the so-called multi-scale
approaches[1,2,3,4].
The methods used for the atomic-level descriptions, namely the quantum mechanics approaches and the force
field (FF)-based molecular dynamics (MD) simulations (also called all-atom (AA) simulations), are very well
established techniques that have reached satisfactory levels of standard and accuracy[3], and are implemented in
software packages capable of exploiting massively parallel computational resources. However, parallelization
algorithms (at least the most commonly used domain decomposition) have intrinsic limitations and even taking
into account the current trend of computer power increase, atomic level simulations are not likely to be able to reach
the biologically interesting scales shortly. This is especially true considering the time domain: while large
macromolecular assemblies are currently addressable up to the nsec timescale, the -msec scale is currently
considered the limit for simulations of single proteins. This excludes a large portion of the biological processes,
generally involving macromolecular aggregates and the macroscopic timescale.
In order to overcome these limitations, the old idea of using models at less than atomic resolution[5] was
recently reconsidered after several decades of latency, probably triggered by the development of new experimental
techniques to investigate bio-systems at the nano-micro scale. The reduction of the amount of internal variables used
to describe the system (the Coarse Graining) brings a save in computational burden and the consequent possibility
of simulating larger systems for a longer time, in principle with no limitation. In fact, the level of coarsening can be
modulated[6]: the coarser the representation, the larger the saving in computational cost. However, the effect of
eliminated degrees of freedom (DOFs) must be implicitly reintroduced into the effective forces acting among the
residual explicit DOFs, which become increasingly complex in coarser representations[7]. Different recipes were
proposed to solve the related problems, and a large variety of different Coarse Grained (CG) models, differing by
the level of coarsening and by the philosophy of the parameterization are available, making the CG models
landscape very complex.
Theory and Applications in Computational Chemistry: The First Decade of the Second Millennium
AIP Conf. Proc. 1456, 187-200 (2012); doi: 10.1063/1.4730659
2012 American Institute of Physics 978-0-7354-1057-2/$30.00

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 This paper focuses on a sub-class of CG models, namely those representing one amino-acid or nucleotide with a
single interacting center (also called bead[7,8]). These one-bead (OB) models implement the maximum level of
coarsening that still allows explicitly representing the secondary structures, and can thus be considered minimalist
with respect to the representation of internal structural transitions of biopolymers. The OB models are also
paradigmatic and proper to describe the problems emerging in the parameterization of CG models in general. These
are related to the preservation of accuracy and predictive power in coarsening, while keeping low the number of
parameters. To solve these problems a number of different parameterization strategies were considered, that are
reviewed in this paper. Overall, this analysis outlines a possible global strategy to build an optimal minimalist model
and systematically assign the parameters values, which is illustrated in the last part of the paper.

MINIMALIST MODELS DEFINITION

Coarse Graining
Coarse Graining means reducing the amount of internal DOF of the system, describing a set of atoms with a
single bead (see Figure 1 a). However this can be done in several different ways[6]. Indicating with {ri} the set of
the cartesian coordinates within the atomistic representation and with {QI} the set of internal coordinates within the
CG representation one can write
Q I = Q I ({ri } BI ) = M r Ii i (1)
{ri }B I
where BI indicates the set of atoms belonging to a given bead and defines the level of coarse graining. In the case of
OB models this set includes all the atoms belonging to a given amino-acid or nucleotide. The second equality
implies the linear dependence of the CG coordinate on the AA coordinate. Linearity does not generally hold, but it
generally it does when one considers the cartesian CG coordinates. Due to coarse graining, MIi is a rectangular nm
matrix, where n is the total number of atoms and m is the total number of beads (residues). Within the class of OB
models, a further distinction can be done based on the location of the bead[7]. Three different possibilities are
generally considered, corresponding to three different forms of the MIi matrix, namely (a) the center of mass of the
residue (b) the geometrical center of the residue and (c) a specific atomic position within the residue
mi 1
(a) M Ii = (b) M Ii = (c) M Ii = I s i (2)
m i
nI
{R i }B I
(nI is the number of atoms of the Ith amino acid or nucleotide, is the Kronecker delta and Is is a specific atom
location of the Ith amino-acid or nucleotide).
There are advantages and disadvantages in each of these three different approaches. Options (a) and (b) are
apparently
more obvious[9] since the bead is located approximately centrally with respect to the atoms it represents.
This brings some advantages in the parameterization of the non-bonded interactions (see next section). However,
using a specific properly chosen atom as the location of the bead (option c) brings advantages in the description of
CG-AA mapping, allowing more easily back-mapping to the atomistic representation and a simpler parameterization
of the bonded interactions ([10] and see below).

Models topology and internal variables

Even restricting to the (c) case of eqn. (2), one has the freedom to choose the specific atom over which locating
the bead. Again, the most obvious choice would seem to choose an atom that is quite central with respect to the
amino-acid. In fact several one-bead models for proteins are C based[11]. However, the C based one-bead models
for proteins (hereafter minimalist) have unique advantages with respect to others, especially in the description of
the secondary structures and in the in the reverse mapping of the backbone from the CG representation to the
atomistic one[7-10]. The internal variables of this model are the pseudo-bond distances l (often treated as constraints
because of the rigidity of the peptide bond) and the backbone conformational pseudo-bond angles and dihedrals
(,) (see Figure 1 (b)). In some of the models hydrogen interactions are treated as explicit topological terms, by
adding for instance 1-4 bonds to represent the hydrogen bonding in -helices (orange bonds in Figure 1 (b)).

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 (b) Q I = rC (c) Q I = rP
QI = M r Ii i
(a) { ri }B I
FIGURE 1. (a) Coarse Graining: the atomic and Coarse Grained representations of the nucleosome are reported
(green=histone proteins, magenta=DNA). A portion of the structure is enlarged to show the CG beads and the atomic

representations superimposed. (b) The C based one-bead model for proteins. The beads and pseudo-bonds are reported in
green balls&sticks. The larger sphere indicatively represents the range of the non-bonded interaction. In orange are reported
additional interactions representing hydrogen bonds. The conformational variables are reported. (c) Similar representation
for the P based one-bead model for nucleic acids. Pseudo-bonds representing BP interactions are in orange. The scheme of
the topology of pseudo-bonds and BP interaction is reported on the right. The CG coordinate for each case is reported below
the pictures.

CG models for nucleic acids (NA) generally have separate beads for each of the three component of the
nucleotide (phospate group, sugar and base). Consequently the CG level is generally three to seven
beads[12,13,14,15]. By analogy with the proteins, the minimalist model for NA is the one-bead P-based model, in
which the bead is located on the phosphorus atom of the phosphate group[16] (Figure 1 (c)). The P-P pseudo-bond
represents the phosphodiester bond, whose geometry, at variance with that of the peptide bond, is not rigid, and can
consequently be influenced by the conformation of the sugar ring and orientation of the bases. As this is found in
different conformations (e.g. C3endo or C2endo), the average P-P distance dependents on the helix type (A, B,
Z or more in general on the secondary structure). The accounting for hydrogen bonding (Watson-Crick coupling,
or in general base pairing BP) is crucial to describe the secondary structure. For this reason in the minimalist model
for NA explicit topological terms are introduced to describe the BP interactions. Three different P-P bonds are
considered for each base pair (see Figure 1 (c), in orange). These, together with the two P-P phosphodiester bonds
form a tetrahedron unit enclosing the base pair. Since the tetrahedron geometry is rigid, if the equilibrium lengths
are chosen coherently with the given helix type (see next section and Table 2), the set of internal variables including
the P-P bonds and P-P BP bonds determines uniquely the conformation of a nucleotide pair, also reproducing the
correct hydrogen bond directionality. The base-pair stacking is accounted by the and variables, which fix the
relative orientation of two subsequent tetrahedrons.
This particular definition of minimalist models (number and location of the beads) make these models perfectly
matching with experimental low resolution data, by e.g. cryo electron microscopy, that normally resolve only the
C and P positions. This is a further important advantage, allowing a direct comparison with those data and their use
in the parameterization.

Internal variable distributions, representability and reverse mapping

Given such an extreme level of coarsening and the peculiar choices of the bead locations, some questions
spontaneously arise: are these representations enough to uniquely describe the secondary structures and their
changes? And is it possible to uniquely reconstruct the atomic structure from the CG model?
To answer these questions, it is convenient to analyze the internal variable distributions and their dependence on the
secondary structures. For proteins, this analysis was performed in detail for instance in [8]. The distributions of l,,
are reported in Figure 2, (a). The peptide bond is geometrically constrained: the C-NH-CO-C group lies on a
plane and the C-C pseudo-bond crosses the peptide bond (see Figure 1 (b)). As a consequence, the l distribution
is very well peaked at the value 3.8, corresponding at the C-C distance for the trans peptide bond conformation,

189
independently on the secondary (and tertiary) structure of the protein. An almost invisible peak is present at 2.9
corresponding to the very rare cis conformation of the peptide bond.

(a) (b)
FIGURE 2. Probability distributions of internal conformational variables of minimalist models (see Figure 1 for the variables
definition). (a) Distributions for proteins, of different subsets including prevalently unstructured proteins (dotted lines),
prevalently helical structures, (short dashed) prevalently sheet structures (long dashed), and a generic set with naturally occurring
amount of secondary structures (solid line). (b) Distributionas for nucleic acids, using different subsets including only RNA (red),
DNA (blue) or hybrid (green) and different experimental techniques (X-ray of crystallized structures and NMR in solution). Data
from PDB database[17].

Conversely, the secondary structure appears in the distributions of and variables, displaying separate peaks
for helices (at ~90 deg, see also Table 1), and for extended or sheet structures (labeled in the graphs). Their relative
height depends on the prevalence of helical, sheet or unstructured proteins in the data set. From this analysis one can
infer that, while the l variable is completely uncorrelated with secondary structure, the and - also called
conformational variables are proper to describe them. This can be formally demonstrated by the explicit
derivation of an analytical mapping between the (,) canonical dihedral angles describing the protein backbone
conformation in the atomic representation and the (,) variables of the CG representation[10], showing that the
correspondence between the allowed (,) couples in the Ramachandran plane (corresponding to different
secondary structures) and the allowed (,) couples is one to one. This resolves both the representability issue (i.e.
the possibility of describing the different secondary structures) and the reverse mapping problem (i.e. the possibility
of re-building the atomic structure from the CG one), at least for the backbone (of course the location and
conformation of the side chain is not straightforward, depending also on the tertiary structure). It is to be noted that
these properties depend on the choice of C as the interacting center, and are not strictly true for other choices. For
instance, choosing the center of mass as the interacting center, even the C-C distribution depends on the
secondary structures, and the back-mapping is not unique.
The question of representability and back mapping are less straightforward in NA. As it can be seen in Figure 2
(b), at variance with proteins, the variables (,) do not easily identify the secondary structures (e.g. kind of double
helix), nor even the kind of NA. The pseudo-bond angle differ in A, B and RNA helices for less than 1% (see also

190
Table 2), and the width of its distribution is only slightly larger in the NMR structures. A similar behavior for the
pseudo-dihedral, for which larger differences are visible in the distributions width, being smaller for RNA and Xray
structures, in agreement with the known larger rigidity of RNA secondary structures with respect to DNA ones.
Conversely, the secondary structures are clearly distinguishable in the P-P pseudo bond distance distribution. For
instance the distribution for X-ray DNA structures show two peaks corresponding to ideal B type (at ~6.5 ) and A
type helices (at ~5.6, see also Table 2), while the X-ray RNA structures are prevalently A type, and the hybrid
structures contains both peaks. This is due to the flexibility of phospho-diester bond, whose length changes
according to the sugar conformation. This flexibility is even more evident looking at the NMR set of data, especially
those of RNA: more peak are present and in different positions. In fact, while the crystal packing favors the helical
conformations, NMR data are mostly taken in aqueous solution, where helices can have larger non ideal, and the
NA (especially shorter RNA) can assume non helical conformation, responsible for the presence of the large
population at intermediate distances between the A and B conformations. In conclusion, the situation is the opposite
with respect to proteins: the main variable identifying the secondary structure is the pseudo-bond length, not and
. However, as in proteins, the variables describing the BP hydrogen bonding (see Table 2, the last three lines) are
also correlated with the helix type.
The atomic reconstruction from the P-based representation is less straightforward than in the protein case, though
still possible[18], passing through the definition of intermediate conformational variables, such as the relative
orientation of the bases plane. On the other hand, NA are simpler with respect to proteins in other respects, namely
the fact that there are no any additional degrees of freedom to be fixed independent on the backbone conformation,
such as those relative to the side chains in proteins.

TABLE 1). Internal variables values of the C based model for the selected secondary structures. Statistical
data from [8].
-helix -sheet Polyproline I
C-C pseudo-bond () 3.8 3.8 2.8
C-C-C (deg) 92 120 100
C-C-C-C (deg) 52 178 95
C-C H bond () 5.2 4.6-5.6

TABLE 2). Internal variables value for the P-based model for the main types of NA double helices. See Figure 1
for the definition of i-j indexes of the BP variables.
A DNA B DNA RNA
Xray NMR Xray NMR Xray NMR
P-P pseudo-bond () 5.9 6.2 6.7 6.7 5.8 5.6
P-P-P (deg) 148.7 149.3 148.7 148.6 152 152
P-P-P-P (deg) 15.9 23 19.1 15.6 19 16
Pi-Pj PB () 18.4 19.5 19.2 19.5 18.4 18.4
Pi-Pj+1 BP () 17.4 18.0 17.9 18.1 17.3 17.7
Pi+1-Pj+1 BP () 16.1 16.2 15.3 15.4 16.1 16.4

FORCE FIELDS OF MINIMALIST MODELS

Force Field terms

The general form for the force field (FF) of minimalist models is
U = U b ({RI ,I +1}) + U ({ I ,I +1,I +2 }) + U ({ I ,I +1,I +2,I +3 }) + U nb (RI ,J ). (3)
I,J are the bead indexes and RI,J are the distance between the beads I and J. The non-bonded term Unb is usually
separated in two parts, local and non local, based on the definition of a subset of locally interacting beads Sl
U nb = U local (RIJ Sl ) + U non local (RIJ Sl ). (4)
The definition of S l and of the interactions type is model dependent. For instance in the network and Go-like
models the local interaction (inkling also U and U) are topological connections, represented with either harmonic
or anharmonic bonds, whose parameterization is based on a single reference structure, the non-local interactions are

191
generic weakly attractive, repulsive or null, and Sl is defined either simply based on a distance cutoff, or based on
more sophisticated criteria including the local chemistry or the local density of beads or others (see [8] for a review).
These models are both topologically and structurally biased. To go further with respect to these models, one can for
instance consider a separation between local and non-local interactions based on the real local physics-chemistry and
write Unb as
U nb = U Hb (RIJ S Hb ) + U Hyd (RIJ ) + U el (RIJ ) (5)
with a separated hydrogen bonding term. Here the Uhyd and Uel represent the hydrophobic+excluded volume
interaction and electrostatic respectively (in some models included in a single term), and are evaluated among all the
couples not involved in a bond. One can subsequently release the bias (structural, topological or both) as in the
Fawzi-Yap-Sorenson-HeadGordon
(FYSH) model [19].

TABLE 3). Features of minimalist models. For models with a (partial) bias, the terms included in the local
and non-local part of U are indicated (Uhyd is usually shared among the two).
Ub U ,U U Hb U Hyd U el
Network Constrain Included in Ulocal, different functional forms, equilibrium values taken from a ref
(for prot and to the value structure (bias)
NA)[20] of a ref Included in Unon-local, absent or
structure weak, non-specific (generic)
Go Constrain
Harmonic or cosine, Included in Ulocal, representing

the native contacts.
(for prot and to the value biased towards the Topologically defined, detachable potential biased
NA) [21] of the native struct towards the native structure
native Included in Unon-local, purely
structure repulsive, generic
Partially biased Harmonic, Multiple well, biased Ulocal, including Hbonds and local steric and
model for unbiased or unbiased bead-type hydrobphobic interactions. Topologically defined,
proteins and based biased towards the ref struct
NA[23] Unon-local, including hydr and
electrostatics. Non-biased, bead-
type based parameterization.
Minimalist Harmonic, Harmonic, unbiased Fixed topology (possibly Unbiased, complex multi-well
generic model unbiased multi-configuration), potential
for DNA[16] detachable, unbiased but
including secondary
structure knowledge
Minimalist Constraint, Multi-well, unbiased Fixed but multi- Unbiased, complex multi-well
generic model unbiased configuration topology, potential
for oligopeptide detachable, unbiased but
[10] including secondary
structure knowledge
Minimalist Constraint, Multi-well, unbiased. Based on dipole-dipole 12-6 potential, non-specific
generic model unbiased Additional dihedral interaction, including a
for correlation potential priori secondary
polypeptide[22] structure
FYSH [19] Constraint Harmonic/ cosine, Anysotropic potential 12-6 potential
unbiased including a priori involving three bead type specific
secondary structure subsequent C.
Connectivity based on a
priori secondary
structure

The UHb term includes the BP interactions in the NAs or the backbone hydrogen bonds in the proteins, and is
particularly complex to parameterize, because anisotropic and secondary structure specific. For this reason a number
of models retains a certain level of bias only in this term (or in Ulocal) [10,16,19,23]. These locally biased models
allow a variable level of bias, and use a distance or interaction-type dependent force constants to realistic represent
the local interactions. The influence of the reference structure in the dynamics can be controlled and reduced at
minimum in order to obtain a good predictive power. The bias can be even only topological, which frees one from
the need of a reference structure. In this case, however, the knowledge of the secondary structure is needed, which
can be either known or evaluated by means of statistical prediction algorithms.
Of course in order to have a really general and predictive model all the FF terms should be unbiased and the
parameterization exclusively sequence based. The FYSH model one of the nearest to this ideal situation, having the
hydrophobic-electrostatic term parameterized depending on the bead type, while the other terms depend on their a

192
priori evaluated secondary propensities. Thus the bias is released although the parameterization is not completely
structure free. A summary of the features of the mostly known minimalist models is reported in Table 3.

Correlations between internal variables

One important question in CG models (and in particular in the minimalist ones) that is sometimes disregarded
concerns the correlations among internal conformational variables. Given the topological simplicity of the
minimalist models, the internal variables (l,,) are geometrically independent and totally amount at 3N-6, thus a set
(l,,) of could completely define the conformation of the system. Thus one might thing that a bare sum Ul+U+U
would be sufficient to completely describe the system. This is not generally true. In the reality these variables are
correlated, and, as anticipated in the previous section, the simple sum of term is not a complete representation of the
energy of the system.

FIGURE 3. Correlation maps of biopolymers. (a) Correlation between and in proteins. The scatter plot is for proteins with
natural occurrence of secondary structures. The colored lines roughly enclose the helical regions (right helicity = green, left
helicity = red) and sheet structures. The black lines are obtained keeping constant the 1-4 distance at the indicated values. The
colored lines are the correlation curves of Levitt-Warshell[5] (rielaborated). (b) Correlation between the P-P distance and the
pseudobond angle in nucleic acids. Red and blue scatter plots are for RNA and DNA respectively (X ray structures set). The lines
are obtained keeping constant the 1-3 distance at the reported values. (c) - in nucleic acids. Colors as in (b). Solid lines are
obtained keeping constant the 1-3 distance, dotted keeping constant the 1-4 distance.

In order to better understand the origin of correlations, we first must observe that part of them is due to the coarse
graining procedure itself. Considering for instance the case of polypeptide, and using the analytical (,)(,)
mapping, it was shown that a uniform distribution in the (,) plane is mapped onto a butterfly shaped image in the
(,) plane, with an accumulation of probability density in the external borders of the butterfly wings (see [8] for
details). This distribution can be viewed as generated by a sort of effective interaction acting on (,) degrees of
freedom which is completely geometric in origin and present even in absence of any real interaction (except the
binding of beads in the chain).
However, the real (,) correlations (Figure 3, (a)) are different from the butterfly shape, and the differences can be
ascribed to the real interactions. For instance the accumulation of points at ~120 is due to the steric hindrance that
pushes the system towards a preferential extended conformation (the (,) scatter plot for proteins can be interpreted
as the CG equivalent of the Ramachandran map (different secondary structures areas are enclosed in colored lines in
Figure 3 (a) [10]). Other accumulations can be understood by means of the following, relating the variables l, ,
with the distances between beads separated by two or three bonds along the backbone, namely the R1-3 and R1-4
distances
R13 / l = 2sin( /2) (6)
R14 2 /l 2 = 4 sin2 ( /2)sin 2 + [2 cos ]2 (7)
Eqn (7) can be explicitly written solved with respect to or

193
 1 4 sin 4 ( /2) sin 2 ( /2)[3 + (R14 /l) 2 ] + (R14 /l) 2
cos = (8)
2[1 sin2 ( /2)]
(R14 /l) 2 [2 cos ]2
sin( /2) = (9)
2 sin
The black
lines on the map correspond to () curves obtained imposing R1-4 =const in eqns (7-9). For instance, if
const=5.16 the line crosses the areas corresponding to helices and describes roughly their stretched shape. In fact,
the helices are stabilized by hydrogen bonds that can be conveniently described by 1-4 bonds (having approximately
that bond-length). Similarly,
the regions corresponding to the extended structures can be roughly described imposing
a larger R1-4 distance. This does not correspond to any real 1-4 hydrogen bond, but is rather maintained by inter
strand hydrogen bonds such as those stabilizing the sheets. Other authors have described the - correlations with
explicit FF terms depending on and [5] rather than the effect of hydrogen bonding, or have included both explicit
correlations and hydrogen bonding[22]. We report, for instance, the empirical explicit correlation term included by
Levitt and Warshell (LW) [5], used as a paradigm by subsequent authors
= 0 + cos( 0 ) (10)
with 0~110 deg and ~20 deg, 0= 120 deg and + and are for the lines of right and left helicity. It is interesting
to observe that the lines at constant R1-4 and the LW correlation lines intersect in all the relevant areas, representing
the most populated secondary structures. At variance with the constant R1-4 lines, the LW lines can describe the
extended to helical transitions
and the intermediate forms, although they do not describe very well the shape of each
secondary structure region. A combination of eqn (10) with (7-9) would probably give the best description of the
correlations in the system.
In the nucleic acids l is not constant, consequently even its correlations with and are non trivial. For instance
the (l,) correlation maps (Figure 3 (b)) are able to discriminate the RNA (red) from DNA (blue). In addition the
most populated areas seem to follow lines obtained from Eqn (6) by imposing R1-3 = const. A hypothesis to explain
this is the stacking interaction, that tend to maintain the bases in a given orientation with respect each other. This
relates the conformation of the phosphodiester bond (i.e. l) and the relative orientation of two subsequent
phosphodiester bonds (i.e. ) in a complex way, determining a complex correlation between l and , that only in a
very first approximation can be described by the depicted lines in Figure 3 (b). The correlation between and
(Figure 3 (c)) in this case seems less informative. The superimposed lines are obtained with R1-4 = const and R1-3 =
const but do not seem to describe any relevant structure.
Both for proteins and NA additional correlations are induced by the Unb term. For instance, in proteins the steric
hindrance of the side chain and the intrinsic chirality of the peptide bond determine the asymmetry in the
distributions, which is not accounted for by the UHb term.

PARAMETERIZATION STRATEGIES

What discussed up to here should help tracing a strategy to parameterize minimalist models. The first step is
choosing the type of model among those listed in Table 3, and its binding topology (the real connectivity along the
chain and the Sl or SHB subsets). This choice influences the second step, i.e. the choice of the FF terms. Normally the
conformational terms and UHyd are present, while the UHb can or cannot be implicitly included in Ulocal. The
electrostatic term is almost always treated in a unique non-bonded term with UHyd. In addition one has to choose the
numerical or analytical representation of the FF terms. The first choice is more flexible and convenient with
particularly complex potentials shapes, which is most often true in the case of CG models. On the other hand the
second choice is usually preferred, resulting in faster and more precise calculation of the forces during the
simulation.
Whatever the choice, building the FF implies the optimization of a set of parameters, which are either the
parameters of analytical FF terms, or the values numerical FF terms assume in a given subset of the variables value.
Optimization generally means finding the set of parameters minimizing the difference of a given objective function
(describing a property of the system) with respect to a given target value. The objective function, the source of the
target values, and the algorithm used for the minimization define the parameterization strategy, which is often
considered an integral part of the model itself, because it influences the final value of the parameters. The most used
parameterization strategies are described in the following.

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 Single structure Based Parameterization
The Network and Go models are typical examples of single structure based parameterization. The FF terms are
analytical and as simple as possible. Taking as example the case of harmonic network, each interaction is described
by a spring. The equilibrium distance is assigned as the value taken in the reference structure, requiring no fitting at
all. In the simplest version of the model, the spring constant is taken the same for all the interactions and is one of
the two free parameters of the model, together with the cutoff radius determining the Sl set. These two are
determined by fitting on measured observable or known properties, typically the experimental values of the thermal
fluctuations. This very basic model describes the harmonic motions around the equilibrium structure.
The parameterization procedure is similar in the Go model, although the slightly more complex functional form
implies a larger number of parameters, which are fitted in this case on different properties, including the
experimental denaturation or folding temperature. The Go model is able to roughly describe the folding kinetics.
Evolutions of the Network[24] or Go[25] models involve one or more of the following improvements: (i) more
realistic interactions (e.g. distance dependent elastic constants or more complex functional forms) (ii) more realistic
connectivity (e.g. chemical based) (iii) possibility of multiple equilibrium states. Each improvement implies the
introduction of additional parameters, requiring more input data and multi-variable fitting procedures.

Statistics Based Parameterization

Boltzmann Inversion and related strategies

The total bias intrinsic in network and Go models make them little useful in describing structures different from
the reference one. In order to parameterize more general models one has to use statistical information from a set of
structures, whose diversity influences the transferability. The statistical information included in the data set can be
extracted and used by means of the distribution functions of internal variables Q (see Figure 2). These once
normalized are assumed to be a good approximation of the probability distribution functions P(Q). For any given
internal variable Q, its probability distribution function is related to the so-called potential of mean force (PMF)
W(Q) by means of the relationship
P(Q)
W (Q) = kT ln 0 (11)
P (Q)
P0(Q) being the probability distribution of a reference system, where the interactions are absent (e.g. the ideal gas).
This formula, allowing the straightforward evaluation of the PMF from the statistical data set, is called Boltzmann
inversion (BI). If the PMF coincided with the FF potential term for the Q variable, the parameterization of the model
would be straightforward as well, and could proceed according to the following steps: (i) evaluate the P(Q) from the
input data set (ii) Boltzmann-invert it (iii) use the PMF directly as FF term for Q in the numerical form or fit it with
an analytical function. This procedure would allow obtaining all the parameters (equilibrium values, elastic
constants and other energetic parameters), and could be repeated for all the FF terms. Unfortunately, the single
variable W(Q) coincide with the potential FF terms U(Q) only if two (related) conditions are satisfied (i) the sum of
the UI(QI) exhaustively describes the interactions in the system (completeness) and (ii) the correlation among UI(QI)
are null (orthogonality). In this case the total FF would be the sum of UI(QI) and the multi-variable probability
distribution would barely factorize in single variable PI(QI) (see [8] for a detailed discussion). However, this is not
the case, as shown in the previous sections.
One way is obtaining U from W an empirical physical-driven approach[10,23,28]. One can first assign W to all
the FF terms and subsequently correct them on the basis of the results of simulations, until specific quantities (e.g.
the probability distributions themselves or other observables) are reproduced. A second strategy is explicitly
recognizing FF terms that mainly induce the correlations (e.g. UHb), then first parameterize a quasi-correlation free
FF using as input a dataset in which those interaction are absent. Then parameterize the FF term inducing
correlations by means of eqn (11) where the reference system is the one without that interaction. However this
strategy is vey system-dependent, because implies a control on the effect of specific FF terms that is not always
possible.
These physical-driven strategies, however, have their formal counterpart that do not require too a strong human
intervention. One is the so-called iterative BI[26]. One starts with the PMF, and corrects it by subsequent steps by
adding the logarithmic difference between the target distribution (P) and the distribution obtained by the simulation
using the potential itself (Pn). This correction lead to an improved Un+1

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 P(Q)
U n +1 (Q) = U n (Q) kT ln n (12)
P (Q)
and can be repeated until the correction is negligible. In this formula Un(Q) represents a single variable FF term. The
total CG potential is a finite sum of single variable FF terms
U({Q}) = U I (QI ) (13)
I
The iterative BI performed over all the terms simultaneously, targets the multi-variable PMF that is the Boltzmann
inverse of the multi-variable probability distribution
P(Q1,,QN ) dr 1 drn p(r1,,rn ) (QI (r1,,rn ) QI ) (14)
I
where Q({r}) defines the relationship between the CG variables and the atomistic coordinates and p({r}) is the
atomistic probability distribution. Using this P as target realizes the so called thermodynamic or statistic consistency.
Iterative BI requires generating one equilibrated CG model trajectory for each iterative step and gives the best
approximation
of the multi-variable P with a product of single variable Ps. Cross-terms correlations are neglected.
However they can be explicitly treated by considering variables dependent by others, such as for instances the R1-4
involved in hydrogen bonding, or explicitly parameterize multi-variable potential terms by explicitly targeting multi-
variable Ps. In principle one could even consider a single many-body potential term including all the independent
variables of the system U({Q})=U(Q1,,Qn), i.e. the complete PMF, and in this case all the correlations would be
exactly includede and U=W already at the first BI iteration. Of course, such a potential would be intractable in
simulations, and very difficult to evaluate, requiring a prohibitively high statistics to evaluate the multi-body Ps.

Reverse Monte Carlo

Among the methods targeting the probability distribution functions, one must include Reverse Monte Carlo[27],
which iteratively corrects the CG potential with a term U derived from the fluctuation-dissipation theorem
1
Pn P =
kT
2
(
U P n P n
2
) (15)
Here P is the target distribution and the dependence on the CG variables is omitted. As in the previous procedures,
single or multi-variable potentials/distributions can be considered. At each step the Pn must be evaluated, which is
usually done by Monte Carlo simulations (naming the procedure). The advantage with respect to iterative BI is
mainly numerical: the use of the MC to evaluate the distributions and their moments is more numerically rigorous,

and more prone to be used in the multi-variable case, implying that correlations can be more accurately included.

Relative Entropy Minimization

Iterative Boltzmann inversion and reverse Monte Carlo both target the probability distribution of internal variables.
An alternative is minimizing the relative entropy of the CG system with respect to the reference (atomistic) one
p({r}) 1
Srel = p({r})ln P({Q({r})}) + ln { (Q({r}) - Q)} = kT ( E F ) + Smap (16)
at conf at conf
here the statistic average is performed over the atomistic system. Srel measures the information loss in coarse
graining, thus its minimization would lead to a FF minimizing the error with respect to the reference system. The
term Smap is totally independent from the FF, and reflects the fact that the CG mapping itself implies a non-uniform
conformational space population in the coarse grained representation. For instance, considering the (,)(,)
mapping in the protein backbone coarse graining, we already observed that a flat distribution of points in the (,)
plane leads to a complex distribution of points in the (,) plane that acts as an additional potential term[8]. This
term must be included in the CG FF, but is independent on the parameterization and can be evaluated once for all.
Conversely the first part is FF parameter dependent and its minimization is the core of the method. It was shown that
the relative entropy minimization leads to equivalence of probability distributions of the CG and reference
system[28], thus in this sense it is equivalent to the previously described methods, with the additional possibility of
controlling errors in FF term specific way.

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 Simulation Based Parameterizations
Force Matching

All the mentioned methods target the statistical probability distributions or equivalently the PMF and rely on
their accurate evaluation, usually from a statistical set of structures that can be either experimental or from higher
level models, e.g. from an atomistic simulations. An alternative approach is to target the forces acting on CG sites.
In this case the input data can only derive from a higher level theory or modeling approach: they are typically
obtained from trajectories of simulations performed with a given atomistic FF. Consequently the quality of the
parameterization will also depend on the quality of the atomistic FF used for the simulations and on the extent of the
phase space sampling of the atomistic simulation. In its variational, formulation the Force Matching (FM) method
consist in the minimization of the functional[29]
1 2
2 [F] =
3N I
FI ({Q({r})}) f I ({r}) (17)

where F and f are the forces on the CG sites evaluated within the CG and atomistic representation respectively and
the average is on the atomistic simulation trajectory. The functional must be minimized with respect to F (or to its
parameters in a given analytic representation), and eqn (16) realizes the so-called mechanical consistency between
the atomistic andCG representations. It was show that the optimal FF obtained with this procedure can be derived as
the gradient of the multi-CG variable PMF [29].
Consequently this method and the previously described ones are related: provided the same input data set is used
(e.g. forces and structures taken from the same atomistic simulation) they target the same quantity (the multi-
variable P). However, their practical implementation generally includes different approximations that lead to a
different treatment of the correlations and to different final results.

Energy Matching

Related with the previous approach is the direct matching of the energy landscapes of the atomistic and CG
representation. This can be achieved by minimizing the mean squared deviation differences of the potential energies
in the CG and atomistic representations (U and u):
1 2
S= 2 [(U({Q({r})}) u(r)) U u ] (18)
2(kT)
It was shown that at high temperature and for good representation of the CG potential S coincides with the relative
entropy, thus in this case this approach is equivalent to all the others. Otherwise it can be considered a rough
approximation of the real relative entropy method[28].

Exact Correlations Theories
All the above described methods aim at reproducing at best the multi-variable PMF W({Q}). Beyond the procedure-
dependent numerical approximation, there is another source of error that is common to all the methods. In order not
to lose the advantage of coarse graining, the a complex multi-variable representation of W({Q}) cannot be adopted,
and it is rather expanded in a finite sum of single variable terms (eqns (3-5,13)). It was shown that all these methods
could be reformulated considering the FF terms as the components of a vector in the space of the multi-variable
functions, and the FF as a truncated expansion of the true many body potential. This given, even the best FF will
not reproduce the PMF exactly, but rather will be its orthogonal projection onto a space spanned by the FF
terms[30]. In addition, the correlations are implicitly and approximately included, but in general the exact
reproduction of n-order correlations can be achieved only with explicit n-body term in the FF[28].
Exact correlations can be included within the generalized Yvon-Born-Green (YBG) approach reformulated for
CG models[30]. A simplified version of the general theory applied to Unb, that more closely resembles the many-
body theory of liquids from which it stems, is based on the following equation describing the correlations between
RIJ at any order
d d d
kT
dR
g(R) + g(R) U(R) =
dR
dR'K(R,R') dR' U(R') (19)

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here g(R)=Pnb(R)/P0(R) is the radial pair distribution function describing the probability of finding a bead at distance
R from a given one. For simplicity we omitted the I,J subscript to R and the nb label to U. The YBG approach is
here applied to the non bonded potential to describe correlations among FF terms coming from different IJ couples,
although in the general formulation can be used also to describe correlations among any FF term (e.g. angles and
dihedrals etc). In eqn (19) the kernel K is related to the Green function of the system and in principle can describe
exactly the correlations. In practice, however, approximations are used to evaluate it. If K=0 one has U(R)=W(R)=-
kTln(g(R)), that is the bare BI totally neglecting correlations. To go further, one could assume isotropy, and factorize
the three body correlation function in terms of two body ones. Under these conditions one obtains that the correction
W is (Abe approximation)
U(R) W (R) = dR'[ g(R') 1]U(R R') (20)
and the equations can be resolved recursively. However, using the BI in the second term of the eqn and neglecting
the short range correlations one can further simplify the eqn
U(R) W (R) = kT dR'[ g(R') 1][ g(R R') 1] (21)
which can be explicitly evaluate in a single step procedure from the input probability distribution. Other
approximations are possible in analogy with the corresponding ones in the classical liquids theory, which evaluate
more correctly the higher level correlations[31].

Including physical observables
All the described methods are based on the assumption that the input quantities, either the PMF or equivalently
on the probability distribution functions can be evaluated accurately. This is a task more difficult than it might seem.
In fact, it implies that the structures/forces included in the statistical set are distributed according to thermal
equilibrium, which is very difficult to achieve, especially when the set is generated by a simulation. In addition in
this case additional possible errors might be included by the atomistic FF. This is a problem that has recently come
to the attention of the simulators community: since all the currently used atomistic FFs were optimized to reproduce
at best the experimental structures, they are able to reproduce them locally in time, but there is no guarantee that
they correctly reproduce the long time behavior. In fact, only recently when the -sec time scale in atomistic
simulation were reached, errors in the evaluation of relative energies of secondary structures were detected.

Targeting experimental observables

An escape from this situation consists parameterize based on targeting experimental values of specific
observables of any nature: thermodynamic (transition temperatures, binding affinities or energies, energy barriers,
specific heats, ), structural (root mean squared deviations from a known structure, a priori known secondary
structures), kinetic or dynamical (normal modes frequencies, kinetic constants, characteristic times). One starts with
a reasonable approximation for the FF (e.g. obtained by BI) and optimize the parameters until the distance of the
simulated quantities with respect to the target quantities is reasonably small. We already mentioned this strategy
among the physically driven empirical approaches [16,32], but it can be it can be more rigorously performed using
multi-variable fit procedures. However as the number of parameters or the number of target observables increase,
these become more and more numerically unstable, and the human intervention is again usually necessary at least to
drive the parameters into reasonable ranges.

Genetic algorithms

Genetic Algorithms (GAs) were proven efficient in this situation, because they combine the possibility of having
multiple target observables with an heuristic and physically sound approach[32,33]. GAs are used to minimize the
distance of a set of observables evaluated in simulations from the set of their given values (usually experimental).
There is no limit to the kind of observables used, and the minimization proceeds taking inspiration from the
Darwinian evolution: the set of parameters to be optimized is the genome while the single FF is an individual;
these are eliminated or survive according to a ranking based on the objective function to minimize (the distance
between reference values of observables and their values obtained in the simulations) that mimics the selective
pressure. Subsequently, the next generation stems from the survivors according to given mating rules, and the
procedure is repeated until a reasonably evolved pool of survivors is reached, which represent a set of optimal FFs.

198
As in the case of previously described iterative methods, one equilibrated simulation for each set of parameters to be
evaluated is necessary.
A key role in this algorithm is taken by stochasticity. This is introduced through nature-mimicking procedures:
mutations of the genome (random parameters change) and cross-over (exchange of parameters values among FFs in
a given generation). These are counterbalanced by elitism, i.e. the conservation of the best FFs across generations.
The relative probability with which these processes occur is user-defined, and must be optimized to maximize the
efficiency and robustness of the search. Another important parameter is the relative weight given to each observable
in the multi-objective function (MOF). For instance, the results of BI related methods could be recovered by
including in the MOF only the probability distribution functions. Of course to exploit the advantages of the method,
the MOF must include additional target observables, with relative weights based on physical considerations.

CONCLUSIONS AND PERSPECTIVES: INNOVATIVE PARAMETERIZATION

STRATEGIES
We summarize the choices and action to be taken to build a CG model in form of flowchart in Figure 4. The very
first level of choice, namely the level of coarsening and location of the bead, is omitted because here we focused on
minimalist models (one-bead, C or P based).

FIGURE 4. A flowchart describing the building of a minimalist coarse grained model.

The topology of the model, FF terms and their type, the parameterization strategy, input data and algorithm must
be chosen in the given order, and the possible choices here described are reported on the right. Since each level of
decision offer multiple choices, the number of possible different minimalist models is very large. However, not all
the possible options are compatible with each other. For instance, the single structure parameterization requires the
topological bias, while the vice-versa is not true (though usually done); FM requires an atomistic simulation data set;
other choices are correlated though not compulsory (BI with experimental data set, GA with non-PMF based, ).
Nevertheless, the landscape of CG models remains vast and diverse and a standard is quite far from being reached.
Some important steps forward have been done to clarify some fundamental questions, related to the
representability and to the importance of correlations. However, a minimalist model combining accuracy and
predictive power at the level of the current atomistic models is still lacking. An open question is to which extent
these two issues can be combined in such a simple model. We believe these questions and the building of optimal
strategies to parameterize minimalist models will stimulate the research in this field for several years more.

ACKNOWLEDGMENTS

We thank Filip Leonarski and Joanna Trylska for useful discussions.

199
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200
 Exploring Folding Pathways of Single Proteins Using
Mechanical Manipulation
Ptur O. Heidarssona and Ciro Cecconib
a
Structural Biology and NMR Laboratory, Department of Biology, University of Copenhagen, Ole Maales Vej 5,
2200 Copenhagen N, Denmark
b
CNR-Nano Institute, Department of Physics, University of Modena and Reggio Emilia, Via Guiseppe Camp 213/A,
41125 Modena, Italy

Abstract. Protein folding is still a major area of active research. Despite significant progress in understanding the
underlying principles, we still cannot efficiently predict the folding mechanism for even a moderately sized protein.
Proteins are generally thought to fold by diffusion over a three-dimensional energy landscape. Traditional bulk methods
have proven to be very powerful in the study of the folding process but they often suffer from inherent ensemble
averaging. Single molecule techniques open up new vistas for studying protein folding, allowing direct analysis of the
distribution of events that characterize the heterogeneous folding process. Recently it has become possible to directly
manipulate individual proteins using optical tweezers. Here we illustrate the experimental strategy and how this approach
has provided a fresh perspective on the protein folding problem.
Keywords: Protein folding, single-molecule, optical tweezers, energy landscape
PACS: 82.37.Rs, 87.80.Cc, 87.15.hm

INTRODUCTION
The folding of a protein molecule into its functional three-dimensional structure is a process that has been the
focus of active research for decades. It involves a largely unstructured polypeptide of tens to thousands of amino
acids spontaneously rearranging into a native structure that is only marginally more stable than the random coil at
physiological conditions. Levinthals paradox states that if the folding process was merely a random search through
all of the conformational space available to a protein, then it would take a moderately sized protein (100 amino
acids, small in the context of most proteins) longer than the age of the universe to find its native state [1]. Despite
the staggering amount of conformations available to a polypeptide of average size, proteins manage to fold in the
timescale of milliseconds to seconds. The current view of protein folding is represented in an energy landscape on
which the protein diffuses, balancing the favorable reduction in potential energy with the counteracting decrease in
conformational entropy as the protein approaches the native state [1]. The energy landscape can have multiple
parallel pathways which may or may not include intermediate states (Fig. 1). The energy landscape theory has been
successful in explaining biomolecular behavior yet our understanding of the folding process is still incomplete. This
is especially true for multi-domain proteins, which represent 75% of the eukaryotic proteome [2], as most folding
studies have focused on isolated domains. Traditional bulk studies on protein folding are complicated by the
heterogeneity of the process as the protein molecules in a given sample can quickly be de-phased due to the multi-
dimensionality of the energy landscape. In addition, rare folding or misfolding events are difficult to examine
experimentally. Misfolded proteins are of significant interest as these can accumulate in cells and can lead to
diseases such as Parkinsons and Alzheimers [3].
Single molecule methods have the prospect of looking at the folding process in unprecedented detail and
resolving different pathways. Recently it has become possible to mechanically manipulate single protein molecules
using optical tweezers [4]. By direct manipulation their behavior under applied force can be described using a
convenient reaction coordinate, the molecular end-to-end distance. This method allows a detailed focus on pathways
and a reconstruction of the free energy landscape. The single-molecule nature of the experiments allows one to look
at distributions rather than averages and, in theory, it should be possible to distinguish rare folding or misfolding
events.
In this paper we aim to give a brief overview of optical trapping and its application to the study of protein
folding. We describe how molecular constructs are produced for use in these experiments. We briefly illustrate the
experimental strategy employed to manipulate individual proteins, and different modes of operation of optical
tweezers. Finally, we discuss some case studies.

Theory and Applications in Computational Chemistry: The First Decade of the Second Millennium
AIP Conf. Proc. 1456, 201-206 (2012); doi: 10.1063/1.4730660
2012 American Institute of Physics 978-0-7354-1057-2/$30.00

201
FIGURE 1. Protein folding and energy landscape theory. A protein diffuses through a funnel like energy landscape on its way to
the low energy native state. Here are shown two main routes though in principle they can be infinite. Reprinted from [5] with
permission from Elsevier.

OPTICAL TRAPPING
Laser tweezers were invented by Ashkin and co-workers in 1986 when they discovered that small particles of
high refractive index, such as plastic beads and oil droplets, were attracted to the focal point of a laser beam focused
by an objective [6]. This technique, which uses light pressure to trap tiny objects, can be used to manipulate a
diverse range of small objects, from living cells down to single atoms, with many applications in biophysics and
related fields [4, 7]. Since the invention of the first device, a diversity of laser tweezers set-ups and experimental
strategies have been devised and used to study a variety of biological processes. In some cases, the optical trap is
created by focusing a single laser beam with a high numerical aperture objective [4]. In other cases, two counter
propagating laser beams are used. In these latter devices, the forces applied on the molecule under study can be
determined directly by measuring the change in momentum flux of the light beams leaving the trap [8]. Individual
molecules cannot be optically trapped and manipulated directly. They need to be attached to movable solid supports.
In the following paragraphs, we will describe the experimental strategy used to manipulate individual proteins with
optical tweezers.

PROTEIN-DNA CHIMERIC CONSTRUCTS

In order to study protein folding using optical tweezers a chimeric construct is used consisting of a single protein
flanked by two ~500 bp DNA molecules that act as molecular handles (Fig. 2). The handles maintain a sufficient
distance between the tethering surfaces to avoid unspecific interactions. This method requires proteins that have
exposed cysteine residues. Thus, any protein that is amenable to genetic engineering can be studied with this
technique. By varying the position of the cysteines, a large set of different pulling axes can be used to study the
anisotropy of the folding free energy landscape. The DNA protein coupling reaction is mediated by 2,2-
dithiodipyridine (DTDP). First, an excess of DTDP is allowed to react with the protein to activate the cysteines. This
reaction is usually completed within minutes and can be followed spectrophotometrically [9]. The activated proteins
are then reacted with a mixture of the two handles carrying a thiol group on one end that can bind to the activated
cysteine side chains. This reaction usually takes several hours to produce a good yield of protein-DNA chimeric
constructs and can be monitored spectrophotometrically, by atomic force microscopy or by gel electrophoresis.
DNA handles have been shown to have negligible effect on the fold and stability of the proteins [10]. Moreover,
double stranded DNA (dsDNA) is a convenient molecule to serve as handle in these experiments because its
mechanical properties have been extensively studied [11]. At 65 piconewton (pN) dsDNA undergoes a characteristic
overstretching transition. This transition can be used to confirm the single molecule nature of the experiment. When
two or more DNA molecules are manipulated, they share the applied load and display the overstretching transition at
higher force than 65 pN.

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FIGURE 2. Protein-DNA chimeric constructs imaged by atomic force microscopy. a) Free DNA handles, b) ribonuclease H
attached to a single handle, and c) ribonuclease H attached to two handles. Reprinted from [9] with kind permission from
Springer Science + Business Media: European Journal of Biophysics.

SINGLE-MOLECULE MANIPULATION
The experimental strategy is illustrated in Fig. 3. A protein-DNA molecular construct is manipulated between
two polystyrene beads. One bead is held at the end of a pipette by suction while the other is held in the optical trap.
The pipette can be moved mechanically with a piezoelectric actuator relative to the trap to stretch and relax the
protein. The applied force is determined directly by measuring the change in momentum flux of the light beams
leaving the optical trap, while the end-to-end distance of the molecule is estimated using a light lever system [8].
These experiments can be performed in a variety of buffer conditions, in the presence of co-solvents or ligands, and
at different temperatures [12]. Typically, the molecule under study is manipulated by changing the applied force
continuously (force-ramp method). However, the folding mechanisms of a protein can also be studied through
experiments in which the applied force is kept constant by a feedback mechanism and fluctuations of the molecules
extension are monitored over time (force-clamp and force-jump methods).

FIGURE 3. Experimental setup (drawing not to scale). The protein is tethered to two polystyrene beads by means of DNA
handles. One end of each handle is attached to the protein through a disulfide bond, while the other end is attached to one bead

203
through either a streptavidin-biotin interaction or an antibody-digoxigenin interaction. The pipette can be mechanically moved
relative to the trap while the displacement of the bead in the trap can be used to infer the forces acting on it.

Force-Ramp Experiments

In a typical force-ramp experiment, the molecule is stretched and relaxed multiple times by moving the pipette
relative to the optical trap to generate force-extension curves like the one shown in Fig. 4a. When the pipette is
moved away from the trap, the force applied on the protein increases until the molecule unfolds. When this happens,
the end-to-end distance of the molecule suddenly increases, giving rise to a sharp transition in the stretching trace.
Indeed, the extension of an unfolded polypeptide chain is much larger (usually ~ 20-30 nm) than that of the folded
structure (usually ~ 3-4 nm). When the pipette is moved toward the optical trap, the molecule is relaxed until it
refolds, regaining its original length. When DNA alone is manipulated, force increases and decreases monotonically,
and no sharp transitions are observed [10]. Force vs. extension curves can be interpolated and analyzed with
statistical mechanical models, such as the worm-like chain model (10), to estimate the number of amino acids
involved in the observed transitions. This analysis helps identify possible intermediate states along the (un)folding
trajectories of a protein [10]. Force-ramp experiments are carried out not only to measure the forces that hold
together tertiary and secondary molecular structures, but also to determine kinetics parameters of the unfolding and
refolding reactions. Specifically, a molecule can be stretched and relaxed multiple times to generate
unfolding/refolding force distributions that can be used to estimate the (un)folding rate coefficients at zero force and
the position of the transition state(s) along the pulling axis [10].

Force-Clamp Experiments

The unfolding/refolding processes of a single protein can also be studied through experiments in which the force
is kept constant with a feed-back mechanism (force-clamp) and the extension of the molecule is monitored over
time. Figure 4b shows extension vs. time traces acquired with ribonuclease H (RNase H). In these recordings, RNase
H can be observed to hop between a folded and an unfolded conformation. The equilibrium between the two
molecular states can be affected by force; higher forces move the equilibrium toward the open state, while low
forces favor the closed state. In these experiments, rate coefficients can be obtained directly from the dwell time
distributions of the open or closed states, and free energies can be calculated from the ratio of the kinetics
coefficients. Force-clamp experiments are ideal to characterize the kinetics and thermodynamics of the
interconversion between different molecular conformations at equilibrium. However, these studies are effective only
when the rates of the forward and reverse reactions are high enough to allow the observation of a large number of
transitions in a relative short amount of time. If the acquisition of a statistically significant number of events require
hours of recording, the reliability of the measurements can be compromised by the mechanical and optical instability
of the instrument. In these cases, the folding of a protein can be more effectively studied through force-jump
experiments.

Force-Jump Experiments

In a force-jump experiment the force is increased (jumped) or decreased (dropped) quickly to a preset force value
and kept constant with a feedback mechanism until an unfolding or refolding event is observed (Fig. 4c). These
experiments allow the direct measurement of rate constants in force ranges where the probability of observing either
an unfolding or refolding event is high. The force-jump/force-drop cycle can be repeated multiple times until a large
number of events have been observed. At each cycle, the time that the molecule takes to unfold or refold can be
directly measured and plotted in dwell time histograms to estimate the rate coefficients. From the dependence of the
rate coefficients on the applied force, kinetics parameters, such as position of the transition state along the reaction
coordinate and rates at zero force, can be estimated. This method was introduced for the first time to study the
kinetics and thermodynamics of the (un)folding mechanism of an RNA molecule [13].

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FIGURE 4. Data acquired through different modes of operation of optical tweezers. a) Force-extension cycle of RNase H from a
force-ramp experiment. The stretching trace is characterized by a sharp discontinuity at ~ 16 pN that marks the mechanical
unfolding of the molecule. The relaxation trace is characterized by a refolding transition at ~ 5 pN. b) Extension vs. time traces of
RNase H at various forces in a force-clamp experiment. The probability of populating either the unfolded conformation (upper
level) or the folded conformation (lower level) is affected by the applied force. c) Two successive force-jump/force-drop cycles
of TAR RNA. The top and bottom panels show the force and extension, respectively, monitored over time. Figure 4a is reprinted
from [9] with kind permission from Springer Science + Business Media: European Journal of Biophysics. Figure 4b is reprinted
from [10] with permission from AAAS. Figure 4c is reprinted from [13] with permission from Elsevier.

CASE STUDIES
A number of systems have been studied with the methods described above. Impressive results have emerged
from these studies that have furthered our understanding of protein folding. A subset of these results is described
below.

Ribonuclease H

Optical tweezers were employed to study the folding of a single globular protein for the first time by Cecconi
and co-authors [10]. By manipulating one molecule at a time using DNA molecular handles, these authors
characterized the (un)folding processes of individual RNase H molecules with unprecedented details, uncovering
information inaccessible to more traditional bulk techniques. Bulk studies had previously revealed the existence of a
partially structured intermediate (I) in the folding trajectories of RNase H [14]. The intermediate, however, formed
within the dead time of the measuring instrument (12 ms) and thus could not be observed and characterized directly.
By manipulating one molecule at a time and slowing down the refolding process with tension, Cecconi and co-
authors were instead able to watch directly single molecules fold part way to the intermediate structure, and then go
from there to the folded protein. Using this experimental approach, they showed that RNase H folds through a
compact, thermodynamically distinct intermediate state, which is both obligatory and on-pathway to the native
structure. In force-clamp experiments, they observed the protein fluctuate between the intermediate and the unfolded
state (U), and characterized the U to I transitions in terms of kinetic and thermodynamic parameters. They also
characterized the mechanical properties of the intermediate and showed that it is highly pliant and stretchy under
force. This is a property characteristic of structures, such as those of molten globule-like states, mainly stabilized by
secondary interactions and weak, non-stereospecific tertiary contacts.

T4 Lysozyme

In optical tweezers experiments the denaturant (force) can be selectively applied to specific portions of a protein.
This is a unique capability of optical tweezers that makes this technique particularly well suited to study the
cooperativity of the folding processes of different protein domains. An example of the effectiveness of these single
molecule studies to investigate the cooperative communication between different structural regions of a protein is
represented by the work published in Nature by Shank et al. [15]. In this work, the authors studied the folding
cooperativity of T4 lysozyme. They applied force selectively to either the N-terminal or C-terminal domain of this
protein and used the Crooks fluctuation theorem to probe the status of the protein portion not directly subject to
force. The results of these studies showed that the folding processes of the two structural domains of T4 lysozyme
are strictly coupled. Additionally, by creating a topological variant with a circular permutation, Shank et al. showed
that helix A is a key determinant of the cooperative unfolding of T4-lysozyme.

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 Calmodulin

Stigler et al. studied the calcium sensor calmodulin, a two-domain EF-hand protein that is involved in a number
of signaling cascades [16]. Using ultra-stable high-resolution optical tweezers and performing force-clamp
experiments, they observed a total of six intermediate states in the folding mechanism of calmodulin. Four of these
intermediate states were on-pathway in a relatively fast folding process. The presence of two off-pathway
intermediate states, which had non-native inter-domain interactions, slowed the overall folding process. From their
results, Stigler et al. were able to show that calmodulin folds through three competing pathways where different
intermediates were populated giving rise to different folding rates. Their results lend support to the theory of kinetic
partitioning in which a fraction of a given set of molecules folds fast towards the native state while others are
kinetically trapped and fold slower. The overall result demonstrates the high degree of complexity of the dynamical
folding network of these signaling molecules.

CONCLUSIONS
Here we have described how optical tweezers can be used to study chimeric protein-DNA constructs on the
single-molecule level. This method is robust and generally applicable to any protein that can be modified with
genetic engineering. A wide range of experimental conditions can be applied and experiments can be chosen that fit
the specific system under study.
The advent of single molecule methods has opened up new vistas of possibilities when it comes to exploring the
phenomenon of protein folding. Optical tweezers permit a direct and gentle manipulation of biomolecules within
both the thermodynamic and kinetic regimes of the energy landscape of a protein. Here, we have outlined a subset of
the vastly growing number of studies in which optical tweezers have been used to study the folding behavior of
proteins. As the technology of optical trapping advances further we can expect exciting results on even larger and
more complex systems in the future.

REFERENCES

1. K. A. Dill and H. S. Chan, Nat Struct Biol 4 (1), 10-19 (1997).

2. M. B. Borgia, A. Borgia, R. B. Best, A. Steward, D. Nettels, B. Wunderlich, B. Schuler and J. Clarke,
Nature 474 (7353), 662-665 (2011).
3. J. H. Han, S. Batey, A. A. Nickson, S. A. Teichmann and J. Clarke, Nat Rev Mol Cell Biol 8 (4), 319-330
(2007).
4. J. R. Moffitt, Y. R. Chemla, S. B. Smith and C. Bustamante, Annu Rev Biochem 77, 205-228 (2008).
5. J. N. Onuchic and P. G. Wolynes, Curr Opin Struct Biol 14 (1), 70-75 (2004).
6. A. Ashkin, J. M. Dziedzic, J. E. Bjorkholm and S. Chu, Opt Lett 11 (5), 288 (1986).
7. D. G. Grier, Nature 424 (6950), 810-816 (2003).
8. S. B. Smith, Y. Cui and C. Bustamante, Methods Enzymol 361, 134-162 (2003).
9. C. Cecconi, E. A. Shank, F. W. Dahlquist, S. Marqusee and C. Bustamante, Eur Biophys J 37 (6), 729-738
(2008).
10. C. Cecconi, E. A. Shank, C. Bustamante and S. Marqusee, Science 309 (5743), 2057-2060 (2005).
11. S. B. Smith, Y. Cui and C. Bustamante, Science 271 (5250), 795-799 (1996).
12. H. Mao, J. R. Arias-Gonzalez, S. B. Smith, I. Tinoco, Jr. and C. Bustamante, Biophys J 89 (2), 1308-1316
(2005).
13. P. T. Li, D. Collin, S. B. Smith, C. Bustamante and I. Tinoco, Jr., Biophys J 90 (1), 250-260 (2006).
14. T. M. Raschke and S. Marqusee, Nat Struct Biol 4 (4), 298-304 (1997).
15. E. A. Shank, C. Cecconi, J. W. Dill, S. Marqusee and C. Bustamante, Nature 465 (7298), 637-640 (2010).
16. J. Stigler, F. Ziegler, A. Gieseke, J. C. Gebhardt and M. Rief, Science 334 (6055), 512-516 (2011).

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 Molecular Dynamics Techniques in the Studies of the
Bacterial Ribosome
Joanna Panecka, and Joanna Trylska

Centre of New Technologies, University of Warsaw, Zwirki i Wigury 93, 02-089 Warsaw, Poland

Department of Biophysics, Institute of Experimental Physics, Faculty of Physics, University of Warsaw,
Zwirki i Wigury 93, 02-089 Warsaw, Poland; Interdisciplinary Centre for Mathematical and Computational
Modelling, University of Warsaw, Pawinskiego 5a, 02-106 Warsaw, Poland

Abstract. We summarize here the recent applications of molecular dynamics (MD) and enhanced sampling methods used to
elucidate the role of exibility in ribosome functioning. In the last decade, many atomic resolution structures of the bacterial
ribosome have been solved, which allowed for extensive all-atom MD studies of this system. However, the time scale of
such simulations is often not sufcient due to the large number of atoms building the ribosome complex. One of the ways to
overcome this problem are enhanced sampling techniques. For instance, steered MD gave us knowledge about the dynamics
of nascent peptide chain in the ribosomal exit tunnel. Targeted MD was used to study pathways of tRNA accommodation
into the ribosome. Other MD-based techniques (MDFF and MDt) allowed for generation of full-atom models from medium-
resolution cryo-electron microscopy (cryo-EM) maps. Also, the studies on models of ribosomal aminoacyl-tRNA binding site
(A-site) improved our understanding of the mRNA decoding process. For example, replica exchange molecular dynamics
(REMD) was used to study the movement of the two key adenines, involved in the mRNA decoding process. The REMD
extensive sampling allowed for construction of free energy landscapes. In summary, the MD-based techniques are very helpful
in expanding our knowledge of the ribosome functioning and they successfully complement the experimental studies.
Keywords: molecular dynamics, enhanced sampling, ribosome
PACS: 87.15.ap, 87.14.gn, 87.14.E-, 87.15.hg, 87.15.hp

INTRODUCTION

The Ribosome Structure

Ribosomes are large ribonucleoprotein assemblies that serve as workbenches to perform synthesis of proteins, the
process essential for each living cell. These huge macromolecular entities are divided into two asymmetric subunits
small (in bacteria denoted 30S, in accordance with its sedimentation coefcient) and large (50S) (Fig. 1a). The
full bacterial ribosome consists of approximately 250 000 atoms and occupies the volume of over 2 500 nm3 . The
crystallography and cryo-electron microscopy (cryo-EM) are the basic experimental techniques that provided us with
the detailed structural knowledge about the ribosome [1]. The rst crystal structures of ribosomal subunits were
solved in 2000: the archeal 50S of Haloarcula marismortui at 2.4 resolution [2] and bacterial 30S from Thermus
thermophilus (3.05 ) [3]. Then, in 2001 Yusupov and coworkers solved the crystallographic structure of the full
T. Thermophilus ribosome, with mRNA and three tRNAs at 5.5 resolution [4]. A few years later the rst atomic-
resolution structure of the full ribosome at 3.5 was resolved [5]. Currently, hundreds of prokaryotic ribosomal
structures are deposited in the Protein Data Bank [6]. The experiments capture different stages of protein synthesis
and the ribosomes are complexed with various cofactors. In parallel, another technique, cryo-EM, has been used to
gather data about ribosomal conformations. The rst cryo-EM maps of the E. coli ribosome were solved in 1995 at
25 resolution [7], whereas the current data reach sub-nanometer resolutions [8, 9] and can be used in computational
modelling studies.

The mRNA Translation Process

The ribosome catalyzes peptide bond formation between consecutive amino acids in the peptide chain that will
further be folded into a protein. The sequence of amino acids of the synthesized peptide is encoded in the nucleotide

Theory and Applications in Computational Chemistry: The First Decade of the Second Millennium
AIP Conf. Proc. 1456, 207-214 (2012); doi: 10.1063/1.4730661
2012 American Institute of Physics 978-0-7354-1057-2/$30.00

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FIGURE 1. a) The full ribosome of T. thermophilus (PDB codes of the crystal structure: 3I8G and 3I8F). The three tRNAs occupy
the A-site, P-site and E-site; b) the two mobile adenines A1492 and A1493 in the decoding site of the 30S subunit; c) paromomycin
(only heavy atoms are shown, the neamine core is encircled) a representative of aminoglycoside antibiotics that bind in the A-site
ribosomal RNA bulge in the proximity of A1492 and A1493.

sequence of the messenger RNA (mRNA). Each nucleotide triple (codon) corresponds to a specic amino acid. The
mRNA codons are precisely positioned at particular functional sites on the ribosome. During peptide elongation cycle,
in each step, an aminoacylated transfer RNA (tRNA) binds to the specic site on the ribosome (aminoacyl-tRNA
binding site or A-site). This tRNA carries an amino acid unequivocally determined by its anticodon, that has to
match the A-site codon of the mRNA chain. It is essential for the produced polypeptides to have amino acids in
the correct order exactly as encoded in the mRNA sequence. Therefore, the small subunit of the ribosome uses
various mechanisms to control the accuracy of the decoding process. The error rate of amino acid incorporation is
surprisingly low 104 - 103 [10].
The three tRNAs occupy the three specic sites on the ribosome called A, P, E (Fig. 1a). The peptide bond between
the amino acids attached to the A-site and P-site tRNAs is formed at the specic site in the large subunit called peptidyl
transferase center (PTC). After this reaction, in the process called translocation, tRNAs have to move: from the A- to
P-site, from the P- to E-site and the last one, from the E-site, is released. At the same time, the newly synthesized
polypeptide chain moves one step forward through the about 10-nm-long exit tunnel located in the 50S subunit. Then
the same cycle is repeated until an mRNA stop codon is positioned in the A-site, which triggers the termination stage
of translation.
It should be noted that the ribosome does not work alone. Apart from the tRNA and mRNA molecules, it binds
various cofactors that control the translation process and trigger the key conformational changes. For instance, in
the bacterial ribosome, elongation factors EF-Tu and EF-G are involved in tRNA accommodation and translocation,
release factors (RF-1, RF-2 and RF-3) control termination of translation and in the nal stage ribosome recycling
factor (RRF) helps splitting the subunits and dissociating mRNA.
The bacterial ribosome is also a target for many antibiotics that perturb its functioning. These antibacterials act
at different levels of translation they can disrupt interactions with translation cofactors, tRNAs or affect crucial

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ribosomal movements [11]. For instance, certain aminoglycosydic antibiotics (Fig. 1c) create complexes with the
bacterial A-site causing decreased delity of the decoding process and leading to production of dysfunctional proteins.

Motions in the Ribosome

What we need to emphasize is that the ribosome is a highly dynamical macromolecular machine. It can perform
its function due to the complex conformational changes of its different parts. For example, the subunits rotate with
respect to each other undergoing the, so-called, ratcheting motion, during the translocation process [12]. Also, the
fragments within the subunits move with respect to each other. For instance, the so-called body and head of the 30S
subunit change their mutual positions. The small subunit can adopt a closed or open conformation this change is
particularly important for the delity of translation [13]. Focusing on a smaller spatial scale, one observes local, but
functionally important, movements of single nucleotides. For example, this is the case with the two mobile adenines
(1492 and 1493, according to E. coli numbering) that are located in the A-site on the small subunit (Fig. 1b). They
ip out of the ribosomal RNA helix upon binding of cognate tRNA and this movement is crucial for the accuracy of
decoding [14]. When aminoglycoside antibiotics bind inside the A-site bulge (Fig. 1b,c) the ipped-out congurations
of the adenines, favorable for tRNA binding, are more probable and thus the process of cognate tRNA selection is
impaired.

METHODS
Experimental data give information mostly about static structures at local environment-dependent energetic minima.
However, activity of the ribosome largely depends on its dynamics. Therefore, there is a need to use computational
methods to simulate ribosomal movements. Due to the complexity and huge size of the ribosome, getting insight into its
dynamical functioning at atomistic level is challenging. Nevertheless, computational studies contributed signicantly
to the knowledge about dynamical properties of the ribosome [15].

Classical Molecular Dynamics

The most basic simulation technique commonly used to investigate dynamical and structural properties of biomolec-
ular systems is Molecular Dynamics (MD) [16, 17]. MD models atoms as spheres with element-specic radii and
electrostatic point charges positioned in their centers. Chemical bonds are represented by harmonic springs. The func-
tional form and the parameters (derived from high-level quantum chemical calculations and experimental data) of the
potential are dened by one of the common force elds [18]. The potential is typically composed of the following
bonded and non-bonded terms:

V = V b +V nb = Vdist
b
+Vang
b
+Vdihe
b
+VvdW
nb
+Velec
nb
(1)

b , V b and V b
where Vdist ang dihe describe bonded interactions, respectively: oscillations (usually treated harmonically) of
nb is the potential for van der Waals and V nb electrostatic
bond lengths, angles and rotations of dihedral angles. VvdW elec
interactions. For such mechanical system the classical Newtons equations of motion are iteratively solved.
Although the MD technique can be used even for such a large system as the ribosome, full-atom MD simulations
are often limited by the huge dimensions of this nucleoprotein assembly. Therefore, either reduced models are needed
or computational approaches that accelerate conformational sampling. Here, we focus mostly on the latter solution.

Steered and Targeted MD

The steered MD or targeted MD are two enhanced sampling methods which apply external forces to the simulated
systems. Both these techniques allow for observation of large-scale conformational changes and rare events that are
out of range for standard MD. In steered MD, external force acts on the chosen subsystem to enforce change of its
conformation. In most computational approaches either the force or the velocity of pulling is constant. Similarly, in

209
targeted MD an external force is applied to a set of atoms, that drives them to their nal, target conformation, which is
known, e.g., from the experimental data. The direction and magnitude of the force is guided by the chosen criterion,
for instance the minimization of the root mean square deviation between the current and the nal conguration.

Atomic Models from Low-Resolution Data

Variations of the targeted MD can be also used for specic purpose deriving fully atomistic models from low
resolution experimental data. Knowing atomic details of biomolecular structures is crucial for deeper understanding of
their function. However, the availability of high-resolution data of certain functional substates is often limited, which
is the case for the ribosome. Therefore, different methods have been developed that combine atomic-resolution crystal
structures with low-resolution cryo-electron microscopy maps. Here, we focus on the two of them MDFF [19] and
MDt [20] that have been successfully applied to the ribosome.
In the MDFF (Molecular Dynamics Flexible Fitting) technique MD simulation is carried out on an atomic model
(e. g. crystal structure) using a standard MD force eld and additional forces proportional to density gradient of the
cryo-EM map are applied to each atom. The added potential drives the system coordinates to the highest density points
in the target cryo-EM map. The secondary-structure restraints are often necessary to prevent over-tting and unwanted
distortions in the atomic model. This method is quite computationally demanding, as it uses classical full-atom MD.
An alternative to MDFF is a more recently developed MDt which also ts the atomic structure to a cryo-EM
map. This method takes advantage of the fact that uctuations about the initial structure, described with a structure-
based model [21], can generate functionally-important transition states of the molecule. The potential used for the MD
simulation is composed of the two important terms:

V = V SB +V map = V SB W itheor exp

jk i jk (2)
i jk

The rst one (V SB ) is the structure-based potential with global energy minimum dened by the experimentally observed
conguration (usually a crystal structure). The second term (V map ) is based on the target cryo-EM map density. W
is the weight of the map, and iexp jk and i jk are the normalized electron densities for the volume element (i, j, k)
sim

respectively, experimental and calculated for the current conformation of the molecule. Equations of motion are solved
with the aforementioned potential until the maximum of correlation between the current and the target conformation
is achieved.
In contrast to MDFF, MDt does not require any secondary structure restraints, so unfolding of the structure and
occurrence of disordered states is possible. Moreover, the usage of structure-based models causes that generation of
excited-state conformations is fast. Therefore, MDt does not require signicant computational resources and one can
obtain extensive conformational sampling.

Replica Exchange Molecular Dynamics

In another MD-based technique Replica Exchange Molecular Dynamics (REMD) [22] identical non-
interacting copies (replicas) of the system are simulated at temperatures within a predened range [Tmin , Tmax ]. The
temperatures of neighboring replicas i and j are swapped at certain time intervals with the probability of successful
exchange based on the Metropolis criterion:
  
1 1
p(i j) = min 1, exp ( )(Ei E j ) (3)
kT j kTi

Thus, each replica "travels" across the given temperature range. These temperature changes make crossing of energetic
barriers more probable and prevent trapping of the system in the energetic minimum. The method does not allow for
retrieving kinetic properties, though it can give thermodynamic description of the system.

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 APPLICATIONS

Molecular Dynamics of the Whole Ribosome

The increase in computational power and appearance of high resolution crystallographic structures of bacterial
ribosome [1] enabled the rst full-atom MD simulations of this macromolecule. Due to its huge size, explicit solvent
computations often suffer from poor conformational sampling. In spite of that, classical MD is still used, as the
method requires fewer approximations and is in principle more accurate than enhanced sampling techniques. In
2007 Sanbonmatsu and Tung tested the performance of the NAMD package [23] for the purpose of large scale
computations [24]. Among others, the authors carried out explicit-solvent MD simulations of the full 70S ribosome.
The largest of the simulated systems consisted of approximately 2.64106 atoms, and in this case the trajectory reached
4-ns time. The parallel scaling efciency on 1024 CPUs on Los Alamos National Laboratory Q Machine was found to
be as high as 85%.
In particular, the full-atom MD simulations of the complete ribosome proved to be a good tool for the studies of
tRNA functional dynamics. In the work from 2005 Sanbonmatsu and coworkers investigated the tRNA accommodation
into the ribosome [25]. In this crucial step of the decoding process tRNA converts from the transition state, denoted
"A/T" to the stably bound "A/A" conformation. The authors presented here the rst large-scale simulations of the
whole bacterial ribosome the multiple runs of targeted MD lasted 20 ns in total. In each simulation the tRNA
molecule was forced to achieve the bound state (known from the crystal data) by decreasing the root mean square
deviation between the current and target conformation. The results revealed the probable tRNA pathways and its
interactions with specic ribosomal nucleotides. The study also suggested that not only the anticodon arm of tRNA,
but also the exible acceptor stem plays an important role in selecting cognate tRNAs. In the later work, to more
thoroughly describe tRNA accommodation, Whitford et al. run massive MD simulations of bacterial ribosome [26].
The seven generated trajectories of the 3.2 million atom system summed up to the impressive sampling of about 2.1 s.
These computations allowed for estimating the characteristic times for tRNA accommodation. The relaxation time of
tRNA uctuations was found to be about 10 ns, and tRNA was observed to attempt accommodation with a frequency
of about 1-10 s1 .
Full-atom MD also shed light on the mechanism of nascent polypeptide translocation through the ribosomal exit
tunnel [27]. Ishida and Hayward performed multiple steered MD runs (20 ns in total) of the whole bacterial ribosome
in explicit water (1.9 million atoms). They pulled a 36-residue-long polyalanine through a constriction created by the
two large subunit proteins L4 and L22. The results suggested that Arg92 of L22 plays a role of a conformational switch
closing and opening the tunnel for the movement of the peptide.
In the most recent work [28] Brandman and coworkers performed two explicit solvent MD simulations of about
2.2 million atom T. thermophilus ribosome system. The two simulations were run: with three tRNAs and mRNA (32 ns)
and without these molecules (53 ns). The study revealed that the movements of the A-site and P-site nucleotides are
uncorrelated, which suggested that the A-site and P-site are functionally independent.

From Cryo-EM Maps to Atomic Resolution Structures and Pathways

The cryo-EM method allows for capturing different functional states of the ribosome in the native environment, in
contrast to non-native experimental conditions in crystallography [7]. However, its important drawback is relatively
low resolution. Even though in some studies the method reached subnanometric scales, this still does not allow
to directly retrieve atomistic details from cryo-EM maps. The two recently proposed hybrid modeling methods
MDFF [19] and MDt [20] try to overcome this problem by combining all-atomic models with cryo-EM density
maps.
MDFF was used mostly to better understand the interactions of the ribosome with its various cofactors. In one of
the rst applications of this method, the conformational change of the elongation factor Tu (EF-Tu) upon binding
to the ribosome was studied [8]. The authors created a 6.7 resolution cryo-EM map of the E. coli ribosome in
complex with tRNAPhe EF-Tu GDP, and with the antibiotic kirromycin. The MDFF method in vacuum was used to
generate full-atom model of the complex. The results showed that one of the structural elements in EF-Tu interacts
with ribosomal RNA and thus triggers the GTPase activity of EF-Tu. The catalytic histidine (His 84) in the active
site of EF-Tu changes its position towards GTP, acquiring the conformation optimal for catalysis. In the later work,
renement of EF-Tu and its surrounding in explicit solvent was performed to compare with the results obtained in

211
vacuum [29]. The results showed that explicit solvent simulations reproduce more native contacts of EF-Tu observed
in the crystal structure. The conformational change of another ribosomal cofactor, EF-G, during translocation was also
studied using the MDFF method [30]. In this case, additional harmonic restraints were applied to backbone hydrogen
bonds, which improved the stability of beta sheets while creating an atomistic model.
Other studies focused on the interactions of the ribosome with the membrane-bound protein conducting chan-
nels [31, 32]. The atomic model based on cryo-EM maps allowed for identication of important interactions formed
between the bacterial ribosome and the conserved amino acids of the protein channel [31]. These ndings were cor-
roborated by similar MDFF model of a mammalian ribosome [32].
In another work Seidelt et al. examined the interactions of TnaC a specic peptide that stalls translation with the
ribosomal exit tunnel [33]. First, the authors determined the cryo-EM model of the ribosome with the TnaC peptide
at 5.8 resolution. Next, with the atomic model created with MDFF, they showed that the two conserved residues in
PTC changed their conformation. The authors suggested that this change may explain why the release factors cannot
bind to the ribosome and translation is stalled by the TnaC peptide.
Cryo-EM studies also proved to be useful in explaining tRNA conformational changes. Agirrezabala et al. used
the MDFF approach in explicit solvent to characterize the tRNA motions during decoding [9]. They found that
the acceptor stem of a near-cognate tRNA is mobile and the CCA-terminus does not adopt a stable conguration.
Whitford et al. also studied tRNA conformations, using the MDFit method [20]. Based on the crystal structures, cryo-
EM maps and available biochemical data they generated a series of, probably functionally relevant, excited-state tRNA
conformations.

Studies on Ribosomal Fragments to Determine Local Movements

It is not always necessary to simulate the whole ribosome to gain valuable insight about polypeptide synthesis. To
investigate local, single-nucleotide movements it is often enough to focus on a small ribosomal fragment. One such
example is the intensively studied A-site where mRNA decoding takes place.
In particular, there are many works focusing on the two exible adenines A1492 and A1493 and the inuence
of aminoglycoside binding on their mobility (Fig. 1b,c). Classical MD studies allowed us to observe the ipping
movement of these nucleotides [34, 35]. Also, REMD simulations of a 17 nucleotide-long RNA duplex containing a
single A-site gave us thermodynamical characterization of their mobility [36]. The authors calculated the free energy
landscape for A1492 and A1493 and estimated the energetic barrier for adenine ipping to be in the range of 0.5-5
kcal/mol. This value is small enough for the tRNA or antibiotic to shift the equilibrium towards ipped-out states.
In 2001 Vicens et al. crystallized a small oligoribonucleotide duplex containing two mirror A-site models that proved
to reect well the properties of the A-site as in the whole ribosome [37]. This and other models (reviewed in [38])
were often used in computational studies to investigate aminoglycoside binding and exibility of the two adenines.
Vaiana et al. used 25-ns long MD explicit solvent simulations of the aforementioned model [37] to study the binding
of an aminoglycoside representative paromomycin (Fig. 1c) [39]. The results suggested that the two pseudo-sugar
rings of paromomycin, which form the so-called neamine core, create crucial hydrogen bonds stabilizing the antibiotic
in the binding cleft. The two other rings are more mobile and their interactions with RNA are transient and weaker.
The results also revealed the importance of water-mediated contacts in the drug recognition process.
In another work, Romanowska et al. used MD to study the dynamics of the model A-site [35]. The authors inves-
tigated the inuence of the A1408G substitution, that occurs in eukaryotic organisms, on aminogycoside recognition.
The characterized ipped-in and ipped-out conformations of the adenines were consistent with the experimental
data. The calculated ion and water distributions in the A-site were found to differ depending on the bacterial or eu-
karyotic variant. In a more recent study, Romanowska et al. performed MD simulations to investigate how other
mutations of the A-site, that were experimentally conrmed to cause bacterial resistance against aminoglycosides, af-
fect the physicochemical properties and dynamics of the A-site [40]. They found that the resistance-causing mutations
change the aminoglycoside interactions in their binding pocket, and also affect ion densities. In one of the mutants
(U1406C:U1495A) the key hydrogen bonds between paromomycin and RNA were broken during the simulation.
In 2009 Vaiana et al. used REMD to study the complex of the A-site with another aminoglycoside gentamicin [41].
Based on a total of 5 s sampling they constructed the free-energy landscapes for the movement of the adenines in
the presence and absence of the antibiotic. Flipping of the adenines was found to be faster than gentamicin binding
suggesting that the mechanism of the antibiotic binding is rather stochastic gating, not the induced t.

212
 SUMMARY
Structural experimental data that appeared in the last decade allowed for atomistic simulations not only of ribosome
fragments but, most importantly, the whole ribosome. Full-atom MD of this nucleoprotein assembly is already feasible,
even on quite long time scales. However, enhanced sampling techniques, such as steered MD, targeted MD or REMD
also help to gain knowledge about the ribosome functioning. These methods helped us understand such processes as
tRNA translocation or peptide movement in the exit tunnel. Furthermore, MD-based approaches were used to recreate
transient conformations of the ribosome and to increase the resolution of the cryo-EM models. Full-atom models
generated from cryo-EM maps shed light on the interactions of the ribosome with its cofactors such as EF-G, EF-Tu
or protein channels. Also, MD and REMD studies on ribosomal fragments proved to be useful in the investigation of
dynamical properties of the decoding site and its interactions with the antibiotics.
Most of the methods presented here require signicant computational resources and long simulation times to achieve
sufcient conformational sampling. Therefore, approaches that would reduce the computational cost of the ribosome
simulations at the same time preserving the necessary details, are still needed.

ACKNOWLEDGMENTS
We acknowledge support from the University of Warsaw (BST and ICM G31-4), Polish Ministry of Science and
Higher Education (N N301 245236), National Science Centre (2011/01/N/NZ1/01558), Foundation for Polish Science
(Focus program and Team project TEAM/2009-3/8 co-nanced by European Regional Development Fund operated
within Innovative Economy Operational Programme).

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214
 Molecular Dynamics Simulation of Water in the Low
Temperature Region
A. Krallafa(a), A. Adda, A. Seddiki and M. Dauchez (b)

(a)
L. P. C. M., Department of Chemistry, Faculty of Sciences, University of Oran, B.P. 1524 El-Menaouer, 31100
Oran, Algeria.
(b)
Sirma, Faculty of Sciences, University of Reims Champagne Ardennes, Reims, France.

Abstract. A comparative molecular dynamics simulation study is carried out on liquid water at normal temperature and
pressure. With classical interaction models such as the SPCE and the TIP4P, the physical model based upon the
tetrahedral cluster architecture composed of 1 central molecule (20% of the sample) and 4 outer molecules (80%) are
compared to first principle molecular dynamics data. This work aims to corroborate the AB4 model of water with a
differentiation within a sample of species, either D-A (Donor Acceptor) or 2D - A and D - 2A type. Structural, transport
and thermodynamic properties compare favourably well with ab initio and experimental data and the hydrogen bond
network is investigated through the cluster size distribution in the liquid.
Keywords: Hydrogen bond network, Water, Molecular dynamics, ab initio, Pseudopotential
PACS: 61.20.Ja

INTRODUCTION
Because of its importance in chemistry and biology, water and aqueous mixtures remain the subject of intense
experimental and theoretical studies over the past few years[1-10]. The cohesive energy of liquid water is important
since water molecules can be trapped with their nearest neighbors through a hydrogen bond network. The correlation
of various properties of water molecule aggregates with the cluster size (n) has been investigated using intensive ab-
initio calculations[10, 11]. Most investigations have focused on binding energies, electronic, thermodynamics, and
structural properties, either from different experimental techniques[12-23].
The molecular self-assembly by H-bonding and van der Walls interactions is a fundamental process in
chemistry and biology. Self assembly processes are difficult to follow by classical molecular simulations when
empirical or semi-empirical intermolecular potential models are used. Although, the later may lead to acceptable
calculated properties in the liquid state, the choice is mainly based upon the energy model of interest of the cluster
which, once obtained, may require a comprehensive study on the potential energy surface of the cluster. Actually, at
present the structural characterizations of the complex water cluster systems are impossible to obtain by classical
simulations or by progressively incrementing their ever increasing size using conventional ab initio quantum
calculation methods. Several classical molecular dynamics simulations, based on effective potentials, have been
performed[4-8, 28-38]. Thus, one is facing two major difficulties when trying to perform simulation of liquid water; the
non-adequacy of the potential models and the relatively few number of experimental data. Since water is a highly
polarizable molecule, several alternatives to the commonly used fixed-point charge models [39-43] were proposed,
such as the Dipole-polarizable models [44] or the fluctuating charge models [45-47]. Such highly polarizable
molecules suggest a systematic analysis of the kinetic aspect (dynamics) with respect to the charge distribution
(dipole) and vice versa [48-50].
Raman spectrometry gives evidence of two hydrogen bond types; those remaining unbroken or SHB (Strong
Hydrogen Bond) and those broken WHB (Weak Hydrogen Bond) subject to the association and dissociation process.
From a recent quantum calculation study [10, 51] we observe that the mean charge on oxygen atoms per molecule
increases with the cluster size, a result found to be consistent with the Morokumas [52-55] analysis of the total
interaction energy where. Moreover, an analysis[10] of the hydrogen bond network and strength with the topology and
arrangement of water molecules type of large clusters appear to follow a D-A (i. e. 1 Donor molecule D 1

Theory and Applications in Computational Chemistry: The First Decade of the Second Millennium
AIP Conf. Proc. 1456, 215-222 (2012); doi: 10.1063/1.4730662
2012 American Institute of Physics 978-0-7354-1057-2/$30.00

215
Acceptor molecule A) and DD-AA (i. e. 2 Donor molecules DD 2 Acceptor molecules AA) combinations
for three dimensional cluster. Such scheme is in perfect concordance with the tetrahedral water edifice with a central
molecule in a DD-AA (4 SHB) state and surrounding molecules in a D-A (2 WHB) state.
The purpose of this work is to put into evidence the permanent dipole moments variations of the trapped
molecules (guest or inner molecule type A within the tetrahedral cluster) and the molecular traps (hosts or outer
molecules type B). These individuals within water molecular species build the hydrogen bond network. We shall
focus on the structural aspects of liquid water and the cluster cluster distribution using different approaches and
levels of theory as a function of temperature. These data are particularly important at melting point, where attempts
made to perform numerical simulations by Molecular Dynamics or Monte Carlo calculations showed the efficiency
and limits of several potential models [54, 55].

COMPUTATIONAL ASPECTS AND NUMERICAL MODEL

Assuming that water structure reflects a continuous fracture and recombination process of water tetrahedral
clusters, the central molecule is in a DD-AA continuum and differences between water molecules are made as either
an inner molecule (type A) or an outer molecule (type B) are considered. Oxygen-hydrogen equilibrium distances
RO-H are found to be different whether the molecule is occupying a central position or is in the first coordination
shell. The complete electronic and structural data reported in table 1, obtained from ab initio calculations performed
at the Hartree-Fock level of theory with a 6-31G(d, p) basis set clearly show the differences between electronic and
structural geometries and in particular the valence bond angle. Slight differences are however obtained as far as
structural properties and electronic charges of the cluster are concerned. These results clearly demonstrate the
complex many body problems involved in the liquid water numerical simulations.

Water Mixture Ratio : 1 (H2O)A / 4 (H2O)B

(H2O)A (H2O)B
Inner molecule type A Outer molecule type B
oo (Kj/mole) 0.6497 0.6497
oo () 3.167 3.167
Valence Angle
107.37 106.517
H-O-H (deg.)
RO-H() 0.954 0.941
dO-M() 0.0 5 0.0
Dipole Moment (D) 2.5 2.38
Charge qH(e) 0.44 0.44

Table 1: Parameters of the water molecule in the cluster with the relative molecular composition (20% of (H2O)A and 80 % of
(H2O)B).

Basically, the sample assembly (H2O)5 is considered here as a fragment made up of two molecular species whose
ratio of proportionality is one central molecule (the trapped molecule type A) for four peripheral molecules
(molecule traps type B). In the following model the trapped water molecules is an optimized TIP4P type whereas the
peripheral water molecules are SPCE type. Parameters and data specific to molecules (H2O)A and (H2O)B are
reported in Table 1. The potential model includes the van der Waals interactions with a Lennard-Jones function
describing the no-bonding interactions and the Coulombic representation of electrostatic interactions.
The classical molecular dynamics numerical model incorporates the Nos-Hoover thermostat for the temperature
control and the Parrinello-Rahmans constant pressure algorithm. The Nos-Hoover thermostat [56, 57] is applied
during the entire simulation run and a fictitious piston mass is applied when performing the Parinnello-Rahmans
algorithm [58] with an integration time step t = 0.5 fs for solving the equations of motion using the 5th order gear
predictor-corrector algorithm. The sample contains a total of 210 molecules (i. e. 42 molecules (H2O)A and 168
molecules (H2O)B) arranged in an hexagonal structure (ice), and the overall runtime reached up to 500 ps, with an
equilibration period of up to 100 ps. Periodic boundaries and long range corrections are applied and the collected
data were saved every two steps to increase precision over calculated properties in particular the viscosity. The
preliminary experiments are performed at room temperature.

216
 First principle molecular dynamics simulations are performed using the Car-Parrinello molecular dynamics
approach[59] with three different pseudopotentials and the Kohn-Sham formulation of the density functional theory[54]
with the gradient-corrected BLYP[60] density functional. The BLYP hybrid functional has been shown to give a good
description of hydrogen bonding in liquid water[61]. The choice of the parameters for the present simulation is chosen
on the basis of series of calculations performed on small water clusters. Actually, it has been shown from a series of
test calculations on the structure and binding energy of water dimer and cyclic trimer[62], that hybrid functionals
enhance the experimental structure and increase the accuracy of the dynamical properties as measured by the radial
distribution function when compared to the pure density functionals.
In the present calculations, the effect of the temperature on the structure and dynamics of water has been
characterized with simulations of 60 ps in the temperature range of 263-280K with the influence and effects of the
pseudopotential in the thermalisation process. To ensure the proper canonical sampling, a Nos-Hoover chain
thermostat was coupled to each ionic degree of freedom throughout the entire 48 ps simulation. Structural and
transport properties are found to be in good agreement with experimental data when available. Three types of
pseudopotentials are used, first, is the norm conserving Martins-Trouillier pseudopotentials[63, 64] with Kleinman-
Bylander transformation (KB pseudopotential) and a planewave cutoff of 70 Ry for their conceptual simplicity of
use and numerical implementation. Additional calculations are performed with the Goedecker pseudopotentials [65]
(GD pseudopotential) and a planewave cutoff of 85 Ry and the Vanderbilt ultrasoft non norm conserving
pseudopotentials (VDB pseudopotential) and a planewave cutoff of 25 Ry is used to reduce the cost of the
calculations. The calculations are performed in the canonical (NVT) ensemble at various temperatures in a
periodically replicated cubic box containing 32 water molecules and optimized fictitious mass
(VDB = 400, KB = 600 GD = 600) for a good thermalisation process. The timestep for the velocity Verlet
integrator is 5.0 a.u. (0.12 femtosecond). Each simulation begins with a 12 ps relaxation run followed by a 48 ps
trajectory as a production. The analysis of the simulation data was carried out using the last 12 ps of the molecular
dynamics trajectories.

RESULTS AND DISCUSSION

The permanent dipole moment difference between the two water molecular species A and B reported in figure 1
is mainly the consequence of the charge asymmetry on oxygen atoms for A and B type water molecules. The
negative charge originally located on the oxygen atom and subsequently delocalized on a dummy site M at a
distance dOM = 0.05 gives evidence of the existence of two distinct zones: zone A occupied by a central molecule A
(trapped) and zone B formed by the outer molecules B (traps). Data of the radial distribution function gOO(r) between

1.0

0.9 Martins-Trouillier (MT-KB) Pseudopotential

Goedecker (GD) Pseudopotential
0.8 Vanderbilt Pseudopotential
[67-69]
Exp
0.7
AB4 Model (1-TIP4P/3-SPCE)
0.6 TIP4P
goo(r)

0.5

0.4

0.3

0.2

0.1

0.0
2 3 4 5 6
r(Angstrom)

Figure 1: Plots of the RDFs goo(r) for different M. D. Simulations correlated to experimental data.

oxygen atoms reported in Figure 1 are in perfect agreement with experimental data. They also give detailed
information on instantaneous electronic molecular structures as they yield to a better space correlation of closest
molecules. The pair distribution function gOH(r) between oxygen and hydrogen atoms reported in figure 2 yields the
number of intermolecular hydrogen bonds (ROH = 1.9 and the coordination number is nOH = 1.6) in good

217
agreement with neutron scattering data reported A. K. Soper and co-workers [66-68] obtained the same value for ROH =
1.9 and nOH = 1.6 to 1.9 (table 2). The study of gHH(r) profile reported in figure 2 is in good agreement with
experimental data with a perfect correlation of the data peaks.
The comparative study of the radial distribution function obtained from classical and first principle M. D.
illustrate the good behaviour of the classical approach based on the AB4 model. The radial distribution functions
gOH(r) and gHH(r) obtained from the last 12 ps of the 60 ps molecular dynamics trajectories are reported in figures 2
and 3 respectively. The calculated RDFs for the CPMD simulations at 298K are compared with different
pseudopotential types used in the simulations. Despite the differences observed in the calculated energies a good
agreement between the three simulations is obtained as far as the structural properties are concerned. We find that
the difference in the first solvatation shell is minimal which means that there is no major variation during the
simulation. The goo(r) function is characterized by pronounced first peak located at about 2.9 , the first minimum at
about 3.4 A and the broad peak centred at about 4.4 - 4.5 region which is assigned to the interactions of the
second neighbours. The maximum value of the oxygen-oxygen radial distribution function RDF for these three
simulations was found to be 2.95 when the 600 a.u value of fictitious mass is used.

1.2 Martins-Trouillier (MT-KB) Pseudopotential

Goedecker (GD) Pseudopotential
1.1
Vanderbilt Pseudopotential
1.0 Exp
[67-69]

0.9 AB4 Model (1-TIP4P/3-SPCE)

[70]
0.8 Exp
TIP4P
0.7
gOH(r)

0.6
0.5
0.4
0.3
0.2
0.1
0.0
1.4 1.6 1.8 2.0 2.2 2.4 2.6 2.8 3.0 3.2 3.4 3.6 3.8 4.0
r (Angstrom)

Figure 2: Plots of the RDFs gOH(r) for different M. D. Simulations correlated to experimental data.

1.4
AB4 Model (1-TIP4P/3-SPCE)
1.3
[70]
1.2 Exp
Martins-Trouillier (MT-KB) Pseudopotential
1.1 Goedecker (GD) Pseudopotential
1.0 Vanderbilt Pseudopotential
[67-69]
0.9 Exp
0.8
gHH(r)

0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0
r(Angstrom)

Figure 3: Plots of the RDFs gOH(r) for different M. D. Simulations correlated to experimental data.

The value obtained using Vanderbilt pseudopotentials is 2.80 which is in excellent agreement with
experimental values, namely, 2.75 from the neutron diffraction[67-69] and 2.83 from the x-ray scattering
measurements [70]. Recent CPMD simulations in the canonical ensemble[71] using BLYP-TM at T = 300K reported a

218
value of 3.1 for the maximum value of the oxygen-oxygen radial distribution function as for other calculations[72]
the maximum was found at 3.0 at T= 315K. Kuo et al reported a value of 2.8 for bulk water. The oxygen-
hydrogen gOH(r), and hydrogen-hydrogen gHH(r) radial distribution function RDF (see Figures 2b and 2c) compare
favourably well with all simulation results, as seen through the positions of the first and second peak. Recent path-
integral simulations[68] predict a smaller influence of nuclear quantum effects on gOH(r). In Figure 2, the first peak is
located at 1.9 , the second intermolecular peak in gOH(r) for all simulations is higher than the first peak (3.4 ),
which is in agreement with the experimental gOH(r). Very similar results can be seen in Figure 3 for the hydrogen-
hydrogen intermolecular peak.
The differences between calculated first principle M. D. and the experimental data are more likely a consequence
of the proton transfer processes that occur as an incessant recombination all along the simulation and the difficulties
to remain in the Born-Oppenheimer surface. The hypothesis of combined molecular species to describe water in the
low temperature region compares favourably well with ab initio calculations. A good description of the density
versus the temperature profile (Figure 4.) supports such hypothesis when compared to other classical models. The
particular behaviour of the density in the low temperature region makes water among the most difficult molecular
system to simulate.

1.010 AB4 - TIP4P/SPCE

Exp
TIP5P
1.005
AB4 - TIP4P-Ice/TIP5P
Density (g/cm )
3

1.000

0.995

0.990

273 274 275 276 277 278 279 280 281

Temperature (K)

Figure 4: Calculated density as a function of the temperature for different models.

In order to study the formation and stability of molecular aggregates, we have defined a cluster in the following
way. First, the molecules are assigned to aggregates in which no one molecule is separated by greater than a distance
Rcritcal from at least one other molecule in the same molecular assembly. In what follows, the critical distance Rcritcal
is calculated between the centres of mass of individual molecules. For the critical distance Rcritcal we have adopted

70 t = 499.9 ps
t = 500 ps
60
relative proportions

50

40

30

20

10

0
1 2 3 4 5 6 7 8 9 10 11 12
Cluster Size (H2O)n

Figure 5: Cluster size distribution at t = 499.9ps and t = 500ps.

219
 the Stillinger[73] definition (Rcritcal = Rc/2.0), Rc being the cutoff radius. A molecular aggregate is only defined as a
bound cluster, however, if the sum of the potential energy and the kinetic energy relative to that of the centre of mass
is negative. The cluster distribution for the three-dimensional sample is reported in Figure 5 at two different times of
interval 0.1ps. The low proportion of monomers is shown to highlight the dense fluid where large aggregates are
predominant.
Several thermodynamics properties of the system are calculated as a function of the temperature increase from
270K and up to 285K. The starting configuration is the hexagonal structure of ice at 270K subject to a temperature
rise of 1K at 1 atm. The reported data are compared to first principles M. D. performed in the same conditions. The
reported results denote the accuracy and the perfect agreement with first principle molecular dynamics simulations.
If concepts such as inner and outer molecules within a cluster may seem meaningless in the gas phase it is certainly
not the case at low temperatures. Water is a highly polarizable molecule and its surroundings are fundamental and
have a great influence over the both structural and thermodynamic or transport properties. To reproduce
satisfactorily water properties at standard temperature and pressure, it is necessary to have a strong directional
hydrogen bond and this requires a local tetrahedral ordering.

NPT NPT NPT CPMD CPMD CPMD

Temperature Exp[1]
AB4 AB4 AB4 NVT-KB NVT-GD NVT-VDB

Calculated Density D (2/ps) D D D D2 [3, 74]

K density (g/cm3) max max
(2/ps)
max
(2/ps)
max
(2/ps)
(g/cm3)
g OO g OO g OO g OO ( /ps)

270 0.99949 0.99958 0.1588 4.09 4.02 0.117 4.45 0.116 3.84 0.039 -
271 0.99965 0.99969 - 4.38 3.98 0.118 4.44 0.127 3.77 0.047 -
272 0.99977 0.99979 - 4.10 3.91 0.122 4.43 0.128 4.39 0.049 0.114
273 0.99987 0.99987 - 4.46 3.86 0.127 4.50 0.135 4.28 0.064 -
274 0.99994 0.99993 - 4.36 3.81 0.128 4.51 0.137 3.67 0.072 -
275 0.99999 0.99997 0.1652 4.19 3.75 0.131 4.47 0.141 3.85 0.074 0.127
276 1.000012 0.99999 4.19 3.71 0.134 4.46 0.144 3.57 0.086 0.131
277 1.000015 1.00000 4.21 3.67 0.137 4.43 0.153 3.86 0.092 -
278 0.99999 0.99999 4.47 3.63 0.141 4.37 0.166 4.21 0.112 -
279 0.99996 0.99997 0.1640 4.49 3.62 0.146 4.32 0.168 3.98 0.148 -
280 0.9999 0.99993 - 4.49 3.58 0.158 4.27 0.174 4.12 0.137 -
281 0.99983 0.99988 - 4.47 3.53 0.160 4.23 0.177 3.66 0.141 -
282 0.99975 0.99981 - 4.28 3.48 0.165 4.18 0.180 3.64 0.148 -
283 0.99966 0.99973 - 4.26 3.42 0.169 4.13 0.182 3.59 0.152 -
284 0.99955 0.99963 - 4.33 3.38 0.171 3.97 0.191 3.52 0.164 -
285 0.99943 0.99953 4.39 3.34 0.174 3.92 0.215 3.56 0.169 -
298 0.99948 0.99707 0.22696 4.44 2.66 0.269 3.14 0.322 2.84 0.310 0.227

Table 2: Calculated thermodyanmic, structural and transport properties of liquid water at different temperatures.

CONCLUSION
Molecular modelling of liquid water is a complex task; the present work highlights the conditions and the routes
both in the classical or the first principle molecular dynamics that lead to a better agreement between theoretical and
experimental data. The concept of a pseudo crystal AB4 configuration structure is essential for a good three-
dimensional representation of liquid water in the low temperature region. Finally, this hydrogen bond type
proportion is directly correlated to a double constraint: optimal local structure associated to the water local charge
dynamics distribution. Our theoretical water model based on a mixture of two H2O species A (20%) and B (80 %)
correlated to the SPCE potential interaction parameters gives a better understanding of the existence of these two
type of hydrogen bonding (strong and weak). The series of longtime first principle molecular dynamics trajectories
for liquid water at different temperatures, yield to a detailed structural and transport properties of water using density
functional theory with BLYP exchange and correlation and different pseudopotential types. In order to ensure the
proper canonical sampling, a Nos-Hoover chain thermostat was coupled to each ionic degree of freedom throughout
the entire 48 ps simulation. A good agreement in the radial distribution functions is achieved between theory and
experiment, the gOO(r) value obtained from simulation in canonical ensemble with the norm-onserving Troullier-
Martins pseudopotential with Kleinman-Bylander transformation, to the fully nonlocal form when compared to x-ray

220
scattering data and neutron scattering data. The results presented here clearly demonstrate the complexity and the
influence of different parameters particularly the cutoff radius and the fictitious mass introduced in the cpmd code
particularly when studying a system in different thermodynamic environment.

SPECIAL APPENDIX

I would like to thank Pr. E. Clementi for his kind invitation to attend this international conference and the
opportunity he gives me to present a short talk about scientific research in Computational Chemistry in Algeria and
the Maghreb region. It is a tough task to cover the research work in Quantum and Computational Chemistry over the
Great Maghreb area; however, with the help of a recent survey and on the basis of our research and teaching
experience, two points will be developed in this review. First, as far as the scientific research is concerned, I shall
focus on what can fall under a general heading as Quantum and Computational Chemistry within the Great Maghreb
Region; then progressively I shall move in on more specific aspects of the research activity in Algeria and
particularly within the western part of the country. The latest development from the economic and social standpoints
in the region will be developed with a correlation between the GDP (The Gross Domestic Product) and research
financial support. I will particularly focus on the understanding at the atomic and molecular level of the physico-
chemical principles (structure function relationship, thermodynamics and kinetics) which underlie the complex
dynamic processes strongly related to molecular recognition, molecular self assembly and organization (static and
dynamic). In our laboratory, such processes are considered as the starting point to the transfer of information and a
better understanding of organized systems from chaotic molecular structure. Spectroscopic approaches (NMR, FT-
IR, Raman) and computational chemistry at different levels of theories are used to achieve such investigations. Our
research group has developed a sound expertise in the following theoretical approaches:
Computational chemistry and Molecular Modelling
Algorithms and data analysis techniques
Second, the teaching and learning processes as part of research development and perspectives of incoming cohorts of
university graduates and post graduates is discussed, with a particular emphasis on efforts made towards the teaching
and learning over the last 10 years at the University of Oran both at the graduate and post-graduate levels. The last
reform introduced in 2003 is considered as a challenging and competitive educational process, with large
improvements when compared to the previous reforms introduced since the early 70s. We shall discuss the fourth of
the Projects review cycles which targeted programs in the field of Sciences and Technology. Launched by the
UNDP Regional Bureau for Arab States, the quality assessment of engineering programs in Arab universities is
based on detailed internal and external reviews of engineering programs in 19 Arab universities, scattered over 10
Arab countries. The review experience of the University of Oran in 2008 is particularly interesting, since the
assessment of the Sciences and Technology curriculum has concerned both the previous and the new process of
teaching and learning.

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222
 Sttructure of Crown Ethers
A. A. El-Azhary, N. Al-Jallal,
A A. Al-Kahtani, N. Al-Badri, K. Al-Farhan, and
M. Al-Qunaibit
Department of Chemistry, Facultyy of Science, King Saud University, P.O.Box 2455, Riyyadh, 11451, Kingdom of
Saudi Arabia

Abstract. We use the combined coonformational and vibrational analysis methodology to preddict in what conformation
different crown ethers and some of their complexes exist. Comparison between the structure off some of the low and high
energy conformations allows the prrediction of the factors that affects the conformational stabbility of the studied crown
ether. Using the conformational anaalysis, it was predicted that 12-crown-4 (12c4) and 18-crowwn-6 (18c6) have S4 and S6
conformations, respectively, as the gas phase ground state structure. This was rationalized sincce in both of the S4 and S6
conformations there is one hydroggen bond for each oxygen atom and at distances shorter than any other predicted
conformation of either molecule. This
T suggests that crown ethers adopt the conformation thatt maximizes the hydrogen
bond rather than to have an endoddentate structure. Using vibrational analysis, it was conclud ded that both of 12c4 and
18c6 have Ci conformation in thee solid phase. Using the combined conformation and vibbrational analysis, it was
concluded that 12-thiacrown-4 (12t44) exists in the D4 conformation in the gas and solid phasess. Conformational analysis
of 18-thiacrown-6 (18t6) predicted a new C2 conformation as the ground state gas phase conforrmation which is lower by
4.67 kcal/mol at the MP2/6-311G** level than the solid state structure. The ground state C2 conformation
c of 18t6, and
also the D4 conformation of 12t4 haveh all the SCCS angles adopt an exodentate structure wiithout any exception. It is
concluded that for the stability of thhiacrown ethers a SCCS dihedral angle of 180 requirement is more important than a
gauche CSCC dihedral angle requireement.

Keywords: Crown ethers, conformaational analysis, vibrational analysis, structure of crown etheers, ab initio.
PACS: 33.15.-e

IM
MPORTANCE OF CROWN ETHERS

Pedersen while working in DuPo ont discovered the outstanding binding properties of crrown ethers.1,2 Thus he was
awarded the Nobel Prize in 1967 wh
hile he was only a M.Sc. degree holder.

12-crown-4 (12c4) 18-crown-6 (118c6)

Due to the selective binding prooperties of crown ethers, crown ethers have wide applications. For example, they
are used in cancer treatment,3 treatm
ment of nuclear waste,4 treatment of contaminated water,5 catalysis,6 ion transport
systems, macrocyclic liquid crystals8 and zeolite synthesis.9 In addition, a new field in chemistry called molecular
7

design10 has developed with a large variety of molecules, e.g. cavitands, cryptands, cycliddenes, cryptophanes, etc.

Theory and Applications in Computational Chemistry: The First Decade of the Second Millennium
AIP Conf. Proc. 1456, 223-229 (2012); doi: 10.1063/1.4730663
2012 American Institute of Physics 978-0-7354-1057-2/$30.00

223
 THEORETICAL AND EXPERIMENTAL DETAILS

Crown ethers are large ring flexible molecules with large number of possible conformations. We use the
combined conformational and vibrational analysis methodology to predict in what conformation crown ethers and
their complexes exit. To predict the possible conformations of a given crown ether, conformational search is done
using the efficient CONFLEX11 method of conformational search of cyclic molecules. To predict the gas phase
ground state conformation, computations are performed at different levels of the ab initio theory as the B3LYP and
MP2 levels. Comparison between the structure of some of the low and high energy conformations allows the
prediction of the factors that affects the conformational stability of the studied crown ether. Comparison between the
calculated and experimental vibrational spectra, usually solid and solution phases, makes it possible to predict in
what conformation the considered crown ether exists.

FREE 12C4 AND ITS COMPLEXES

Conformational analysis followed by ab initio computations at the MP2/6-31+G* level for 12c4 predicted, in
agreement with the previous studies,12 that the S4 conformation is the ground state conformation, Figure 1.13 It was
concluded that the S4 conformation is the ground state conformation of 12c4 since it has one hydrogen bond per
oxygen atom and at distances shorter than any other predicted conformation of 12c4. However, a vibrational study
of 12c4 showed that IR active modes are Raman inactive and IR inactive modes are Raman active, Figure 2.14 This
led to the conclusion that 12c4 in the considered phases exits in the Ci conformation. Conformational and vibrational
analysis of the 12c4 alkali metal cation complexes concluded that these complexes exist in the C4 conformation,
Figures 34.15,16 This is with the exception of the Li+ complex which may exist in the C4 or Cs conformation. These
reported structures of the 12c4 alkali metal cation complexes were confirmed later by gas phase IR predissociation
spectroscopy study.17 Notice that in the C4 conformation of the 12c4 complexes, Figure 4, since the metal cation is
larger than the ring cavity, the metal cation is displaced out of the ring plane, thus allowing the existence of optically
active enantiomers.

12c4

S4 Ci

18c6

S6 Ci

Theoretical Experimental
FIGURE 1. Comparison between the gas phase and experimental, usually solid and solution phases, conformations of 12c4
and 18c6.

224
 FIGURE 2. Vibrational spectra of 12c4, showing that IR active modes are Raman inactive and IR inactive modes are Raman
active.

FIGURE 3. Left: IR and Right: Raman, spectra of the solid phase of the 12c4 alkali metal cation complexes. No Raman
spectrum could be obtained for the 12c4Rb+ and Cs+ complexes. The Figure shows a shift of the position of some of the bands
of the 12c4Li+ complex compared to the corresponding bands of the other 12c4 alkali metal cation complexes, especially in the
1300800 cm1 region.

(a) (b)

FIGURE 4. (a) Structure of the C4 conformation of the 12c4 alkali metal cation complexes, (b) Structure of the D3d conformation
of some of the 18c6 alkali metal cation complexes.

FREE 18C6 ANS ITS COMPLEXES

It is known by X-ray18 that 18c6 in the solid phase exists in the Ci conformation, Figure 1, which was also
confirmed by us using vibrational spectroscopy.19 However, conformational analysis of 18c6 concluded that a new
S6 conformation is the ground state conformation of 18c6.19,20 This is quite interesting since the case now is similar
to that of 12c4, as both of 12c4 and 18c6 have similar S4 and S6 conformations, respectively, as the ground state
structure, and the similar Ci conformation in the solid state. Similar to the S4 conformation of 12c4, it was
rationalized that the reason behind the stability of the S6 conformation of 18c6 is that it has one hydrogen bond per
oxygen atom and at distances shorter than any other predicted conformation of 18c6. This indicates that the
hydrogen bond is what controls the structure of crown ethers. This is contrary to the original irrational statement
which is based on solid phase structure that crown ethers have endodentate structure. Assuming that crown ether

225
have endodentate structure, they would have a structure similar to that found in their complexes, Figure 4. A more
accurate statement is that crown ethers, due to the hydrogen bond, have an endodentate-like structure.
Conformational analysis of the 18c6 alkali metal cation complexes predicted C1, D3d, D3d, C3v and C3v conformations
for the 18c6Li+, Na+, K+, Rb+ and Cs+ complexes, respectively,19 Figures 4 and 5. The vibrational analysis
concluded that the 18c6Li+ complex exists in the C2 or D2 conformation, the Na+, K+, Rb+ and Cs+ complexes exist
in the D3d, D3d, C3v and C3v conformations, respectively. This is in agreement with the structure determined by X-ray
for the 18c6Na+, K+, Rb+ and Cs+ complexes, although a C1 structure was also reported for the Na+ complex.21-25
This is also in agreement with the combined gas phase infrared multiple photon dissociation spectra and quantum
mechanical calculations which was published later which predicted C1 and D3d structures for the 18c6Na+ complex,
and D2, D3d, C3v and C3v structures for the 18c6Li+, K+, Rb+ and Cs+ complexes, respectively.26

FIGURE 5. Left: IR and Right: Raman, spectra of the 18c6 alkali metal cation complexes. The 18c6Na+ complex was obtained
in an emulsified form, thus the poor Raman spectrum. Notice the similarity between the 18c6K+, Rb+ and Cs+ spectra. Notice
that the 18c6Li+ spectra are different especially in the 750-850 and 12001300 cm1 regions in the IR and 500-600 cm1 region
in the Raman.

FREE 12T4 AND ITS COMPLEXES

Conformational and vibrational analysis of free 12t4 predicted that 12t4 exists in the D4 conformation, Figure
6.27,28 This is in agreement with the X-ray results29 and the previous conformational studies.30 Comparison between
the dihedral angles of some of the low and high energy conformations concluded that for the stability of 12t4, a
SCCS dihedral angle of 180 requirement is more important than a gauche CSCC dihedral angle requirement.
Conformational analysis of the 12t4 complexes predicted C4, C4, C4, C2v and C4 conformations for the 12t4Ag+,
Bi3+, Cd2+, Cu+ and Sb3+ complexes, respectively, to be ground state conformations. This is in agreement with the
experimental X-ray data for the 12t4Ag+31 and Cd2+32 complexes but experimentally, by X-ray, the 12t4Bi33 and
Cu+34,35 complexes have Cs and C4 structures, respectively. To the best of our knowledge, there is no experimental
geometry available for the 12t4Sb3+ complex. Notice that, except for the 12t4Cu+ complex, similar to the 12c4
alkali metal cation complexes, all of the 12t4 complexes have a C4 structure, Figure 4. Synthesis and measurement
of the vibrational spectra of 12t4 complexes is currently underway in our Lab.28

FREE 18T6 AND ITS COMPLEXES

Conformational analysis of free 18t636 predicted a new C2 conformation to be the ground state conformation,
Figure 6. At the MP2/6-311G** level this new C2 conformation is more stable by 4.67 kcal/mol than the
experimentally known C2 conformation of 18t6.37 It is known that crown ethers adopt endodentate structure, as was
mentioned above, and thiacrown ethers adopt exodentate structure and that in 18t6 two of the sulphur atoms violate
this rule.26 A problem with this definition, for either crown ethers or thiacrown ethers, is that it is based on crystal
structure where crystal packing forces may affect the molecular structure while the structure of molecules has to be
judged by that of the gas phase. Since computations correspond to gas phase isolated molecule, the reported
predicted ground state conformation of free 18t6 in Ref. 36 has all of the SCCS dihedral angles, without any
exception, adopt exodentate structure. It was also concluded, similar to 12t4, for the stability of 18t6 a linear SCCS
angle requirement is more important than a gauche angle requirement. Vibrational analysis of 18t6 in the solid
state28 predicted the same C2 conformation as that determined by X-ray37. Conformational analysis of the 18t6Ag+,
Co2+, Cu+ and Ni2+ complexes predicted C2, Ci, C1 and C2 structures for these four complexes, respectively.36
However, X-ray studies indicate C2h,38 S639 and C140 structures for the 18t6Ag+ complex, Ci structure for the 18t6

226
Co2+ complex,41 C142 and Ci43 structure for the 18t6Cu+ complex and Ci structure for the 18t6Ni2+ complex.44
Vibrational analysis of these complexes is underway in our Lab.28

12t4

D4 D4

18t6

C2 C2
Theoretical Experimental
FIGURE 6. Comparison between the gas phase and experimental, solid phase, conformations of 12t4 and 18t6.

Special Appendix.

Chemistry in Egypt and in the Arabian Gulf Countries Trying to Catch the West up.

Due to the recent developments in the Middle East after the amazing revolutions, which is known as the Arab
Spring, I have been kindly invited by Prof. Clementi to attend this international conference and to give a talk about
my research work and about Chemistry and especially Quantum Chemistry in Egypt and the in Arabian Gulf area.
It is too tough to talk about Chemistry in Egypt and in the Arabian Gulf area in this short space. However, few
points can be made. Firstly, in terms of history, the word corresponding to Chemistry in the English language is
quite similar to that in the Arabic language Al Chemeia. The origin of the word Chemistry or Al Chemeia is
Greek, first appeared in the fourth century as chemeia. It is believed that this name was given to Egypt due to the
black soil of the Nile Valley. Jabir ibn Hayyan, born in 721 AD, is considered as the father of Chemistry. He is the
first to establish the notation that science, including chemistry, is based on experimental research rather than being
based on theory.
Secondly, to give a short idea about Chemistry in Egypt and in the Arabian Gulf area, this can be divided into
three parts.
1. Undergraduate. In fact, most of the contents of all Chemistry subjects are known for a quite long time and
more or less the same textbooks are available and taught everywhere in the Globe. In addition, most of the
Universities is the area have now been through the process of Academic Accreditation. However, a major
problem in the Middle East is that the system of home work and teaching assistant is hardly being followed.
As a result students depend mainly on memorizing rather than thinking.

227
 2. Graduate. This area is suffering the most. There are several problems which cannot be discussed in this
short space. It is simply can be stated, as an example, that none of the Universities in the Middle East has a
library, with the needed journals, as that in an average University in Europe or USA.
3. Advanced academic institutions. There are probably three. These were made in an effort to close the gap
with the West or even precede it. These are the Qatar Foundation in Qatar, King Abdullah University of
Science and Technology (KAUST ) in Saudi Arabia and Zewail City of Science and Technology in
Egypt.
I have to add here that I am proud of being Egyptian, my wife is Syrian while I am working in the Kingdom of Saudi
Arabia. Thus in a way, I represent the Arab Unity. While I am working at King Saud University (KSU), King
Abdullah bin Abdul-Aziz Al Saud became the King of Saudi Arabia. I myself, at least, consider him a man of
wisdom. King Abdullah set three goals, concerning Education, Economy and the country Infrastructure. Concerning
Education, as an example, the budget of KSU increased from about one Billion to two billion dollars. It is a nice
picture to see labs which were rarely opened now full of researchers and research equipments. As a result, the
number of publications of the University increased from 412 to 1112 publications.

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 Controlling Drug efficiency by encapsulation into carbon
nanotubes: a theoretical study of the antitumor Cisplatin
and the anti-HIV TIBO molecules
R.BESSROURa,Y. BELMILOUDb, Z.HOSNIa and B. TANGOURa
a
Research Unity of Theoretical Chemistry and Reactivity, University of Tunis-El Manar, Tunisia
b
Laboratory of Theoretical Physical Chemistry and Computational Chemistry , HouariBoumediene University of
Sciences and Techniques, Alger, Algeria

Abstract. From the beginning of last century, Paul Ehrlich, a specialist in the immune system and the Nobel Prize
(1908) had raised the possibility of "magic bullets" can directly address, in an organism, drugs in a particular area of the
body, sparing all other parts of side effects. Carbon nanotubes (CNTs) have particular property to cross cell membranes
easily. In an effort to optimize the use of CNT as drug nanocarriers, we divided our study into two parts. In the first, our
concern was to find the minimum diameter of a single wall CNT can encapsulate an anticancer drug that iscisplatin
without altering its geometry in order conserve its therapeutic power. Behavior of one and two Cisplatin( Cp) molecules
confined in capped and opened single-walled carbon nanotubes (CNTs) is studied by means of ab-initio calculations.
Single molecule binding energies clearly exhibit encapsulation dependence on tube diameters that range from 6.26 to
12.04 . A weak stabilization energy of the Cp@(11,0) equal to -70 kcal.mol-1 has been obtained corresponding to a
CNTs diameter of 8.5 . We noticed that Cisplatin molecule changes shape when encapsulated into CNTs whose
diameters are less than 7.6 . In the presence of a second Cisplatin molecule in the (10,0) CNT, preferred position stays
parallel to CNTs axis leading to a linear density of roughly 1588 molecules/m of CNTs length corresponding to a
linear density of 7.9 10-19 g / m. The 195Pt chemical shift tensors are calculated using GIAO method. NM R calculations
reveal that Platinum chemical shift is sensitive to CNTs diameter and is linearly correlated to confinement energy. 195Pt
chemical shift measurement may be a direct method to access to the diameter of the encapsulating CNTs and to control
the amount of drug molecule transported by this CNT. In the second part, the opposite has been sought is to say how the
use of nanotubes with different diameters can control the change in a geometry of an anti-HIV drug that is TIBO
molecule to bypass the mutation of the virus which wiped out its therapeutic effect.This work deals with the butterfly
conformation control of the anti-HIV TIBO molecule confined into carbon nanotubes (CNT). This theoretical study
concerns the variation of some pertinent conformation descriptors such as butterfly angle, wingspan, volume, dipole
moment, solvation energy and confinement energy versus carbon nanotube diameters. Obtained results show that it is
possible to describe the configurations of actual drugs as 8-Cl or 9-Cl TIBO as the parent molecule TIBO encapsulated in
an adequate CNT. Our approach indicates that drug confinement inside CNTs may be a promising way to use a same
drug in order to fellow HIV virus mutations.
Keywords: Carbon nanotube, Anti-HIV, Inhibitor Non-Nucleosidic of Inverse Transcriptase, TIBO, butterfly
conformation, virus mutation, Cisplatin, drug nanovector, nanocarrier, antitumor, confinement energy,
PACS : 31.15.A
PART 1
195
Pt chemical shift ability to control the antitumor drug Cisplatinencapsulatedinto
carbon nanotubes: A theoretical study
Introduction
Our study concerns the anticancer drug Cisplatin. It was shown [1,2] that Cisplatin possessed significant
cytotoxicity toward cancer cells growing in vitro and also had antitumor activity in vivo. In spite of its pronounced
activity, particularly in testicular and ovarian cancers, and its ability to block cell division while still allowing cell
growth, Cisplatin has a number of dose-limiting side effects [3-7]. The aim of pharmacology does not keep only to
finding new molecules with therapeutic effects but also to choosing the best way allowing their dispatching directly
to the right target. Recently, various experimental [8-17] tagged drug delivery processes have been successfully
operated. Carbon nanotubes have been functionalized to allow their solubility in blood and filled with active
principle and iron. The nanocarriers have been closed by a temperature sensitive membrane and also contain a
temperature sensor. Guidance by an external magnetic field can approach CNTs to the area of drug application and

Theory and Applications in Computational Chemistry: The First Decade of the Second Millennium
AIP Conf. Proc. 1456, 230-240 (2012); doi: 10.1063/1.4730664
2012 American Institute of Physics 978-0-7354-1057-2/$30.00

230
bring them out at the end. Thus the release of carboplatin is highly controlled. Interestingly, Carboplatin@CNT
release caused a 3-fold reduction in cell count and an increase in apoptosis to 70%.
In this work, we will try to calculate the diameter range of carbon nanotubes that allow the Cisplatin molecule to
be confined without any geometry alteration. Moreover, active principle would have to be in low physical
interaction with the carrier vector for easy transport and release into the blood. On the other hand, we will calculate
the values of some descriptors for discussing physical and chemical properties between the free molecule and the
confined one. In addition, we studied the maximum capacity of Cisplatin molecule encapsulation into a nonotube
with fixed diameter based on its length. This linear density will help to better choose the length of the nanotube to
minimize its toxicity depending on the transported dose. Finally, NMR study was carried out to bring to light the
relationship between the confinement process and 195 Ptchemical shift. Indeed, a paramount correlation between
these two parameters was found directly related to the nanovector diameter.
Computationally, several advanced researches were made in order to more understand the mechanism of hosting
the chemotherapy drug inside the CNT. [18,19] The influence of nanotube diameter on the possible encapsulation
was investigated in the work of Hilder and Hill [20, 21] using the Lennard-Jones potential to identify the stable
system that may facilitate the filling of the nanovector. We will compare our obtained values to the proposed ones in
order to test the validity of their model.

Computational details
Full geometry optimizations are performed for the (8,0), (9,0), (10,0),(11,0), (12,0), (14,0), and (9,9) SWCNTs
using Gaussian 03 suite of programs [22]. Geometry optimizations are carried out using restricted Hartree-Fock
method. Basis sets aug-cc-pVDZ-PP [23] and STO-3G [24,25] were used respectively for Platinum atom and the
rest of the system. The choice of those basis sets was an obligation with the available computer performance as the
number of atoms exceeds in some cases 240 atoms. Furthermore, metal center possess 78 electrons. Thus, core
electrons were treated using effective core potential (ECP) for Platinum.[23]
The starting CNT geometries are generated using TubeVBS tool based on a hexagonal unit cell [ 26]. All
nanotubes are capped from the both sides by half fullerenes, with an average C-C bond length of 1.432 . In
addition, two Cisplatin molecules were introduced inside the uncapped nanotube (10,0) in the aim to assess the
linear density and to check the arrangement of both molecules in the nanovector by comparing the obtained
geometrical results to experimental ones.
Chemical shielding tensors are computed for the SWCNT-molecule systems by means of the Gauge Invariant
Atomic Orbitals (GIAO) method [27]. In this work, we were essentially interested in Platinum chemical shift wh ich
is correlated to the electronic environment of the ligands and the carbon atoms of the nanotubes. All measured
results were referenced to the K2 PtCl4 [28] which is the common reference used by NMR experimenters. Indeed, the
K2 PtCl4 molecule was optimized separately by taking into account the same calculation technique and basis sets
quality utilized above. All the 195 Pt values were referenced to 195 Pt(K2 PtCl4 )=-1628 ppm. For our investigation, we
used the following formula: ( 195 Pt) Cisplatin@CNT= ( 195 Pt)Cisplatin @CNT /GIAO - ( 195 Pt) K2 PtCl4 /GIAO.

Results and Discussion

We begin by introducing the Cisplatin in opened carbon nanotubes whose length has been chosen that all atoms
of the studied molecule are far from CNT edges, therefore the latter will have no influence. We tested both
possibilities for Cisplatin initially placed perpendicular and parallel to the CNTs axis. We noticed that in the two
cases, no minimum energy has been detected but Cisplatin molecule leaves the nanotube. This reflects the
hydrophilicity of Cisplatin because of its high polarity [29] as shows of its obtained dipole moment equal to 12.3 D
which is closer to other calculated values. [30] In the aim to study the confinement effects, we were forced to use
CNTs capped by fullerenes portions. The optimized structure exhibits the Cisplatin in a parallel position relatively
to the CNTs axis.
We optimized the molecular geometry of the studied molecule in order to obtain a starting point tha allows us to
locate any change in geometry induced by the confinement inside the nanometer-sized hollow spaces of single-wall
carbon nanotube. The calculated and experimental geometry parameters are gathered in Table 1 and depicted in
figure 1a. We see that our results are in agreement with experimental values or those calculated by other authors .
[31-33] We also indicated in Table 1 the geometry parameters values of confined molecules into the various
nanotubes represented in the figure 1b. We note between brackets the variations of these latter values compared to
that of the free molecule. We can notice that calculated bond length values are greater t han the experimental ones for
Pt-N1 and Pt-Cl1 by only 0.07 and 0.02 , respectively.

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 TABLE 1. Calculated geometry parameters for free and encapsulated Cisplatin molecule. The experimental data
refers to the crystal phase. Percentages of structural modification (Standard deviations) are mentioned between
brackets. Bond lengths are in , bond angles and dihedral angles are in degrees . D represents CNT diameter in
Cisplatin Cisplatin@CNT
Geometry
Cal. Theo. Exp. CNT (10,0) (11,0) (12, 0) (14, 0) (9, 9)
parameter
[31] [32] D 7.82 8.61 9.39 10.96 12.20
Pt-N1 2.12 2.06 2.05 2.05 2.06 2.06 2.06 2.07
0.04 (-0.03) (-0.02) (-0.02) (-0.02) (-0.02)
Pt-N2 2.12 2.05 2.05 2.06 2.06 2.07
(-0.03) (-0.03) (-0.02) (-0.02) (-0.02)
Pt-Cl1 2.34 2.31 2.32 2.26 2.27 2.29 2.30 2.29
0.01 (-0.03) (-0.02) (-0.02) (-0.01) (-0.02)
Pt-Cl2 2.34 2.26 2.28 2.29 2.29 2.29
(-0.03) (-0.02) (-0.02) (-0.02) (-0.02)
N1-Pt-N2 95.0 87.0 79.0 86.6 90.2 91.9 94.4
(-0.1) (-0.08) (-0.05) (-0.03) (-0.006)
Cl1-Pt-Cl2 95.8 91.9 78.4 85 89.3 93.1 95.2
(-0.1) (-0.10) (-0.06) (-0.02) (-0.006)
N1-Pt-Cl1 84. 90.2 100.9 94.2 90.2 87.3 84.8
(0.1) (0.11) (0.06) (0.03) (0.003)
N2-Pt-Cl2 84.5 90.2 101.5 94.0 90.1 87.4 85.2
(0.2) (0.11) (0.06) (0.03) (0.008)
Cl-Pt-Cl-N2 180.0 179.2 179.7 179.6 179.2 175.6
(-0.004) (-0.001) (-0.002) (-0.004) (-0.02)

The dimensions of the studied molecule in solution were estimated to 6x4x1 3 . [34] Those values have been
proposed by a clever argument based on an estimation of the hole left by the edges of a nanotube functionalized with
groups of increasing geometrical constraints effects. They correspond to dimensions forbidding the leaving of the
molecule from the CNT. It is clear that the proposed dimension of 1 is lower than the real one. Calculated molar
volume of single Cisplatin molecule (103.827 cm3 /mol) is compatible with a box of 3.5x5.8x5.6 3 dimensions The
figure 1a represents the optimized Cisplatin molecule placed in this box. The comparison between the two sets of
dimension values indicates that Cisplatin leaves the CNT diago nally and not by a frontal way.

Fig. 1a Fig. 1b Fig. 1c

FIGURE 1.(a) : Optimized structure of Cisplatin molecule. (b) Radial representation of the different CNTs with different
diameters D: a/ (8,0) D=6.26, b/ (9,0) D=7.05 , c/ (10,0) D=7.83, d/ (11,0) D=8.62, e/ (12,0) D=9.40 and f/ (14,0)
D=10.95, g/ (9,9) D=12.04, (c) : Optimized structure of Cisplatin molecule confined into the nanotube (10, 0)

Confinement energy was evaluated according the equation below:

E (Confinement) = [E (Cisplatin + Nanotube)] - [E (Nanotube) + E (Cisplatin)]
First of all, we detected the diameter Dmax from which we observed an asymptotic behavior of interacting energy as it is
depicted in figure 2a. We can conclude that any tube whose diameter is greater than roughly 0.9 nm will not have any influence
on Cisplatin molecule geometry.

232
 Second, we searched for the diameter Dmin from which we observed energy modification inferior than 25 kcal
mol-1 . This value may be representative of a very weak bonding in organic chemistry. From figure 2a, Dmin may be
estimated at roughly 0.77 nm. Among the studied CNTs, only the tubes (8,0) and (9,0) seem to react chemically with
Cisplatin. We noticed that the studied molecule changes shape when encapsulated into CNTs whose diameters are
less than 7.7 and is completely destroyed when placed into the narrowest CNT (8,0) inducing to Pt, Cl 2 and
N2 H5 HCNT(8,0). This behavior is not desirable in this case because its adverse effect on drug therapeutic
specificity. The presence of the (9,0) CNT in the neighbouring of the Cisplatin molecule leads to a departure of one
ammoniac molecule in agreement with the labile bonding of this ligand with Platinum atom. Such type of gust
molecule modifications have been yet observed [27,28] and will be studied in a separated work.

TABLE 2. Confinement energy and Platinum Chemical shifts of Cisplatin in nanotubes of different diameters .
CNTs (8, 0) (9, 0) (10, 0) (11,0) (12, 0) (14, 0) (9, 9)
D ( ) 6.26 7.05 7.82 8.61 9.39 10.96 12.20
Eencaps 1955.3 529.8 -21.6 -64.5 -59.4 -62.8 -64.9
195 Pt 533.36 166.96 103.72 81.61 48.99 41.77 37.83

For a range of diameters between Dmin and Dmax, the molecule of Cisplatin undergoes a weak and stabilizing
interaction due to the presence of the nanotube. However, the geometry of this molecule does not undergo notable
changes. The weak stabilization energy of the inclusion complex Cp@(11,0) which is -70 kcal.mol-1 , can also allow
the release of this molecule from nanotube once it sustains stronger interactions with the blood medium. Its
departure will be facilitated by the hydrophobicity inside the CNT, which tends to expel the polar compounds even
those of low polarity.It is interesting to compare the calculated values of Dmin and Dmax to those proposed by Hilder
et al [21]. In the latter work, the authors proposed a mathematical model based on the repulsion between a molecule
of Cisplatin and a carbon nanotube. We notice that the values proposed by these authors, which are 9.57 and 10.6
for Dmin and Dmax respectively are a little greater than those obtained by our calculations (7.7 and 9
respectively). This difference was foreseeable because the authors themselves sus pected that their values may be
ameliorated because their model does not take into account all interactions.

Fig. 2a Fig. 2b
FIGURE 2. (a)Energy variation (in kcal mol-1) between free Cisplatin and Cisplatin@CNTs versus nanotube diameter (in ).
(b) Variations of both 195Pt and confinement energy versus CNTs diameters.

The optimization of two Cisplatin molecules inside the opened nanotube (10,0) gives excellent similitude with
DRX results as shown in table 3. By starting from a superposed couple of Cisplatin, the convergence was orientated
to the coplanar arrangement. Indeed, the dihedral angles defining the plans of both adjacent molecules are -20.266
and -6.993 for the theoretical and experimental investigations [32], respectively. Therefore, the distance separating
the Platinum atoms are almost the same. The distances between Chlorine atoms and Nitrogen ones are comparable
which is in good agreement with our thesis. Finally, the internal coordinates of each molecule remained
unchangeable. For instance, the angle Cl1-Pt1-Cl1 was equal to 92.320 in our optimization; while it was 92.453 in
DRX. Then, the biological activity was influenced neith er by the Carbon atoms of the CNT nor by the neighboring
Cisplatin. These results may be explained by the existing hydrogen bonds NHCl that stabilize the system
formed by the two Cisplatin facing the hydrophobic area owing to the CNT cavity. In the presence of a second

233
Cisplatin molecule into the (10,0) CNT, preferred position stays parallel to CNTs axis. Starting from the distance
separating the two Platinum atoms that is 6.238 , we can estimate that the maximal linear density is roughly equal
to 1588 molecules/m of CNTs length corresponding to a linear density of 7.9 10 -19 g / m.

TABLE 3. RHF optimized geometry parameters of a couple Cisplatin molecules encapsulated into the opened
nanotube (10,0) compared to experimental DRX values. Into parenthesis are shown Cp@(10,0) calculated values.
Distances are in and angles in degrees.
Geom. parameter Cp 2 @(10,0) DRX[32]
Pt1-Cl1 2.3151(2.34) 2.3127
Pt1-N1 2.0638 (2.12) 1.9229
Cl1-N2 3.2760 3.4271
Cl1-N2 3.3206 3.3455
Pt-Pt 6.238 6.23(2)
Cl1-Pt1-Cl1 92.320 92.453
N1-Pt1-N1 90.725 88.480
Cl1-Pt1-Cl1-N2 -20.266 -6.993
Cl1-Pt1-Cl1-N1 174.370 179.952

The calculated value of 195 Pt of Platinum in free Cisplatin gives a value close to those obtained in the
experiment [35] and by using the ANN algorithm [36]. We can notice the decrease of 195 Pt when diameter of the
nanotube increases (Table 2). This is a new behavior directly linked to Cisplatin molecule confinement process. We
remark an asymptotic behavior above (10,0) CNT diameter when there is no interaction between the CNT and
Cisplatin. Then, we can conclude that 195 Pt is correlated to the CNT diameter. Figure 2b depicts the variations of
both 195 Pt and confinement energy versus CNTs diameters. Because the two curves are similar in shape, a linear
correlation is expected. In fact, we obtain the following equation : Eencaps =0.2325 195 Pt +71.437 with R2 =0.98

Conclusion
In the present work, restricted Hartree-Fock method has been employed to investigate the capabilities of carbon
nanotube to confine Cisplatin. Our calculations confirm that the drug reach its target with the same crystal structure.
Indeed, side effects can be reduced dramatically by controlling the concentration of both cisplatin and nanotube.
Therefore, only selected type of nanotube full of cisplatin molecules is injected in blood. The ratio of toxicity is
dramatically decreased. NMR investigation exhibited, interestingly, a paramount c orrelation between the chemical
shift of the metallic center, the confinement energy and the nanovector diameter. Our work shows that 195 Pt
measurement is able to inform about the diameter of the used CNT and also to lead directly to confinement energy.
Because NMR is a quantitative spectroscopy, the measurements of signal intensity allow an instantaneous access at
the quantity of drug filled into each CNT.

PART 2
Theoretical Study of the anti-HIV TIBO moleculeConfined into carbon nanotubes
Introduction
The Human Immuno-deficiency Virus (HIV) is the causative agent of Acquired Immuno -Deficiency Syndrome
(AIDS). Until now, treatment of a patient infected with HIV is based on the use of chemicals designed to disrupt the
various stages of virus replication cycle. Reverse transcriptase (RT) is a multifunctional key enzyme, which is an
important target for developing new antiviral agents. Inhibitors of HIV-RT are one of the most important goals in
the treatment of AIDS patients.[37, 38]. Among them the TIBO molecule ( Figure 3a) is a Non Nucleoside Reverse
Transcriptase Inhibitor.Such inhibitors are a common feature which has a butterfly -shaped rigid configuration
(Figure 3b) that fits in an internal cavity of the enzyme [39-45]. It was found that the butterfly shape fits perfectly
into an internal cavity of the large area of the allosteric enzyme. So the likelihood of developing drug resistance will
also closely correlate with the degree of butterfly-like shape of the ring.[46]
A butterfly-shaped configuration can be represented as shown in Figure 3b. According to Schfer [47], in this
configuration, an aromatic ring and a second conjugated S system should be organized in a butterfly-like orientation.
The distance between the midpoints of the two systems should be about 5 and the angle between two planes that
we can define by the term "Butterfly angle", can range from 108 to 115 degrees. For the studied products, we chose

234
to replace the distance between the two centers mentioned above by the distance between fa rthest atoms from the
two wings that can be noted by the word "wingspan" by analogy with birds or aircraft (Figure 3b).
The molecular framework of TIBO derivatives (Figure 31a) consists of a 7-membered diazepine ring (-ring), an
aromatic bicycle and dimethylallyl moiety attached to the -ring.

Fig. 3a Fig. 3b Fig. 3c

FIGURE4. (a) Structure and labeling atoms of the TIBO molecule. (b) Schematic representation of a butterfly -like configuration.
(c) The TIBO molecule inside the CNT (11,11).

The drugs of the TIBO family include chlorine in different positions such as 8-Cl, 9-Cl, 10-Cl etc.
Changing butterfly angle can also be done by the possibilities of expansion or contraction of the seven -membered
ring in cycles to eight or six-membered.[48-50] Another way might be an approach to adapt the configuration of the
same drug to a virus mutation. Therefore, there is great demand to find new methods to be able to control the closing
and opening of this angle so that the molecule may have a high affinity both in the absence and presence of specific
mutations.
The approach of nanotechnology based on drug delivery control is a focus of therapeutic research
today.[51-60] . Carbon nanotubes (CNT) are in fact one of the most powerful drug carriers because of their non -
reactivity with transported drugs and biocompatibility. CNTs have already been successfully tested in the protocol
for drug delivery especially for carboplatin.[61]
In this part, we are interested in studying the ability of the CNT to control the butterfly conformation of the
TIBO molecule. Confinement inside the nanotube can impose a more compact structure, but having a butterfly angle
smaller than the isolated molecule. Our study concerns only the contraction of the butterfly -angle because we
believe it is likely that the virus mutation causes a strain to the allosteric site which makes it more difficult for drugs
entrance.[41] In particular, we chose to study some CNTs whose diameters range from 12 to 15 for a contraction
of the butterfly-angle less than 10%. The CNT chirality has not been taken into account because we focus only on
their transport capacity.

Calculation details
CNTs geometry is built from 1.432 for C-C bond distance by means of a specific program. The choice of its
length is based on the presence of TIBO molecule sufficiently far from edges in order to neglect their effects. The
CNT chirality has not been taken in account because we are not interested with electric properties. Only the steric
effects engendered by TIBO molecule confinement inside CNT are the goal of our study. To minimize chemical
interaction between TIBO molecule and a CNT, we have choice diameter dimensions roughly superior 3 rounding
atoms of the studied molecule. The diameter interval is limited superiorly by a TIBO structure inside the nanotube
equivalent to the free molecule.
The geometry of the TIBO molecule has been optimized by DFT/B3LYP/6-31G* and by HF/6-31G* techniques.
Our studied systems concern a total number of atoms ranging from 221 to 261. Among them, 41 atoms belong to the
TIBO molecule. To keep the quantum calculations in reasonable consuming time, the standard basis set 6-31G* was
used and a constraint optimization with fixed CNT geometry was imposed. All calculations have been performed
with Gaussian 03 and 09 packages [22]. We verified that the free TIBO molecular geometry corresponds to a
minimum in potential energy surface because the absence of imaginary frequencies. However we do not performed
frequencies calculations for TIBO molecule inside CNT because the calculated encapsulated TIBO structures do not
correspondent to local minimum but to geometry obtained when interactions with carbons of a nanotube exist.
We used B3LYP-CAM, that is a long-range corrected version of B3LYP using the Coulomb -attenuating method
[62] in order to evaluate the part of dispersion forces in the total confinement energy. Dynamic molecular

235
calculations have been also performed by means of Hyperchem program package. [63] We used the corresponding
parameters: MM +[64] force field, Starting temperature : 0K, Simulation temperature : 300K, Temperature step : 10
K, Heat time steps: 10 ps, Run time : 49, Step size : 0.001 ps.

Results and Discussion

The atomic numbering for TIBO compound is shown in figure 2a. Calculation results were compared to the X-
ray experimental data of 8-Cl TIBO [65] and 9-Cl TIBO [66] in the association with HIV-1 reverse transcriptase
(Table 4). We note that theoretical geometry optimization of TIBO free molecule leads to the same structure
independently of the used calculation method. For this reason we have kept the HF level for the remaining
calculations. The comparison of our results to experimental ones shows in general a good concordance except for
the bond lengths C2S3 and C2N4 in 9-Cl TIBO. The increasing of these two lengths is in favour of a change in the
bond order and probably experimental data corresponds to single bonds involving the addition of hydro gen atoms on
S and C2. The isomer with the S-H bond is very often invoked. The different torsion angles indicate that the
benzenic and imidazolidonic (or thionic) rings are almost planar at different methods. The seven -membred ring
adopts, in this study, a twist sofa conformation. In fact, the angle between the two wings I and II is of 110.2 and
110.5 degrees at HF/6-31G* and DFT/B3LYP/6-31G* levels respectively.
In order to better control the opening or the closing of the two wings, we introduced the TIBO molecule inside
different carbon nanotubes presenting several dimensions. In this work, CNT diameters range from 12.35 to
15.10 (Figure 4a). We have calculated the angle D between the two wings I and II by the bond angle C7C18C22
for the studied structures. Obtained values are gathered in table 5 and theirs variations are depicted in figures 4b and
5a. Our results show that the confinement effect engenders butterfly angles ranging from D1 =71.31 in the smallest
CNT to D5 =110.18 in the biggest one. As it is shown in figure 5a, dynamic molecular calculations lead to roughly
the same results obtained by quantum mechanics technique. This angle variation may be also visualized by the
distance modification between the atoms H13 and H25 as represented in figure 5b. All conformations are obtained
under constraint from a butterfly angle interval of [71.3, 110.2]. Changing this angle could be used to compensate
for mutations in the HIV virus.

Fig. 5a Fig. 5b

FIGURE5 . (a) Radial representation of the different CNTs with different diameters D. (b) Evolution of the butterfly
angle C7C18C22 versus CNTs diameters.

By placing experimental values of butterfly angles for 8-Cl and 9-Cl TIBO derivates on the figure 5a we can
estimate that corresponding TIBO@CNTs diameters are close to 14. From figure 5b, we can attribute more
precisely those diameters: 13.75 and 13.92 for 8-Cl and 9-Cl TIBO respectively.
The volume occupied by the TIBO molecule has been calculated by the Monte -Carlo method implanted in the
Gaussian program, even for the gas state and in water. Obtained values are gathered in table 5. Our values are close
to experimentally ones. Volume calculations allow us to estimate the contrac tion percent (Table 5) of each TIBO
molecule when confined in a CNT.
The dipole moment variations (Table 5) are less than 0.5D. We can consider that they are not very important. So
it is reasonable to conclude that encapsulated TIBO geometry does not perturb the molecule p olarity which is
responsible of the interactions in the allosteric site. The low values of dipole moments that are less than 3D is the
cause of the negligible solvation energy in water that is less than 10 kJ mol-1 .

236
 TABLE 4. Selected structural parameters of free TIBO and TIBO@CNTs. Bond lengths are in ,
bond and dihedral angles are in degrees . D designs CNTs diameter in . For labels, see figure 4a
Structural Theoretical Experimental TIBO@CNT
8-Cl 9-Cl CNT (9,9) (16,0) (17,0) (18,0) (11,11)
parameters HF DFT
[65] [66] D 12.35 12.68 13.47 14.26 15.10
N1-C2 1.34 1.37 1.43 1.44 1.40 1.40 1.40 1.40 1.40
C2-S3 1.68 1.67 1.68 1.77 1.60 1.60 1.60 1.60 1.60
C2-N4 1.35 1.38 1.38 1.47 1.42 1.423 1.42 1.42 1.43
C5-C6 1.39 1.41 1.33 1.38 1.39 1.40 1.40 1.40 1.40
N1-C6 1.38 1.38 1.45 1.39 1.40 1.41 1.41 1.41 1.41
C6-C7 1.38 1.39 1.42 1.38 1.38 1.38 1.38 1.38 1.40
N4-C15 1.46 1.46 1.42 1.45 1.47 1.47 1.47 1.48 1.47
C16-N17 1.46 1.47 1.46 1.47 1.48 1.48 1.48 1.49 1.48
N17-C20 1.46 1.47 1.51 1.47 1.48 1.49 1.49 1.49 1.49
C20-C21 1.50 1.50 1.51 1.45 1.53 1.53 1.53 1.52 1.52
C21-C22 1.32 1.34 1.32 1.34 1.31 1.31 1.32 1.31 1.31
N1C6C5 106.0 111.7 105.5 107.5 106.9 107.0 106.8 106.8 106.7
C7C6C5 122.9 122.5 117.8 119.6 122.3 122.2 122.4 122.0 122.2
N4C5C10 132.7 132.5 119.5 121.6 132.2 132.3 132.4 130.9 131.6
C5N4C15 127.5 127.3 129.2 131.4 125.3 126.0 127.1 121.6 124.4
N4C15C16 115.7 116.0 110.2 118.0 115.1 115.0 115.4 115.4 115.4
N1C2N4C5 -1.3 -1.1 0.3 0.3 -4.0 -3.1 -2.8 -6.2 -4.3
C2C4C5C6 0.5 0.4 0.2 0.0 2.2 1.9 2.5 3.1 2.9
S3C2N4C5 177.8 178.0 179.0 179.0 176.5 177.3 176.8 175.5 176.3
N17C20C21C22 135.7 134.9 153.8 160.0 109.5 109.6 100.6 141.1 136.5

Finally, we estimate the confinement energy (table 2) by the following formula [67]:
E(Confinment ) = [ E(TIBO@CNT) ] - [ E(CNT) + E (TIBO) ]
Its evolution is depicted in figure 5c. Confinement energy is a variable entity that is nanotube diameter
dependent. Its value may be very important (some thousands of kJ mol -1 ) for low diameter value because its origin is
chemical in type and it decreases to some kJ mol-1 when the interaction is controlled by physical interactions.
Sometimes, the hybrid system TIBO@CNT is relatively stable leading to a negative value. For large nanotube
diameters, confinement energy vanishes leading to an asymptotic behavior from diameters greater than 15.
Computational techniques that are commonly used (ab -initio, DFT) do not properly reflect the long-rang forces.
Currently, corrected DFT functionals are proposed for evaluating the energy from dispersion forces. We chose to
perform calculations only for the tube (17.0) with a diameter of 13.47 because the latter value is being at the
center of the domain variations of our work that is [12.35, 15.10]. We calculated the confinement energy of the
TIBO molecule in the tube (17.0) using both B3LYP and B3LYP-CAM functionals [62]. We found that dispersion
forces generate stabilization energy of -19.25 kJ mol-1 .

Fig. 6a Fig. 6b Fig. 6c

FIGURE5 (a) Representation of the butterfly angle C7C18C22 variations versus CNTs diameters for both QM
and DM calculation levels. (b): The wingspan H13H25 at QM calculation level versus CNTs diameters.
Experimental values are indicated for 8-Cl and 9-Cl TIBO molecules.(6c) :Confinement energy in (kJ mol-1) versus
CNTs diameters. The last point represents the angle of the Free TIBO molecule.

237
 TABLE 5. Some calculated descriptors of TIBO@CNT. Angles are in degrees, distances are in , volumes are in
3 , dipole moments are in D and energies are in kJ mol-1 .
Experimental TIBO@CNT
DESCRIPTORS
8-Cl [65] 9-Cl [66] (9,9) (16,0) (17,0) (18,0) (11.11)
Butterfly angle C7C18C22 99.3 97.1 71.3 72.8 77.4 96.8 110.2
wingspan H13H25 8.11 7.37 6.01 6.48 9.87 10.63 10.62
Volume Gas ----- ----- 574.2 578.5 598.9 609.29 612.8
Water 571a 567a 581.9 592.1 609.3 619.8 626.8
% contraction Gas ----- ----- 6.3 5.6 2.3 0.6 0.0
Water ----- ----- 7.2 5.6 2.8 1.2 0.0
Dipole moment ----- ----- 2.83 2.70 2.77 2.59 2.41
Solvation energy ----- ----- 6.81 2.63 7.14 9.11 1.04
Confinement Energy ----- ----- 7462.3 7302.0 4166.6 3102.8 3.4
a
This value is the difference of pocket volume (700 3 [66]) and the solvent-accessible volumes of 9-Cl TIBO
(133 3 ) and 8-Cl TIBO ( 129 3 ) .[65]

We can then conclude that dispersion forces energy contribution in the confinement energy of the TIBO
molecule in the nanotube (17.0) is low because it represents only a fraction equal to 0.46%. However, considering
that the dispersion forces energy is the same for all CNTs, we find that the confinement energy of the TIBO @
(11,11) is negative and equal to -14.75 kJ mol-1 .

Conclusion
We presented in this work a theoretical study of the effect of TIBO molecule encapsulation within different
carbon nanotube forcing a contraction less than 10%. All conformations are obtained under constraint from a
butterfly angle interval of [71.3, 110.2]. Changing this angle could be used to compensate for mutations in the
HIV virus. For example, 8-Cl and 9-Cl TIBO derivates may be replaced by appropriate composite TIBO@CNTs
presenting the same butterfly-angle. Ongoing studies in our team concerning the functionalization of the CNT edges
to detect the virus and target the Transcriptase Inhibitors cavity. Such proximity will optimize the transfer of TIBO
in its constrained structure to the cavity.
S pecial Appendix.

Knowledge is the main cause and the powerful tool of the Tunisia revolution.

The Tunisian revolution that initiated what was called the Arab spring has surprised everyone. Tunisia was considered an
emerging country whose freedom was the ransom to be paid for the relative well-being of its population. This paradox hides
behind itself the phenomena at the origin of this revolution. Indeed, Tunisia is a country that has no natural resources that are the
cause of its development. However, it was able to generate an educated population with an education policy that kept almost one
fifth of the entire state budget. In addition, to prevent the rise of Islamists in the eighties, the M inistry of Education, Pr M ohamed
CHARFI, an independent progressive personality, introduced the teaching of the basic ideas of freedom, democracy and good
governance by betting that this educated generation, can not accept living under a dictatorship. The unhealthy business climate of
President Ben Ali and his entourage leads at a situation that the economy has not been able to absorb the growing number of new
graduates. The Tunisian revolution was triggered and maintained by the unemployed graduates and not by the poorer segments of
the population. This shows that knowledge is at the origin of the Tunisian Revolution. M oreover, the Tunisian youth have
surprised the police by his judicious use of modern tools of information technology, particularly the social network Facebook
despite a sophisticated censorship by the national agency that controlled the Internet circuit. So the revolution has spread from
disadvantaged areas to the cities and the capital Tunis, which sounded the death knell for the regime of Ben Ali. Since then, a
learning of democratic citizenship behavior has settled in Tunisia, and with acquired overruns but to date is in line with the
completion of democratic transition. In this battle, civil society plays the major role with its vigilance not to allow any party,
including the former Islamist party, to divert the revolution by partisan practice.
Chemistry is an important sector both in higher education and at the industrial level. Given the limited resources available, the
experimental part is more developed in the University than the theoretical one. The number of theoretical chemists in Tunisia is
in the tens only. Paradoxically, the international visibility of theorists is much larger than those of the experimenters. This stems
from a continued cooperation with the M aghreb and Europe, triggered by the 29th Congress of Chitel at M arrakech, M orocco in
2003 and reinforced by the 32nd one at Ctes de Carthage in Tunisia in 2006.The watchwords of the Tunisian Revolution were
echoed by other Arab revolutions and "Outraged" as "Occupy..." by all the world. The words THE PEOPLE WANT ..."

238
introduces a concept of participatory democracy that wants to break with the rigidity of current political systems and can also
include theoretical chemistry. The immaterial side of this science allows greater flexibility in international cooperation. It is a
based-intelligence science tools and it would be wise to minimize stays researchers in developed countries because their presence
side dearly and promote the movement of senior scientists in both directions to frame an educated youth and still eager to learn.
Necessarily, the choice of relevant topics will allow greater development in the southern edge of the M editerranean and greater
complementarity with the countries of the northern edge of the blue sea. I hope that the Tunisian revolution represents the
beginning of a new era in promoting a better understanding of the Arab-M uslim world.

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 Nanoscale chemical mapping through plasmonic tips on
AFM-based cantilevers
M. Patrinia, F. De Angelisb,c, R. Proietti Zaccariab, M. Francardic,d, M. Lazzarinoe,f,
L. Businarof , E. Di Fabriziob,c
a
Department of Physics A. Volta and UdR CNISM, University of Pavia, via Bassi 6, 27100 Pavia, Italy
b
Fondazione Istituto Italiano di Tecnologia (IIT), Nanostructures Department, via Morego 30, 16163 Genova, Italy
c
BIONEM lab, University of Magna Graecia, Germaneto, viale Europa, 88100 Catanzaro, Italy
d
SISSA, Cognitive Neuroscience Sector, via Bonomea 265, 34136 Trieste, Italy
e
CBM scrl Area Science Park Basovizza, 34149 Trieste, Italy
f
IOM-CNR-Laboratorio TASC, Area Science Park Basovizza, 34149 Trieste, Italy

Abstract. Noble metal tapered waveguides supporting plasmon-polariton modes are able to localize the optical fields at
nanometer level producing a remarkable local electromagnetic field enhancement, which enables the realization of high-
sensitivity biochemical sensing devices. Here we report on the design, fabrication and experimental test of a novel
photonic-plasmonic device that can be operated as an Atomic Force Microscopy tip and simultaneously for local probing
of Raman scattering spectra. This result has made possible by recent approaches in nano-fabrication methods, which
allow 3D nanostructuring of metals down to the nanoscale. The device demonstrates label-free detection capabilities on
single inorganic nanoparticles and on monolayers of organic compounds in label-free conditions and native
environments, allowing a topographic and chemical mapping of the materials with spatial resolution of a few nanometers.
Keywords: nanotechnology, plasmonics, Raman scattering, atomic force microscopy, molecular sensing.
PACS: 81.07.-b, 73.20.Mf , 82.80.Gk, 07.79.Lh.

INTRODUCTION
Optical microscopy below the diffraction limit and label-free single-molecule detection are two major issues in
material science, biophysics and sensing applications. In the last decades, micro- and nano-scale tips are used for
Scanning Tunneling Microscopy and Atomic Force Microscopy, which are capable of atomic-scale visualization and
manipulation [1]. Moreover, fluorescence microscopy has revolutionized imaging of live cells; it is noninvasive,
potentially 3D and it allows the observation of molecular-specific signals [2]. Also, the developments of colored
fluorescent proteins as specific genetically manipulated molecular markers carried noticeable improvements in
imaging techniques. However, conventional optical microscopy lacks the required nanometer resolution needed for
the task described above due to the diffraction limit of light, which is of the order of 250300 nm.
In recent years, in response to this challenge, innovative solutions that successfully break the diffraction limit of
light have been proposed and realized. Among them, nanoscale optical fibers are used, in combination with a light
source, in scanning near-field optical microscopy (NSOM) [3] and aperturless tips in the tip-enhanced Raman
scattering (TERS) [4]. Both techniques have reached sub-30 nm near-field resolution, with some drawbacks
represented mainly by the need of labeling for fluorescence signals, a strong tip-sample interaction in the near-field,
and a poor reproducibility.
Following the concept of waveguiding light on the nanoscale [5] and exploiting state-of-the-art nanofabrication
techniques [6,7], we have proposed and realized a sub-10-nm light concentrator that works simultaneously as an
atomic force microscope tip and as a probe for the Raman scattering spectrum analysis. The core of the device is a
noble metal tapered waveguide, first proposed by M. Stockman in 2004 [8], coupled to an external laser source. By
converting light into surface plasmon polaritons - coupled oscillations of electromagnetic fields and electrons in a
metal - the optical energy can be adiabatically focused towards a region just a few nanometers wide. This
concentration is limited by the nanoantenna tip apex size high quality results have been obtained as low as 5 nm
in diameter - and Raman scattering signals have achieved factor of 105 106 enhancement with respect to a far-field
standard measurement.
This plasmonic probe has been tested as an Atomic Force Microscopy (AFM) tip with optimal results in tapping
mode on inorganic and polymer samples. Simultaneous to the topographic image, near-field Raman excitation
Theory and Applications in Computational Chemistry: The First Decade of the Second Millennium
AIP Conf. Proc. 1456, 241-248 (2012); doi: 10.1063/1.4730665
2012 American Institute of Physics 978-0-7354-1057-2/$30.00

241
 allows to scan nanostructured samples acquiring Raman spectra with a spatial resolution of 7 nm, with a
straightforward chemical identification of the sample and avoiding fluorescence time decay effects. The integration
of this experiment in a commercial setup can function as a tunable light source for single-molecule detection
experiments.

THEORETICAL MODELLING AND OPTICAL DESIGN

The theoretical calculations for the behavior of the plasmonic tapered waveguide start from the theory first
proposed by M. I. Stockman [8]. Surface plasmon polaritons (SPP) are excited at the bottom of a noble metal
tapered waveguide and propagate towards the tip. The radius of the waveguide smoothly decreases and produces an
adiabatic transformation of the SPPs. Phase and group velocities of the SPPs tend to zero while approaching the tip;
at the same time the electromagnetic fields of SPPs are largely enhanced, thus producing a clear nano-focusing
effect on the tip itself.
A schematic representation of the tapered waveguide and of the optical coupling geometry is shown in Fig.1a.
The expected electric field enhancement E due to adiabatic compression is theoretically evaluated for a Silver cone
by using the theoretical approach in Ref.9, and is reported in Fig.1b. The field has been calculated for the metal-air
interface of a Silver waveguide, with a 100 nm base radius, 1 nm tip apex radius, 2500 nm length and excitation
wavelength of 532 nm; the base of the tapered waveguide is in the xy-plane while its length is along the z-axis.
Figure 1b, inset, shows a snapshot of how the radial component (denoted as Ex) of the SPPs electric field proceeds
from the tapered waveguide base to the tip apex. It can be noticed that the field amplitude is strongly enhanced, and
correspondingly the SPP wavelength decreases as the tip is approached.
The SPP spatial confinement in the near-field is comparable to the radius of curvature of the tapered waveguide
apex, that in our best cases is comprised between 2.5 nm and 5 nm. The enhancement E is defined as

E = Etip / Ebase , where Etip and Ebase are the maximum electrical fields at the apex and at the bottom of the
waveguide. We note that enhancement values of practical interest are in the range of 100 (giving a Raman scattering
enhancement of 108); this value is reached when the radius of curvature of the tip is below 5 nm. For successful
spectroscopy applicationsthis imposes state of the art fabrication quality.

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FIGURE 1. (a) Sketch of the tapered waveguide and optical excitation scheme. (b) Calculated electric field enhancement as a
function of the radius of curvature at the apex of the tapered waveguide. Inset: 3D plot of the Ex radial component of the SPP
field propagating along the tapered waveguide (Reprinted with permission from Ref. 11 Copyright 2010 MacMillan Publishers
Limited). (c) Calculated electric field intensity for a real Silver nanocone (radius of curvature 5 nm, =633 nm) when linear
polarized source with tilt angle 40 is employed.

In the case of our actual devices, in order to evaluate the e.m. field intensity at the tapered waveguide, we
implemented a finite-difference time domain (FDTD) algorithm, using a commercial software [10], with absorbing
boundary conditions, a Drude-Lorentz model for the metal, and a space time discretization [9]. Two main difficulties
have been considered in the design of the device in order to achieve an optimal 3D adiabatic e.m. field focusing.
First, the geometry of the metallic taper plays an important role in defining the SPP mode profiles. If the
variation of the diameter along the taper is slow enough, the e.m. field propagation is adiabatic and almost all the
energy injected at the base of the cone propagates to the tip. On the contrary, if the diameter is reduced irregularly,
part of the energy should be back-reflected at each step, and very little energy reaches the cone tip. In our first
realization the taper had an ogival shape, which is easier to fabricate without failing in device performance [9]. Also,

242
the simulations were performed for an ogival shaped waveguide, instead of a conical one, in order to assure
convergence of FDTD results, which is critical when refining the mesh size at the taper apex. When the shape is
perfectly conical, both our theoretical simulations and Raman scattering experiments confirm that the SPP mode is
strongly localized in a region comparable to the radius of curvature of the tip (about 5-10 nm), providing efficient
coupling for Raman scattering events in the far field [11].
Second, a conical waveguide supports efficiently only TM0 modes (i.e. transverse magnetic modes with radial
symmetry with respect of the cone axis). Linearly polarized laser beams cannot be efficiently coupled with conical
waveguides because of the different symmetry of the beam and the waveguide mode. The problem of efficient
coupling of an external laser beam (light source for Raman scattering experiments) to the tapered waveguide has
been faced theoretically and experimentally. Different solutions have been analyzed, in terms of trade-off between
the difficulties of fabricating the tapered waveguide on an AFM cantilever and the overall device performances [12].
Among them, we cite the insertion of i) a zone plate, compatible with radial symmetry, on the back surface of the
cantilever, in correspondence to the waveguide base, or ii) a L3 photonic crystal (PC) cavity with its centre just
below the basis of the tapered waveguide. PC structures have been widely used to increase light-matter interaction,
such as for nonlinear optics or chemical and biological sensing [13-14]; here we use a PC cavity as a photonic sink
for the excitation laser to the nanoantenna. Fig. 1c shows the square modulus of the e.m. field Ex2 + Ey2 calculated
along a cross-section of the waveguide, in presence of the PC cavity. The physical mechanism is that the external
laser pulse is coupled to the PC cavity mode and therefore focused at the basis of the tapered waveguide (see Ref.9,
Figs. 2a and b); the e.m. field is then radiatively coupled to the tapered waveguide, exciting the SPP modes.

ADIABATIC FOCUSING OF SPP AND RAMAN SPECTROSCOPY

The difficulty in fabricating 3D tapered waveguides with these severe geometrical constraints highlights the
importance of the experimental demonstration of 3D adiabatic focusing in our device. We first demonstrated the
ability of a plasmonic waveguide of ogival shape, optically coupled to a dielectric PC cavity, to convert the
intrinsically evanescent SPP field into a propagating e.m. signal to be detected through Raman scattering in the far
field [9]. In this way, the device avoids experimental difficulties associated to the use of a near-field configuration,
as it is required by TERS experiments.
Our nanolithography techniques rely on two powerful fabrication methods: focused ion beam (FIB) milling [15]
and chemical vapor deposition (CVD) induced by a focused electron beam [6]. The device consists of a plasmonic
nanoantenna made of a noble metal, such as Gold or Silver, combined with a PC cavity of silicon nitride, with a
resonant cavity mode tunable at the desired laser operation wavelength. The scanning electron microscope image of
a SENSe (Surface-Enhanced Nano Sensor) device is shown in Figure 2a, and the zoom image of the plasmonic
waveguide tip is shown in Fig. 2b. The PC cavity (L3-type, lattice constant 250 nm, hole radius r=0.3 a) has a defect
mode around =514 nm, thus producing an efficient coupling between the external laser source and the
nanoantenna. This last propagates and focuses the SPPs toward the tip where enhancement of the e.m. field intensity
occurs. Assuming the radius of curvature at the apex of about 10 nm, the simulations allow to evaluate an electric
field enhancement factor of about 100.

(a) (b)

FIGURE 2. (a) SEM image of the whole device including the PC cavity and, at its center, the plasmonic nanowaveguide. This is
2.5 microns high and its size gradually decreases from 90 nm in diameter at the bottom down to 10 nm at the tip. (b) SEM detail
of the tapered waveguide tip and its radius of curvature.

243
 (a) (b) (c)

150 nm

FIGURE 3. (a) SEM image of a definite volume of ZnS/CdSe QDs spun on silicon nitride membrane (see text). (b) SEM image
of a single core-shell ZnS/CdSe QDs deposited at the SENSe tip. (c) Raman scattering spectra (lexc =514 nm) taken from the
single QD (red line) as compared to that of a QD bulk sample (blue line). Inset: detail of the asymmetric stretching vibration a-
NH2 at 3580 cm-1. (Panel b and c reprinted with permission from Ref. 9 Copyright 2008 American Chemical Society)

Such a strong enhancement of the excitation field allows the detection of the Raman scattering signals in the far
field from a few molecules localized at the nanometer scale of the tip, in label-free conditions. The experimental
demonstration of this outstanding sensitivity was provided by the Raman scattering spectrum taken on a single
quantum dot (QD), as compared to that of a micrometric assembly of the same material. A single core-shell QD
(ITK amino PEG ZnS/CdSe QDs Invitrogen) was deposited on the plasmonic waveguide tip by a nanomanipulator,
with a 0.25 nm position accuracy, as it is shown in Fig.3b. The reference bulk sample of the same material was
obtained by spinning the same QD on a silicon nitride membrane, and by patterning it in order to obtain a cylinder
of 1.2 m diameter and 200 nm in height (Fig 3a). In Fig. 3c the Raman scattering spectrum of the single QD is
compared to that one of the QD bulk assembly, as obtained in transmission geometry and in identical spectroscopic
conditions (laser =514 nm, power P=0.18 mW, same substrate material). We note that the apparent increase in the
radius of curvature of the tip is due to carbon codeposition during the operation time of QD manipulation and
deposition. Then, the C-C vibrational mode at 1591.8 cm-1 and of the shoulder at 1353.8 cm-1 should be attributed to
this carbon overlayer material. Apart from these features, the Raman intensity spectrum from the single QD on the
nanoantenna matches the spectroscopic information from the bulk sample, but the Raman spectra from single QD
show more clearly the a-NH2 asymmetric stretching vibration at 3580 cm-1 (Fig. 3c, inset). This vibration is in
general weak compared to the CHx one and its evidence in the single-QD spectrum is due to the tip local field
enhancement. In particular, we estimated the number of NH2 molecules contributing to this Raman vibration. In fact,
from the supplier specifications, the QD has an inner core of 2.5 nm radius, on which PEG (poly(ethylene glycol))
molecules are bound with NH2 terminated groups,[16] thus resulting in an average single QD diameter of about 18
nm. A conservative estimation can be done assuming very high close packing of PEG-NH2 groups, that is, 1
anchorage per nm2. With this assumption the total detected number of NH2 groups is equal to 80 and the Raman
scattering signal enhancement with respect to the bulk sample is calculated to be about 105.
Similar results were obtained by taking the Raman scattering spectrum of different materials, physisorbed or
chemisorbed onto the nanowaveguide, even in the case of very low Raman scattering efficiency, such as that of SiO2
nanoparticles [9].

AFM IMAGING AND SIMULTANEOUS RAMAN MAPPING

The high sensitivity and the high signal-to noise ratio found in the experimental Raman spectra of the first
devices had opened bright perspectives for application to single molecule detection. We realized that SENSe device
can straightforwardly be combined with scanning probe microscopes, such as AFM, with the possibility to match the
topographical imaging with the force and chemical spectroscopic mapping at the same nanometer length scale.
In Fig. 4a we present the SEM images of an AFM cantilever with the PC cavity and plasmonic nanoantenna
fabricated on the surface. The whole device was fabricated using an FEI Nova Nanolab 600 dual beam system. The

244
Silicon nitride cantilever is locally thinned on one side in order to obtain a membrane thickness of 100 nm necessary
for the fabrication of the designed PC cavity. The local thinning of the membrane doesn't affect the mechanical
properties of the cantilever. Ion-beam milling was then used to define the photonic crystal (L3-cavity, tuned at 532
nm). A silver tapered waveguide was grown in the centre of the cavity using electron beam induced deposition from
a gas precursor containing a platinumcarbon polymer (CH3)3Pt(CpCH3) [17]. A thin film of Silver was deposited
on the surface of the device (30 nm thick), and then removed locally from the PC surface. The final specifications of
the Silver tapered waveguide is 2.5 m height, the base diameter equal to 300 nm, and the radius of curvature of the
apex is controlled to be 5 nm using low-current ion milling (Fig. 4b).

(a) (b)

FIGURE 4. (a) SEM image of the device (inside red circle) fabricated on a standard silicon nitride AFM cantilever (b) Close-up
image of the PC cavity milled in the cantilever and of the Silver tapered nano waveguide with a conical shape and radius of
curvature at the apex of 5 nm.

The performances of such a nanoantenna as AFM super-tip has been tested to obtain AFM topography images in
wet conditions at nanometer resolution, close to those employed for the study of biological samples.. The test
sample was obtained by laser lithography of an amorphous silicon film previously fabricated by plasma-enhanced
chemical vapour deposition on a silica substrate. The sample appears as a grating of silicon nanocrystals (Fig.5a)
having a macroscopic periodicity of about 0,35 micrometers and local variations of few nanometers: from the
literature the average nanocrystal size was expected to be less than 10 nm [18]. In order to further show the high
geometrical quality of the present device, we also report on the AFM resolution achievable on Celgard membranes
(microporous polypropylene fibers) (Fig. 5b). Measurements were performed in tapping mode on a VEECO AFM
Bioscope II. Tapping mode was used in water to ensure proper operation of soft nitride cantilevers, as well as to be
close to bio applications. For a direct comparison, both standard commercial cantilevers and modified conical ones
were used in same tapping conditions. We notice that high-resolution mapping is achievable thanks to the very sharp
tip end, especially necessary in case of samples characterized by deep trenches (notice the tip vertex angle is about
8) [19].

(a) (b) (c)

1m 200 nm

FIGURE 5. (a) High-resolution AFM image of Si/SiOx sample with a submicrometer pitch patterning with a periodicity of
0,35 micron. (b) and (c) AFM topographies of Celgard membrane obtained on Veeco Bioscope II with a commercial tip and
our SENSe device, respectively.

245
 FIGURE 6. (a) Schematic of the Raman scattering setup coupled to the AFM microscope system. (b) schematic zoom on the
cantilever, illumination and collection paths alignment.

To demonstrate the simultaneous AFM and Raman scattering mapping ability, we coupled an optical set-up with
a commercial AFM (Nanowizard II JPK,Berlin) mounted on top of an inverted optical microscope (Axiovert 200
Zeiss, Gttingen). Fig. 6a illustrates the optical configuration adopted. Two DPSS laser sources at 532nm and
473nm with variable power up to 50mW are first reflected by a suitable notch filter and then directed at the entrance
of the illumination condenser (NA 0.35) of the microscope. During the experiments the light intensity on the device
is always kept below 1mW. The scattered light is collected from the bottom by a microscope objective (oil
immersion NA 1.4). The Raman shifted light is then focused on the entrance of a 750mm-long spectrometer
(Shamrock Andor, Belfast) and dispersed on a TE cooled EMCCD (Newton Andor, Belfast). Fig. 6b illustrates
the detail of the alignment of the two light paths (excitation and collection) with the tapered tip. By using the XY
piezo positioning system of the atomic force microscope, the tip is aligned to the high numerical aperture objective
of the collection path. At this step, position accuracy at the nm level is required, since the focal spot of the objective
at the wavelength used is about 200nm wide. The AFM laser, at 860 nm wavelength, is focused on the back of the
cantilever, approximately displaced towards the cantilever chip body by tens of microns from the tip, to avoid cross
talk in the two optical paths. Finally we scan the sample using a second XY scanner controlled by the same AFM
electronics (TAO module JPK, Berlin).
To test the spatial resolution of our device for chemical mapping the best fabricated tapered waveguide with an
apex radius of curvature of 2.5 nm was used on the sample of Fig.5a by scanning the sample as for AFM imaging
and acquiring Raman scattering intensity across the lithographic structures, point by point [11]. We focused our
attention on the Raman spectral range between 400 and 650 cm1, where the region between 430 and 480 cm-1 is
related to the presence of amorphous silica (SiOx) and amorphous silicon. while the peak centered at 520 cm-1 is the
evidence for a crystallized silicon (c-Si) boundary. Raman spectra were collected in the transmission configuration
by scanning the sample through a boundary between the silica and the c-Si region with a step size ranging from 200
to 7 nm, the corresponding Raman signal contrast being significant, with intensity ranging from 0 to 8000 counts/s.
In Fig.7(a,b) we report three-dimensional mapping of AFM topography and Raman signal at 520 cm-1 as obtained
with the minimum step size of 7nm. The Raman intensity and relative peak amplitudes change from point to point
(with up to 10 repetitions at the same position and 3.5% average signal error) and reflect the chemistry of adjacent
positions. This provides clear evidence that the Raman signal is generated mainly by strongly localized SPP in a
region comparable to the radius of curvature of the tapered waveguide apex, which is therefore sensitive to the local
chemistry. Moreover, we compared the silicon Raman scattering intensity from a bulk crystalline sample in the far
field with that from our sample, to evaluate the experimental signal enhancement due to SPP near field excitation.
Assuming a focal spot of about 5 m2 in the far field and 10-4 m2 in our setup, we estimated the experimental
enhancement to be in the range105-106, which is comparable to the highest values reported in literature [20], with
the remarkable advantage that our setup does not critically depend on the tip/scatterer materials and interactions,
such as it happens in TERS experiments [21].

246
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FIGURE 7. (a) AFM topography image through across a sub-micrometer Si nanocrystal/SiOx trench (b) Raman intensity map
top panel between 500 and 540 cm-1, as measured simultaneously with AFM topography. The dotted red-line corresponds to the
red-line scan in the topography map of (a). Intensity (bottom panel) of the Si Raman peak at 520 cm-1 (black dots) and
corresponding AFM line scan (red squares) along the red line scan of (a). Scan step size is 7 nm. (Reprinted with permission from
Ref. 11 Copyright 2010 MacMillan Publishers Limited).

From the correlation between topography traces and Raman peak intensity (see Fig.7c) we can gain more
quantitative information on the local composition of our sample. The phonon confinement model (PCM) [22-23] is
applied here for fitting the experimental Raman spectra of crystalline Si grains embedded in an amorphous silica
matrix, and allows to determine the grain size and its size distribution. Raman spectra were fitted to stress-corrected
phonon confinement model for asymmetric peak about 520.5 cm-1, associated to the Si nanocrystals, and by a
Gaussian function for amorphous contribution associated to the a-Si component and SiOx. The application of the
PCM model to the long-scan (220 nm) measurements leads to a determination of the grain size distribution and
stress level. In general, as the dimensions of the nanocrystal decrease, there is a redshift in the Raman vibrational
frequency of Si nanocrystals and an increase in bandwidth with respect to the cSi band. In our scan, passing from
the c-Si rich material to the amorphous phase, Si-nc grain size shows an increasing trend from about 4.1 nm to 5.6
nm, and size dispersion increases. At the same time, the stress level changes from tensile to compressive, and both
effects could be attributed to the Si-nc melting in a SiO2 matrix by laser lithography [24].
In conclusion, we have designed and realized a plasmonic nanoantenna coupled to a PC cavity, which is able to
probe the Raman scattering spectrum of a few molecules deposited in its tip. By strongly improving nanofabrication
capabilities, we have realized near-adiabatic tapered SPP waveguides, with conical shape, that were able to
simultaneous record AFM topography and confocal Raman spectra, achieving exceptional chemical mapping at
nanometer resolution. The two experimental techniques are already joined in some commercial instruments [25] and
we believe that our tip sensors based on adiabatic compression of SPP should play an important role in achieving
few/single molecule detection. The approach could be of particular benefit in the nanoscale analysis of biological
matter, such as in the investigation of cell membrane protein spatial distributions, in which chemical/physical bond
strengths and amino acid composition in vivo conditions could be revealed [26].
In addition, in Fig. 8 we show other configurations of the tapered waveguides which could be of use in particular
applications, e.g. selective functionalization of the tip (avoiding sample labeling), coupling to a silica nanoparticle
scatterer, or deposition of down-shaped material at the tip apex. Such a particular structure is mainly caused by the
large quantity of secondary electrons emitted from the silica surface above a sharp gold tip. The very high porosity
gives to the device interesting features in term of capturing and sensing capabilities. Nanoporous silica and
nanoporous silica nanoparticles have already been successfully employed for selectively harvesting low molecular
fraction of complex bio-fluid, including raw human serum [27]. These plasmonic nano-downs could represent a
novel class of devices that combine the harvesting capability of nanoporous materials with the superior sensing
capability of plasmonic antennas.

247
 (a) (b) (c)

FIGURE 8. (a) ,(b) SEM images of silica nanoparticle deposited by means of EBID on the tip of a nanocone. (c) For longer
deposition times the nanoparticle assumes the shape of a down.

ACKNOWLEDGMENTS
We thank Dr. Samuel Lesko (Veeco Company) for AFM measurements. This work was partially funded under
European Project SMD FP7-NMP 2800-SMALL-2 (proposal no. CP-FP 229375-2), and Italian project FIRB Rete
Nazionale di Ricerca sulle Nanoscienze ItalNanoNet (cod. RBPR05JH2P_010).

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Verlag, Berlin, 2002 and 2009.
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3. Nano-optics and near-field optical microscopy, D. Richards and A. V. Zayats, Eds., Boston, Artech, 2008.
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2321 (2008). DOI: 10.1021/nl801112e
10. For further infos concerning the Lumerical Solutions FDTD software see www.lumerical.com.
11. F. De Angelis, G. Das, P. Candeloro, M. Patrini, M. Galli, A. Bek, M. Lazzarino, I. Maksymov, C. Liberale, L.C. Andreani,
and E. Di Fabrizio, Nature Nanotechnology 5, 67, 2010. DOI: 10.1038/NNANO.2009.348
12. F. De Angelis, R. Proietti Zaccaria, M. Francardi, C. Liberale, and E. Di Fabrizio, Optics Express 19, 22268 (2011).
13. M. Galli, M. Agio, L.C. Andreani, L. Atzeni, D. Bajoni, G. Guizzetti, L. Businaro, E. Di Fabrizio, F. Romanato, and A.
Passaseo, European Physical Journal B 27, 79 (2002).
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Fabrizio, A. Passaseo, and M. De Vittorio, Journal of the Optical Society of America B 19, 2122 (2002).
15. F. Schiappelli; R. Kumar, M. Prasciolu, D. Cojoc, S. Cabrini, M. De Vittorio, G. Visimberga, A. Gerardino, V. Degiorgio, E.
Di Fabrizio, Microelectronic Engineering, 73, 397 (2004).
16. For info see www.invitrogen.com
17. E. Di Fabrizio et al. Procedimenti di fabbricazione di un dispositivo a cristallo fotonico provvisto di guida donda
plasmonica, Italian patent TO2008A000693 (2008).
18. T. Mchedlidze, et al. Phys. Rev. B 77, 161304 (2008).
19. A. Bek, F. De Angelis, G. Das, E. Di Fabrizio, M. Lazzarino, Micron 42 313 (2011).
20. B. Yeo, W. Zhang, C. Vannier, R. Zenobi, Applied Spectroscopy 60, 1142 (2006).
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22. H. Richter, Z.P. Wang, L. Ley, Solid State Commun. 39, 625629 (1981).
23. H. Kohno, T. Iwasaki, Y. Mita, S. Takeda, S. J. Appl. Phys. 91, 3232 (2002).
24. L. Khriachtchev, M. Rasanen, S. Novikov, Appl. Phys. Lett. 88, 013102 (2006).
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27. F. De Angelis et al., Nanoscale 2, 2230 (2010).

248
 On the use of symmetry in SCF calculations. The case of
fullerenes and nanotubes
C. M. Zicovich-Wilson,a Y. Nol,b A. M. Ferrari,c R. Orlando,c M. De La Pierrec
and R. Dovesic
a
Facultad de Ciencias, Universidad Autnoma del Estado de Morelos, Av. Universidad, 1001, Col. Chamilpa,
62209 Cuernavaca (Morelos), Mexico
b
Institut des Sciences de la Terre de Paris (UMR 7193 UPMC-CNRS), UPMC, Sorbonne Universits, Paris, France
c
Dipartimento di Chimica, Universit di Torino and NIS, Nanostructured Interfaces and Surfaces, Centre of
Excellence, Via P. Giuria 7, 10125 Torino, Italy

Abstract. The way point symmetry can be exploited to reduce the computational cost (CPU time and memory allocation) in SCF
ab initio calculations is discussed. Crucial for the CPU time are the calculation of the mono- and bi-electronic integrals and the
diagonalization of the Fock matrix at selected points in reciprocal space; as regards memory allocation, the full square density
and Fock matrices must be avoided. Quantitative examples are given in the case of high symmetry compounds such as carbon
fullerenes and nanotubes.

Keywords: point symmetry, Symmetry Adapted Crystalline Orbitals, CPU time, memory allocation, ab initio calculations, Fock
matrix, CRYSTAL code.
PACS: 71, 73.

INTRODUCTION
In the study of the electronic structure of crystalline compounds, it is mandatory to exploit translational
symmetry by using a variational basis of Bloch Functions (BFs), so that a block-diagonal structure is obtained for

the (infinite) Hamiltonian matrix, each block corresponding to a k point in the First Brillouin Zone (BZ) (see
Figure 1). All periodic codes are based on the use of BFs.

Fg Fk fk
 
g k
FIGURE 1. Block-factorization of the reducible Fock matrix. F : basis of AOs (Atomic Orbitals, non-compact form); F :

k
basis of BFs (Bloch Functions, i.e. Crystalline Orbitals); f : basis of SACOs (Symmetry Adapted Crystalline Orbitals).

Point symmetry, on the other hand, is totally or partially neglected in many computer codes; only a subset of
point groups are implemented , whose operators are used only at some steps of the calculation.
Nevertheless, it is discussed here how symmetry permits a drastic reduction in the CPU time and memory
allocation in SCF calculations of the electronic structure for both molecules and solids, by taking the present version
of the ab initio Hartree-Fock/Density Functional computer code CRYSTAL[1] as a reference. The required CPU time
can be reduced through the use of symmetry at various steps:
1. in the calculation of the mono- and bi-electronic integrals, whose number is reduced by up to a factor Nop, the

 Theory and Applications in Computational Chemistry: The First Decade of the Second Millennium
AIP Conf. Proc. 1456, 249-256 (2012); doi: 10.1063/1.4730666
2012 American Institute of Physics 978-0-7354-1057-2/$30.00

249
 number of point symmetry operators in the group;

2. in the selection of the subset of k points of the BZ, within the Irreducible Brillouin Zone (IBZ), at which the

Fock matrix is diagonalized[2] (this applies to periodic systems only). The number of k points is reduced also in
this case by a factor approaching Nop when a dense mesh of points is used;
3. in the diagonalization of the Fock matrix, by using a SACO (Symmetry Adapted Crystalline Orbitals, in the
case of solids) or SAMO (Symmetry Adapted Molecular Orbitals, for molecules) basis. Note that SACOs/SAMOs
are generated from the selected basis set of Atomic Orbitals (AOs) and from the space group operators only; no
tabulation of Irreducible Representations (IRs) or characters is required[3,4]. The reduction in computational time in
this case is even larger than in the previous points, as it is roughly proportional to the third power of the ratio
NAO/MAXIR between the number of AOs in the basis set (NAO) and the size of the largest block in the Fock matrix
once represented in the SACO basis (MAXIR).
As regards memory, the crucial point is to avoid the representation of the Fock, overlap and density matrices as
full square matrices in the AO basis. In this respect, the following strategy can be adopted (from now on, direct
space irreducible matrices will be indicated with handwriting letters; reducible matrices with capital latin letters
and matrices in the SACO/SAMO basis in small latin letters):

1. computation of the irreducible Fock matrix F g ; the saving factor is in the order of Nop;
 
g g
2. storage of the irreducible F and reducible F forms of the Fock matrix in a compact form;
 
g
3. direct transformation from F to f k , the block diagonal form in the SACO basis; this permits to reduce the
bottleneck of memory allocation by a factor proportional to the square of the ratio NAO/MAXIR. This level of
optimization is under implementation.
Effectiveness of the use of point symmetry is shown for highly symmetric compounds: examples are given,
referring to two families of compounds characterized by very high symmetry (see Figure 2): carbon fullerenes[5,6] of
the (n,n) family (120 symmetry operators) and carbon nanotubes[7-9] of the (n, 0) family (8 n symmetry operators;
n up to 150 has been considered).

FIGURE 2. Atomic structures of (1,1) fullerene (left) and (10,0) carbon nanotube (right).

COMPUTATIONAL SCHEME
In the following we illustrate the main steps of the SCF calculation as implemented in the public version of the
CRYSTAL code.[1] We illustrate then the modifications in progress, aimed at drastically reducing the memory
allocation.
a. Symmetry is used to identify the relationships between atoms, shells, atomic pairs, so that linear
transformations along the SCF process can quickly proceed through mapping tables. Then, IRs are constructed,

250
 and the SACO coefficients are generated and stored in a packed way.
b. Mono- and bi- electronic integrals are evaluated.

g'
c. The direct space irreducible Fock matrix is built, by using the computed integrals and the density matrix P :

   
P ( )
   
Fg = g' 0 g
| h h+g' +H g (1)

, , g' 
h
    

( ) contains both the coulomb and exchange contributions, and H


0 g h h+g' g
where the integral | is the
mono-electronic contribution to the Fock matrix.
Note that only the irreducible wedge of the Fock matrix is built (which allows the saving factor in the calculation
of integrals). To sum over the integral indices, screening techniques are applied, essentially based on the overlap
criteria between the two gaussians describing the charge distribution of electron 1 and electron 2; this permits to
store only matrix elements between relatively close atoms so that the direct space Fock matrices assume a very
compact structure that scales linearly with the size of the system.
 
g g
d. F is transformed into the direct space reducible Fock matrix F by applying the set of symmetry operators
of the point group.

g
The reducible Fock matrix F is then Fourier transformed to the reciprocal space, that is from the AO to the BF
basis (see also Figure 1):


(ikg) 
Fk = e Fg (2)

g

In the molecular case, obviously no transformation in the reciprocal space is performed.


e. F k is transformed to the SACO block-diagonal form (Figure 1):
  +  

( )
f k = W k F kW k (3)

The W matrices take a different form for the various k points, depending on their multiplicity.
In the molecular case, the SAMO block-diagonal form f is directly obtained from the direct space reducible Fock
matrix F .

f. Each block of the Fock matrix in the SACO basis f k is diagonalized.
 
k
g. The eigenvectors a of the f k matrices are back transformed to the BF basis:
  + 
A k = W k ak ( ) (4)
 
h. The eigenvectors A k are used to build Pk (BF basis):
 occ  * 
Pk = 2 Aki Avik
i
( ) (5)

 
k g
i. P is back-Fourier transformed to give P , the density matrix in the AO basis:
 
P = e( ) P
 i kg
g k
(6)

k

251
 The scheme illustrated above uses the full symmetry of the crystal. However it is affected by a couple of
 
g g
bottlenecks from the point of view of memory occupancy, as full density P and Fock F matrices are required in
steps c and d, respectively. These two matrices are stored in a compact form, as discussed above and shown in
Tables 1 and 3, so that they are not terribly

memory consuming. Much more memory consuming

is the use

of the
k k k
full square Fock matrix in the BF basis F (Equations 2 and 3), and of the eigenvalues A and density P square
matrices in reciprocal space (Equations 4, 5 and 6).
However, these memory bottlenecks can be by-passed as follows:

g
I. Only the irreducible direct space density matrix P is built; in Equation 1, every block of the density matrix
not belonging to the irreducible wedge is obtained in real time during the calculation of the bielectronic
integrals.
   
g g k k
II. The set of linear transformations F F F f can be merged to a single linear transformation, so
as to generate directly the Fock matrix in the SACO basis

from the direct space irreducible Fock matrix. This

g
eliminates the need for allocation of both F and F k . Looking at their size, for example for the (7,7)
fullerene or (150,0) nanotube in Tables 1 and 3, one can appreciate the huge reduction in memory storage.
 
g k
III. Similarly the irreducible density matrix P can be obtained directly from the SACO coefficients a . The
large matrices (eigenvectors in the BF basis, density matrix in the BF basis and direct space reducible density
matrix) are then avoided also in Equations 4, 5 and 6. Steps II-III are under development in the CRYSTAL
code.

APPLICATION TO FULLERENES AND NANOTUBES

Calculations were performed by using a standard Poples 6-31G(d) basis set. 14 AOs are associated to each
carbon atom.
A fullerene structure (see Figure 3) is completely defined by a couple of indices (n,m). These coefficients are
 , the vector representing the side of a triangular
applied to the lattice vectors of the graphene unit cell, to build R
face of the icosahedral framework of the fullerene. The full structure is then generated by applying the point group
symmetry operators to the irreducible atoms in one triangle.

FIGURE 3. Fullerene structures: construction of the triangular face of the icosahedron. Example for the (2,1) fullerene (140
 vector is in red. Some of the symmetry operators are represented.
atoms). Carbon atoms are in green; R

The (n,n) family of fullerenes has been considered in this work, with n ranging from 1 to 7; data are reported in
Table 1. The symmetry point group is always Ih (Nop = 120), irrespective of n. nat, Nat and NAO are the number of
irreducible atoms, the total number of atoms and the total number of basis functions of the molecule, respectively;

252
these three quantities increase with increasing n. In particular, when going from (1,1) to (7,7), nat increases by a
factor of 28, while Nat and NAO increase by about a factor 50: from 60 to 2940 and from 840 to 41160, respectively.

g
F is the irreducible wedge of the Fock matrix, stored in a compact form as discussed in the Computational
 
g g
Scheme Section. Note that its size SF increases only linearly with Nat. F is generated from F by applying the
symmetry operators of the Ih group.

TABLE 1. Effect of symmetry on SCF calculations for a family of fullerenes. nat, Nat and NAO are the number of
irreducible atoms, the number of atoms and the AO basis set size, respectively. SF and SF are the sizes of the
irreducible and reducible (compact) Fock matrices in direct space. R1 , R2 and R3 are the ratios SF SF ,
2
N AO SF and NAO/MAXIR, respectively. The number of symmetry operators, Nop, and the number of IRs, NIR, are
always 120 and 10, respectively.

(n,n) nat Nat NAO SF SF 51 52 53

(1,1) 1 60 840 1759 169'980 97 401 22
(2,2) 3 240 3360 6707 716'130 107 1683 23
(3,3) 6 540 7560 14570 1'609'020 110 3923 23
(4,4) 10 960 13440 25377 2'847'690 112 7118 23
(5,5) 15 1500 21000 39047 4'432'140 114 11294 24
(6,6) 21 2160 30240 55661 6'362'370 114 16429 24
(7,7) 28 2940 41160 75138 8'638'380 115 22547 24
The ratio R1 = SF SF spans from 97 to 115, and represents the saving factor in the calculation of the integrals
obtained when using symmetry and in memory occupancy if the direct space reducible Fock matrix is avoided. Its
value tends to the number of symmetry operators Nop (which is constant for fullerenes). The R2 = N AO SF ratio,
2

that is as large as 22547 for the (7,7) fullerene, gives the saving factor with respect to the situation in which the full
square Fock matrix is stored. Finally, R3 = NAO/MAXIR gives the saving factor in memory allocation when adopting

the Fock matrix in the SACO basis f k for diagonalization; its value is about 23, almost constant along the series.
Note that for the (7,7) fullerene the size of the square full Fock matrix in the AO basis is 1.3109 with a memory
requirement for its allocation of about 10 Gb. When a SACO basis is used, the largest allocation for the
diagonalization step is reduced by a factor larger than 600, that is to less than 20 Mb.
Factorization of the Fock matrix in the basis of SACOs is detailed in Table 2, where the size of the sub-blocks is
k
reported for each of the 10 IRs of the group. For the largest (7,7) case the size of the blocks of f are 364 and 322
for the Ag and the Au IRs, 1008, 1050, 1008 and 1050 for F1g, F1u, F2g, F2u, 1372 for Gg and Gu and finally 1736 and
1694 for Hg and Hu. It should be noticed that there are three blocks of F symmetry, four of G symmetry and five of
H symmetry, the number of blocks in each IR corresponding to its dimensionality. Due to degeneracy, only one of
the blocks corresponding to one of the rows of the IR must be diagonalized, the other eigenvalues being degenerate;
eigenvectors are obtained by symmetry straightforwardly. In summary the diagonalization of a 41160x41160 matrix
is replaced by the diagonalization of 10 matrices with maximum size 1736 (24 times smaller). Due to the cubic
scaling of diagonalization with the matrix size, the huge speed-up is apparent.
We analyze now the second example, carbon nanotubes. Also their structure is defined by two indices (n, m) (see
Figure 4). They are used as coefficients for the lattice vectors of the graphene unit cell, to build up the rolling vector
   
R (the nanotube circumference is R ). In the Figure, vectors L and H represent the nanotube axis and the helical
vector, respectively (see Ref. 8 and the Tutorial at the CRYSTAL web site http://www.crystal.unito.it/tutorials/ for
more details).

253
 TABLE 2. Factorization of the SAMO block-diagonal Fock matrix f for a family of fullerenes. The size of the
sub-blocks, associated to the various IRs of the Ih point group, is reported. A, F, G, and H IRs are of
dimensionality 1, 3, 4, and 5, respectively.

(n,n) Ag Au F1g F1u F2g F2u Gg Gu Hg Hu

(1,1) 10 4 18 24 18 24 28 28 38 32
(2,2) 34 22 78 90 78 90 112 112 146 134
(3,3) 72 54 180 198 180 198 252 252 324 306
(4,4) 124 100 324 348 324 348 448 448 572 548
(5,5) 190 160 510 540 510 540 700 700 890 860
(6,6) 270 234 738 774 738 774 1008 1008 1278 1242
(7,7) 364 322 1008 1050 1008 1050 1372 1372 1736 1694

a2
H

R
a1

  
FIGURE 4. Construction of nanotube structures. R, L and H vectors in the graphene lattice for a (4, 2) carbon nanotube.
 
Carbon atoms in the primitive cell are in black. a1 and a2 are the cell vectors for the graphene lattice.

The nanotube case differs from the fullerene situation in two main respects: a) nanotubes are periodic (in one
dimension), so that the Fock equation must be solved for a set of kx points of the IBZ (that is one-dimensional too);
b) symmetry of nanotubes increases with the size of the nanotube, while is constant for fullerenes. This implies that
for nanotubes the number of IRs increases, and the maximum size of the Fock matrix remains almost constant.
Nanotubes of the (n,0) family have been considered, with n ranging from 7 to 150 (results are shown in Table 3).
The number of symmetry operators varies from 56 to 1200 (Nop = 8 n); the basis set can contain as many as 8400
AOs, in the case of (150,0). While Nop increases linearly with n, the number of irreducible atoms nat is always equal
to one. As a consequence of this, SF is almost constant along the family, changing from 2638 for (7,0), to 2117 for
n 52; for smaller tubes it is slightly larger than for larger tubes, as additional matrix elements are taken into

g
account corresponding to interactions across the tube between opposite walls. On the contrary F , and thus R1 ,
increases with n by a factor of about 20. As expected, R1 has an almost linear dependence on Nop.

R2 increases by a factor close to 600 along the family, reaching the value of 33330 for (150,0). As regards R3 ,
its value is identical to 2n all along the series. Finally, let us observe the trend for NIR, the number of IRs of the
group, which is related to the number of blocks appearing in the block-diagonal Fock matrix represented in the basis
of SACOs (double and quadruple degenerate IRs produce two and four blocks, respectively). In the case of kx = 0

254
(the kx point with full symmetry), NIR is equal to 20 for (7,0) and to 306 for (150,0), showing an increase by a factor
15, and a nearly linear dependence on n.

TABLE 3. Effect of symmetry on SCF calculations for a family of carbon nanotubes. The number of irreducible
atoms nat is 1 in all cases. Values for NIR refer to kx = 0. See caption to Table 1 as a legend.

(n,0) Nat NAO Nop NIR SF SF 51 52 53

(7,0) 28 392 56 20 2638 99750 38 58 14
(10,0) 40 560 80 26 2361 127'900 54 133 20
(16,0) 64 896 128 38 2149 186'720 87 374 32
(28,0) 112 1568 224 62 2133 324'968 152 1153 56
(40,0) 160 2240 320 86 2133 464'240 218 2352 80
(52,0) 208 2912 416 110 2117 600'184 284 4006 104
(64,0) 256 3584 512 134 2117 738'688 349 6068 128
(76,0) 304 4256 608 158 2117 877'192 414 8556 152
(88,0) 352 4928 704 182 2117 1'015'696 480 11472 176
(120,0) 480 6720 960 246 2117 1'385'040 654 21331 240
(150,0) 600 8400 1200 306 2117 1'731'300 818 33330 300

Table 4 shows the block structure of f k for three nanotubes and for the three different sets of kx points of the
IBZ (the first set contains kx = 0, the second set kx = 1/2, the third set all other points). The table shows that the
number of IRs increases with the tube size; however the maximum size of the matrices to be diagonalized remains
constant and never exceeds 14, 28 and 28 for the three sets of kx points, respectively, also when the AO basis is as
large as 8400 (150,0).
The constant size of the irreducible Fock matrix (that implies that the cost of the construction of the Fock matrix
is constant along the series of nanotubes) and the constant size of the largest matrices to be diagonalized produce a
nearly constant scaling of the calculation, as documented in Ref. 8.


k
TABLE 4. Factorization of the SACO block-diagonal Fock matrix f for carbon nanotubes. The size of the sub-
blocks, associated to the various IRs for each kx point included in the calculations, is reported; the number of sub-
blocks of a given size is in parentheses. Bidimensional and four-dimensional IRs are labeled with an asterisk and
a hash, respectively; the other ones are monodimensional.

(n,0) kx = 0 kx = 1/2 Other kx

#
(10,0) 4(4) 10(4) 14(18)* 8(1)* 14(2)* 20(1)* 28(4) 8(2) 20(2) 28(9)*
(28,0) 4(4) 10(4) 14(54)* 8(1)* 14(2)* 20(1)* 28(13)# 8(2) 20(2) 28(27)*
(40,0) 4(4) 10(4) 14(78)* 8(1)* 14(2)* 20(1)* 28(19)# 8(2) 20(2) 28(39)*

CONCLUSIONS
An efficient use of symmetry allows significant CPU and memory saving factors in SCF ab initio calculations of
both molecular and periodic systems. This is apparent for highly symmetric fullerenes and carbon nanotubes (120
and up to 1200 symmetry operators, respectively).
The cost of the integrals can be reduced by a factor of Nop (number of symmetry operators). The diagonalization
step (that can become dominant for very large unit cells) can be reduced in two ways: i) diagonalizing only at the

irreducible set of k points, and ii) using block factorization of the matrix for both the translational symmetry (BF
basis) and the point symmetry (SACO basis). Overall, the saving factor in this case can be as large as Nop 3.

255
 
g
As regards memory requirements, use of real space Fock and density matrices in the irreducible form ( F and

g
P ) represents the first important saving factor. The representation of the Fock matrix in the SACO basis rather
than in the BF (or AO, for the molecules) basis produces a second dramatic reduction in memory requirement;
calculations for relatively large tubes and fullerenes are feasible with a single-core desktop computer.

REFERENCES

1. R. Dovesi, V. R. Saunders, C. Roetti, R. Orlando, C. M. Zicovich-Wilson, F. Pascale, B. Civalleri, K. Doll, N. M.

Harrison, I. J. Bush, Ph. DArco, M. Llunell, CRYSTAL 2009 Users Manual, Torino: University of Torino, 2009.
2. R. Dovesi, Int. J. Quantum Chem. 29, 1755-1774 (1986).
3. C. M. Zicovich-Wilson, R. Dovesi, Int. J. Quantum Chem. 67, 299-309 (1998).
4. C. M. Zicovich-Wilson, R. Dovesi, Int. J. Quantum Chem. 67, 311-320 (1998).
5. H. Kroto, J. Heath, S. Obrien, R. Curl, R. Smalley, Nature 318, 162163 (1985).
6. H. Kroto, Nature 329, 529531 (1987).
7. S. Iijima, Nature 354, 56-58 (1991).
8. Y. Nol, Ph. DArco, R. Demichelis, C. M. Zicovich-Wilson, R. Dovesi, J. Comput. Chem. 31, 855862 (2010).
9. R. Demichelis, Y. Nol, Ph. DArco, M. Rrat, C. M. Zicovich-Wilson, R. Dovesi, J. Phys. Chem. C 115, 88768885
(2011).

256
 

Nanotechnology Drives a Paradigm Shift on Protein

Misfolding Diseases and Amyloidosis
Vittorio Bellottia,b and Monica Stoppinia
a
Department of Molecular Medicine-Biochemistry section A Castellani, Via Taramelli 3b, 27100 Pavia, Italy
b
Department of Medicine UCL Royal Free Hospital,Rowland Hill Street, London NW3 2PF, UK
vbellot@unipv.it & stoppini@unipv.it

Abstract. In almost a century of scientific work on the mechanism of amyloid diseases much of the attention has been
focused on the amyloid fibrils, which still represent the diagnostic hallmark of the disease and are easily identified in
affected organs for their peculiar tinctorial properties and the fibrillar shape. However, it has been lately discovered that
the seeds of the pathogenesis are deeply hidden in the structure and folding dynamics of proteins at the monomeric state
which almost indistinguishable from the normal counterpart through classical biochemical approaches. In the recent years
soluble oligomeric/prefibrillar species, putatively cytotoxic, were discovered and even more recently polymorphisms of
shape and structure of fibrils was emerging as a property that could dictate the bioactivity of amyloid as well as the
specificity of its tissue localization. Nanotechnology through the biophysical analysis of the single molecules (monomers
or oligomers or fibrils) is the propulsive disciplines in the transformation of our knowledge on the molecular mechanism
of this disease. It will provide, in the forthcoming years, precious analytical devices mimicking the biological
microenvironment where the molecular events causing the amyloid formation will be monitored and possibly modulated
in a real time frame.
Keywords: Protein Misfolding Diseases, Amyloid Fibrils, and Oligomers.
PACS: 87.14.em 87.15.Cc, 87.15.hm

INTRODUCTION
Protein misfolding diseases belong to an emerging category of diseases that are determined by abnormalities
regarding the folding parameters inscribed in what is recognized as a secondary level of the genetic code. Folding
abnormalities can be associated with diseases caused by the deprivation of a specific protein that never reaches a
functional folded structure or can be at the basis of diseases caused by intracellular or extracellular accumulation of
insoluble, abnormally aggregated proteins. Therefore, these two types of mechanisms are responsible respectively
for the lack or the gain of function detectable in "protein misfolding diseases" [1]. The diseases caused by protein
misfolding, i.e. incorrectly folded and rapidly degraded proteins, are extremely heterogeneous and their phenotype
strongly depends on the availability of molecules potentially capable of recuperating the function of the affected
protein. Diseases based on protein misfolding and loss of function are distributed over each phase of life and are
associated with genetic diseases such as cystic fibrosis in the pediatric age or diseases of adult life when, for
example, somatic mutations in proteins controlling the cell cycle, like p53, can cause cancer. Diseases induced by
protein aggregation, on the contrary, are predominantly associated with aging and a long lag phase is observed
before the first deposition occurs. However, regarding the latter thesis exist two emblematic exceptions of protein
aggregation diseases: sickle cell anemia and Z alpha-1 antitrypsin (Z A1AT) deficiency, which are associated with
protein deposition at the level of synthesizing cells and cause disease in the pediatric age. It is worth noting that both
in alpha-1 antitrypsin deficiency and sickle cell anemia, the polymerization of the pathogenic protein does not
require a massive conformational change and the folding motif of the protein in the monomeric/globular state is
recognizable also in the polymer. In amyloidosis, on the contrary, the protein polymerization is primed by partial
unfolding of the precursor that generate new molecular entity difficult to explore for its volatility, scarce
concentration and structural heterogeneity.

The history of the amyloidosis parallel with history of modern medicine and medical technology of the last
century with landmark progress is summarized in Fig.1. The discovery of fibrillar structure of amyloid, through EM,
most likely marks the first molecular characterization of the disease [2] followed by the identification of protein
constituents through amino acid sequence [3] and the genetic characterization of familial form of amyloidosis, in
primis TTR amyloidosis, through DNA sequencing [4]. The last decade of the century was characterized by three
main achievements in the elucidation of the pathogenic mechanisms of the disease: 1. the discovery of abnormalities

Theory and Applications in Computational Chemistry: The First Decade of the Second Millennium
AIP Conf. Proc. 1456, 257-261 (2012); doi: 10.1063/1.4730667
2012 American Institute of Physics 978-0-7354-1057-2/$30.00

257
 

in folding dynamics of the amyloidogenic globular proteins, 2. the identification of cytotoxic pre-fibrillar/oligomeric
aggregates and 3. the reconstruction of amyloid fibrils structure on the basis of microscopic and spectroscopic
evidences.
The progress made on these three lines were impressive and some discoveries have literally shacked well
established postulates regarding protein structure and dynamics and shed new light on the pathogenesis of the
disease. However, new fundamental questions are emerging on the molecular mechanism of the disease such as the
mechanism tissue specificity of amyloid deposition, structure and biophysical properties of fibrillar proteins and real
time monitoring the pathways of dynamic interaction between amyloid aggregates and cell membranes.
Nanotechnology appears the most appropriate approach for tackling the new highly challenging issues.



 

FIGURE 1. a) Electron microscopy of amyloid fibres (Reprinted from Nature, 183, Cohen,Calkins, Electron microscopic
observations on a fibrous component in amyloid of diverse origin, Pages 1202-3, Copyright (1959), with permission from
Nature). b) Tapping mode AFM images of natural amyloid fibrils. c) Model of TTR amyloid protofilament (Reprinted from
Structure, 4 /8, C.Blake, L.Serpell, Synchroton X-ray studies suggest that the core of the transtyretin amyloid fibril is a
continuous-sheet helix, Pages 989-98, Copyright (1996), with permission from Elsevier)

TOWARD BIO-COMPATIBLE METHODS of IN VITRO AMYLOIDOGENESIS

The possibility to elicit in vitro the amyloid polymerization of globular proteins and peptides has been a
fundamental asset for studying the conformational changes associated to the amyloidogenesis and to prove that the
super secondary structure of amyloid fibrils can be considered a generic folding motifs achievable by many more
proteins than those really involved in amyloid diseases [5]. Several methods of protein fibrillogenesis are carried out
in conditions of pH, temperature and buffer composition not compatible with the biological environment and
therefore a key question regards the conditions required for priming the conformational changes necessary to protein
fibrillogenesis in vivo. The extracellular space where fibrillogenesis occurs in vivo cannot be easily reproduced in

258
 

vitro, however nanotechnology offers the possibility to explore the role of various components that could affect the
dynamic conformational changes of proteins. The extracellular space is deeply occupied by fibrous proteins such as
elastin and collagen, which creates alternating, patches of hydrophobic and hydrophilic surfaces. The fibrous
scaffold of the interstitial space is soaked in a continuous flow of fluid driven by dynamic stresses and pressure
gradients.
The role played by surfaces and the shear stress of fluid on protein amyloidogenesis is under extensive
investigation, because both factors could be involved in mechanisms priming the misfolding and formation of
fibrils.
The effect of hydrophobic surfaces has been studied on inorganic hydrophobic surfaces like graphite. The potent
pro-amyloidogenic effect was explained by molecular dynamic simulation showing that the contact between the
surface of the graphite and the peptide through hydrophobic interactions provoked a dramatic loss of helical
structure and a significant increase of random conformation in promoting the fibrillogenesis of the Abeta peptide.
Abeta oligomers, displayed a faster and larger area of adsorption and their secondary conformation, rich in beta
structure, was maintained or even increased under the graphite adsorption [6]. The studies on the adsorption of
Abeta peptide on a prototypic hydrophobic surface, like graphite, illuminate on the rearrangement of the hydratation
surface, loss of the water interface and an effect of orientation of the amphiphilic polypeptide.
Biological macromolecules and in particular large fibrous proteins, like collagen, have large surfaces suitable for
the adsorption and orientation of amyloid proteins precursors. We have reported that collagen [7] can prime the
fibrillogenesis of human 2-microglobulin, the protein responsible in patients in haemodialysis for the selective
deposition of amyloid in bones and ligaments.
Shear forces generated by the fluid flow could also affect conformational changes of the intrinsically unstable
amyloidogenic proteins. The experiments carried out by Webster et al. [8] dissect the role of the shear stress on the
fibrillogenesis of insulin. These authors have analysed in a Taylor-Couette flow cell the conformational changes
occurring in real time on insulin along the formation of amyloid fibrils. The structural transition were monitored
through the acquisition of Raman spectra and Principal Component Analysis (PCA) and clearly showed that the
turbulent flow with a nominal shear stress on the order of 0.3 Pa can induces an helix to beta transition of secondary
structure rapidly followed by self-aggregation and formation of fibrils. Although further research is required to
understand the mechanism by which the shear stress accelerates the structural conversions it is plausible that the
fluid flow in the interstitial space [9] has similar effect and significantly contributes in vivo to protein aggregation
and deposition.

TAKING CORRECT ACCOUNT of PRE-FIBRILLAR AGGREGATES

When amyloid, prepared in vitro or extracted from ex vivo sources, is analyzed by high-resolution microscopy a
remarkable heterogeneity emerges. In particular, the Atomic Force Microscopy (AFM) highlights the presence of
oligomers presenting a globular spheroidal shape. From the first observation of Lambert et al. [10] several other
reports have confirmed that these soluble pre-fibrillar aggregates could play a prominent role in amyloid toxicity
[11]. New analytical tools complementary to AFM such as FTIR micro-spectroscopy [12] and Raman microscopy
[13, 14] could further dissect in the future the structural properties of these pre-fibrillar species. These species are
highly metastable, their kinetics of dissociation/elongation is concentration dependent and the characterization of
their structure is a highly challenging task. However, theres an urgent need to further characterize these species
because several evidences suggest that oligomers presenting apparent similar shape and size could display different
proteotoxicity [15]. The molecular characterization of the dynamic interaction between amyloid aggregates and cell
membrane has a paramount relevance for clarifying the mechanism of cell/tissues damage and tuning the molecular
targets for new more effective therapies [16]. The dynamic interaction between membranes and amyloid oligomers
was elegantly investigated by Calamai and Pavone [17] by quantum dot labeling of oligomers and tracking
fluorescence of the single particles. Through this approach they have established a link between structure and
mobility of amyloid oligomers. Amyloid oligomers, sharing similar structural features, display a common diffusive
behavior on the surface of living cells despite being formed by distinct peptides. Nevertheless, differences in
structure, even for oligomers formed by the same peptide, are reflected in significant differences in mobility These
results are consistent with the hypothesis of a common mechanism of cytotoxicity for all types of amyloids and
highlight important and still unsolved question regarding the relation between structure and pathologic function of
amyloid proteins.

259
 

NANOMECHANICS DISSECTS THE PHYSICAL PROPERTIES of FIBRILS

Amyloid fibrils represents the diagnostic hallmark of all the amyloidosis and were considered for long time as a
protein polymer having a homogeneous cross beta architecture [18] almost identical for fibrils generated from
different peptides and proteins. However, the analysis of natural amyloid fibrils by high-resolution cross-sectional
electron microscopy [19] demonstrates that each amyloidogenic protein can dictate a different supra-molecular
assembly of protofilaments in mature fibrils. Several methods of in vitro fibrillogenesis carried out on different
types of proteins and peptides in different conditions, highlight that fibrils polymorphism can be related to the
environmental conditions such metal ions, pH and interactions with ubiquitous components of fibrils such as
glycosaminoglycans and serum amyloid P component. The polymorphism in shape and assembly of fibrils can
justify the heterogeneity of pathological features observed in patients. A better characterization of the structure and
physical properties of amyloid fibrils would be extremely valuable in order to establish a structure-bioactivity
correlation for this pathological material. Knowledge on the mechanical properties of fibrils such as strength,
adhesive forces between fibrils and co-deposited materials, rigidity and maximum resistance to fibrils breaking is
essential for the interpretation of the effect of amyloid in target tissues and on mechanism of amyloid propagation.
Nanotechnology is offering new potent tools for scrutinizing nano-mechanics of isolated single fibril [20]. Dynamic
mechanical analysis (DMA) and AFM nano-indentation have been used for characterizing the physical properties of
this pathological polymer and it is worth mentioning a few main differences observed between amyloid fibrils and
other polymers. Regarding the Youngs modulus measuring stiffness of elastic material, the E value of fibrils is
similar to dragline silk (one of the most rigid proteinaceous material in nature) and much higher than elastin, cork,
leather and web capture silk. The strength of the amyloid polymers is also remarkable; for insulin fibrils a strength
of 0.6 0.4 GPa, comparable to that of steel (0.61.8 GPa). The impact on target organs of the occupancy of the
interstitial space by this inelastic and hard material is not completely clarified. The scientific community is waiting
for new scaffolds, mimicking the complexity of the interstitial space, occupied by amyloid fibrils and soaked by a
fluid flow containing soluble amyloid precursors. Such a system would represent an extremely valuable device for
discovering the reciprocal influence of each individual player in determining the severe improper function of the
interstitial space. Such devices could properly verify our hypothesis [21] suggesting that the formation of fibrils in
the interstitial space can strongly promote the formation of cytotoxic oligomers by modifying the molecular
crowding, promoting turbulence of fluid flow and offering new hydrophobic surfaces that favour the peptide
orientations and alignment of hydrophobic/hydrophilic surfaces. Such an hypothesis could probably reconcile two
apparently opposite views on the mechanism by which amyloid displays its toxicity: the first accounting all the
pathogenesis to soluble oligomers absolving fibrils, the second denying any role for oligomers and holding fibrils as
full responsible for the disease. However, clinical and pathological evidences suggest that the full expression of
amyloid diseases requires the contemporary presence of fibrils and soluble oligomers; nanotechnology can provide
in the near future proper methods to elucidate the molecular basis of the interdependence of both species in the
pathogenesis of the disease

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L. Verga, A. Rossi, M. Stoppini and V. Bellotti, J Biol Chem 283, 4912-4920 (2008).
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261
 Quantum Chemical Topology:
Knowledgeable Atoms in Peptides
Paul LA Popelier

Manchester Interdisciplinary Biocentre (MIB), 131 Princess Street, Manchester M1 7DN, Great Britain
and
School of Chemistry, University of Manchester, Oxford Road, Manchester M13 9PL, Great Britain

Abstract. The need to improve atomistic biomolecular force fields remains acute. Fortunately, the abundance of
contemporary computing power enables an overhaul of the architecture of current force fields, which typically base their
electrostatics on fixed atomic partial charges. We discuss the principles behind the electrostatics of a more realistic force
field under construction, called QCTFF. At the heart of QCTFF lies the so-called topological atom, which is a malleable
box, whose shape and electrostatics changes in response to a changing environment. This response is captured by a
machine learning method called Kriging. Kriging directly predicts each multipole moment of a given atom (i.e. the
output) from the coordinates of the nuclei surrounding this atom (i.e. the input). This procedure yields accurate
interatomic electrostatic energies, which form the basis for future-proof progress in force field design.
Keywords: Quantum Chemical Topology, Peptides, Amino Acids, Polarization, Multipole Moments, Electron Density,
Kriging, Machine Learning.
PACS: 31.15.A, 31.15.ap, 71.15.Mb, 71.15.Pd, 87.85.dq, 82.20.Wt, 82.30.Rs, 87.14.ef, 87.15.A, 31.15.-e, 34.20.-b.

INTRODUCTION
Calculating the energy of a sizeable condensed matter system very quickly is pivotal in multi-nanosecond studies
of the structure and dynamics of proteins in aqueous solution. Force fields are the only tool that can currently
achieve this goal. This situation will most likely not change in the next decade or more. Even geometry
optimisations of oligopeptides and conformational searches of smaller (drug-like) molecules still take an impractical
amount of time when carried out by standard quantum chemistry. This is why it is important to continue improving
the potentials that underpin force fields.
Ab initio energies and geometries have been used for a while in the parameterisation of force fields. The sheer
amount of ab initio data that can nowadays be routinely generated strengthens this route. Even if ab initio
calculations on a single molecule or cluster take many CPU hours at a respectable level of theory, it needs to be
done only once, at the training stage of the force field. Unfortunately, current computer power is not used to change
the architecture of routine force fields fundamentally. In particular, (atomic) partial charges still dominate
biomolecular simulation in spite of the well documented inherent limitations of this approximation, compared to the
more rigorous use of multipole moments (for a balanced and illuminating discussion see Section 7.7 in ref.1). The
deficiencies of modeling the electrostatic energy by fixed partial charges are documented even at textbook level2.
Two recent examples of force field extension or improvement show that the architecture of the electrostatic
interaction remains stagnant. For example, with the intention of increasing the reliability of the commonly used
force field AMBER3, Simmerling and coworkers proposed a new parameter set called ff99SB4. While refitting
dihedral terms to high level ab initio conformational energies the authors left the partial charges untouched. Such
modifications, while useful5, on the other hand perpetuate the inherent limitations associated with partial charges
into the increasingly larger and longer simulations of the future. A second more recent example is an extension6 of
the force field CHARMM to drug-like molecules. Here again, the dated decisions on how to model the electrostatics
were preserved.
Still, there is a general awareness (e.g.7) that further research into the electrostatic terms is warranted. For
example, in our work on allostery in the catabolite activator protein8 it turns out that varying the water potential
(within the popular TIPnP family) already leads to qualitatively different dynamic behaviour. The questionable state
of affairs in the performance of popular force fields was made abundantly clear, some time ago, in work of Stock et
al. They studied9 the conformational dynamics of trialanine, a small peptide with two peptide bonds. This
molecule has emerged as a paradigm in the study of conformational dynamics of a small peptide in aqueous

Theory and Applications in Computational Chemistry: The First Decade of the Second Millennium
AIP Conf. Proc. 1456, 262-269 (2012); doi: 10.1063/1.4732788
2012 American Institute of Physics 978-0-7354-1057-2/$30.00

262
solution, due to an exceptional amount of experimental and ab initio data. The Ramachandran probability
distribution plots from 20 ns MD simulations were qualitatively different between force fields. Indeed, even the
minor modification between AMBERs parm94 and parm96 parameterisations significantly changed the
population ratio of the conformational states. Furthermore, OPLS could not resolve PII and , and AMBER
parm94 significantly populated the  conformation. The conclusion was very disappointing, suggesting that
commonly used force fields are not capable of correctly describing the (un)folding of a peptide.
It is not the purpose of this short article to review the ongoing work of a community of scientists who continue to
produce excellent work on force field improvement. Many workers of his community, which is very small compared
to community of users of force fields, published their advances in the 2007 special issue of Journal of Chemical
Theory and Computation dedicated to polarisation10. Furthermore there is no space to review the work done so far
leading up to our own force field under construction, called QCTFF. A very recent book chapter covers this
evolution11. Instead we will outline the principles behind QCTFF and briefly discuss some very recent and as of yet
unpublished results.

METHODOLOGY AND DISCUSSION

The true predictive power of a force field depends on the reliability of the information transfer of small
molecules (or molecular clusters) to large molecules. Only if this transferability is high, a force field will make
reliable predictions. Transferability is implicit in AMBER and decided a priori, without quantum mechanical
underpinning. The concept of transferability is closely related to that of an atom type. An atom type is essentially a
transferable molecular fragment, at the scale of a single atom. In spite of the huge importance of atom typing and
transferability, there is little or no work on the quantification of transferability in the context of force field
construction. However, some time ago we carried out a systematic transferability study based on atomic multipole
moments (supplemented volume and energy), leading to the first ever computation of atom types for all natural
amino acids12-14. Investigating transferability through the electrostatic potential15 is one step closer to the goal of
assessing it through atom-atom electrostatic interaction. One case study16 looked at the transferability of atoms from
the supermolecule Ser(H2O)5 and to the corresponding atoms in the superposition of isolated constituent
molecules, i.e. gas phase serine and an isolated water pentamer. The supermolecule is thus separated into two non-
interacting fragments. The question is if one can feed a force field with data (e.g. multipole moments) from isolated
molecules and safely use these data in the ultimate context where they are needed, i.e. a hydrated amino acid.
Interestingly, this case study concluded that atoms of serine are more transferable from the isolated serine to the
supermolecule than the atoms in the water cluster are, again from the isolated cluster to the supermolecule. The
quantification of transferability needs to be re-addressed repeatedly later, in the context of the machine learning
method Kriging, as explained below.
The main idea behind QCTFF is to construct "knowledgeable" atoms. These atoms are drawn from small
molecules (e.g. amino acids capped and made to interact in order to predict properties of large molecules. They are
three-dimensional fragments of electron density, with a finite volume. These atoms have sharp boundaries, which
endows them with a "malleable" character. Their precise shape responds to the immediate environment of the
molecule they are part of. A machine learning method called Kriging then captures how these atoms change their
multipole moments in response to the positions of their neighbours. We have successfully reached the proof-of-
concept stage of this novel idea. Below we expand the details of the approach just outlined.
The force field under construction called QCTFF is thus a high-rank multipolar force field for flexible molecules,
with both intra- and intermolecular polarisation. This is crucial for molecular assembly and recognition, as well as
the realistic modelling of hydrogen bonding, which is a known problem in popular partial charge force fields. In the
long term QCTFF also aims at modeling realistically molecular systems, in the presence of the strong and
inhomogeneous electric fields caused by ions. Some promising results for cations will be published shortly.
There are three cornerstones at the heart of QCTFF:
x the definition of an atom in a molecule (or molecular cluster).
x multipole moments (to factorise the 1/r12 operator).
x machine learning to model polarisation (and charge transfer).
We now demonstrate the advantages of the technical and conceptual choices made for each cornerstone.

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 Topological Atoms
The Quantum Theory of Atoms in Molecules17 is part of Quantum Chemical Topology (QCT), a name
introduced (explanatory footnote [19] in ref 14) in 2003 and justified again later18, 19. QCT defines topological atoms
by means of the gradient vector field of the (molecular) electron density. Details of how this is done can be found in
ref.20. Figure 1 shows how QCT partitions peptide-bond capped histidine into (topological) atoms. Atoms have
finite volumes due to their sharp boundaries. They do not overlap and leave no gaps between them (i.e. they fill
space exhaustively). We have designed well-tested algorithms21-23 to obtain atomic properties as volume integrals of
property densities.

FIGURE 1. Representation of topological atoms in a conformation of histidine, which is capped by a peptide bond at both the
COOH end and the NH2 end. Each atom has a finite volume and its own multipole moments. The monopole moment is treated by
the machine learning method in the same way as the dipole moment (and higher moments). This picture is actually a snapshot of
a movie that shows how the rotation of the imidazole group deforms the (topological) atoms. These can therefore be regarded as
malleable boxes, with open boundaries of ever changing shape and which allow electronic charge to flow in or out.

There are six advantages associated with QCT partitioning:

x QCT is based on the electron density, which is measurable and at the core of Density Functional Theory; the
partitioning works regardless of the type of basis set used, even it involves diffuse Gaussians.
x The electron density describes atoms regardless of whether they participate in intra- or intermolecular
interactions. This overarching description is attractive because it allows the same machine learning
methodology (see below) to be used for both, in a fully integrated way.
x QCT eliminates the problem of the so-called polarisation catastrophe penetration (energy). Hence, there is no
need for damping functions (which are cumbersome24). Penetration energy arises from the overlap of
interacting atoms and this overlap is absent in QCT.
x QCT atoms are rooted25 in quantum mechanics, which enhances their physical meaning. QCT atoms are virial
fragments, i.e. atomic energy is well defined from the kinetic energy density.
x QCT atoms can be visually represented due to their finite shape, which provides an intuitive understanding of
complex interactions. An auxiliary conceptual advantage is the fact that their volume and atomic energy stems
from the same volume integral as that yielding the multipole moments.
x Because we abandon Rayleigh-Schrdinger perturbation theory in favour of molecular cluster partitioning,
charge transfer is treated on the same footing as dipolar (and higher rank) polarisation.

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 Multipole Moments
There is ample evidence in the literature26, 27 that point charges are inherently less accurate than multipole
moments in modelling the electrostatic interaction. Figure 2 shows two interacting oxygen atoms in glycine, each
endowed with their local axis system.
Here, there are three advantages:
x Spherical tensors are more compact (2"+1 components of rank ") than Cartesian ones (3") and have no
redundancies.
x Point multipole moments are placed only on a nuclear site. To match their accuracy, a multitude of point
charges must be positioned off the nuclear site. Because interactions between point charges are long range
(1/R), these extra point charges generate millions of extra charge-charge interactions in a protein. The extra
FLOP count introduced by multipole moments is reasonable due to their short range character.
x The multipolar expansion of QCT atoms still converges at very short range (1-3, 1-4) 28, 29.

FIGURE 2. Two atoms A and B interact electrostatically. Each atom has its own local axis system with respect to its multipole
moments are expressed. The electrostatic energy between atom A and B is given by elaborate formulae, of which qaqb/R is the
simplest, covering charge-charge interaction. Higher moments interact by higher inverse powers of R, which makes interact at
shorter range than two charges do.

The search for a magic partial charge, positioned at the nucleus, and accurate without limitation, is fruitless.
Either one must add extra charges, away from the nucleus, or introduce (point) multipole moments centered on that
nucleus. A partial charge description of an atomic charge density that aims to match a multipole moment description
mandatorily introduces more than one partial charge for each atom. The addition of extra charges increases the
number of site-site interactions that need to be evaluated during a simulation. The computation of a multipole-
multipole interaction admittedly brings about a higher number of multiplications and additions than that of a simple
charge-charge interaction. The problem is that the latter are long range and therefore distant sites still interact
considerably. Already for a 1000 atom system (which is small in biomolecular modeling), 98.8% of the
computational effort consists of evaluating charge-charge interactions compared to the bond stretch, valence and
dihedral terms, which are short range (1-n where n = 2,3,4). Hence, the proliferation of extra partial charges quickly
dominates the overall computational expense by several factors, easily up to an order of magnitude (~9 = 32 if there
are three charges rather than only one per atom, for example). Multipole-multipole interactions are short to medium
range and hence their calculation scales favourably with the number of atoms.
In this article we work with multipole moments because they guarantee an efficient and exact expression of the
electrostatic interaction energy. Moreover, a natural and rather complete framework to incorporate (electronic)
polarisation can be set up in the context of multipolar interaction. The long term goal is to create a force field that
can reliably predict the energy of peptides initially, and eventually proteins. Geometry optimisations are the next
step, made possible by analytical forces, which have been obtained in our group but not published yet.

265
 Machine learning (for polarisation and charge transfer)
It is crucial that we work with a method that can handle the complexity of configurational change in condensed
matter. Interpolation schemes with polynomial functions30 handle only low dimensional fitting spaces (3D), with
compromised accuracy appearing at 9D (e.g. CH4). Neural networks being trained on reproducing multipole
moments have been shown to become inaccurate beyond the water trimer31. A careful study32 on water clusters,
involving multi-objective optimisation and Pareto fronts, demonstrated that a machine learning method called
Kriging33 (aka Gaussian Process regression34) is the most accurate. Moreover, it is able to handle really high-
dimensional spaces (e.g. 30D). Kriging learns the mapping between an (atomic) multipole moment (output) and the
coordinates of the neighbouring atoms (input). Figure 3 illustrates this principle for ethanol35.

FIGURE 3. Schematic of how the machine learning method Kriging works. A molecule of interest (here ethanol) is distorted
around a local energy minimum by distributing energy into its normal modes. A change in nuclear positions causes a change in
the multipole moments of the oxygen atom (which we focus on here, as an example). After training on a sufficient number of
distorted molecules a Kriging model is obtained for each multipole moment of oxygen (here none in total, including monopole,
dipole and quadrupole).

In the formula of Fig.3,  is the mean of the observed values, Ntrain is the number of examples used to build the
model (typically a few hundred for any doubly capped amino acid), wi is the Kriging weight for example i (which is
computed rather than arbitrarily set), d is the number of (geometric) features (or dimensionality of the interpolation
space), and j and pj are the jth components of the Kriging vector parameters  and p.
Kriging offers four important advantages:
x The coordinates (i.e. features in machine learning language) are ranked according to importance in the
construction of the Kriging model. This provides physical insight as well as a secure way to eliminate
coordinates (feature selection).
x The performance of Kriging (in terms of interaction energies) scales linearly with the dimension of feature
space. Neural nets cannot cope with tetramer water clusters (and higher) but Kriging can.
x Kriging delivers the trained model as an analytical formula, linking the multipole moment with the cluster
coordinates. Hence, the interaction energy is analytical and can be differentiated. Hence, forces can be
computed quickly and accurately.
x The knowledge of how an environment influences an atom is stored in Kriging parameters. Hence, there is
no need to perform iterative calculations to self-consistency during a simulation (in which the polarisation
potential is used).

266
 Kriging delivers unprecedented accuracy in both intra- and intermolecular polarisation. For example, 55% of the
water pentamer configurations in an external test set of a thousand water clusters32 show an error in the total
electrostatic interaction of <4.2 kJmol-1 (~1 kcalmol-1). The performance of Kriging for intramolecular polarisation
is equally promising36. For doubly capped alanine the performance of Kriging for intramolecular polarisation is
assessed by measuring the energy error of electrostatic interaction between C only and all surrounding atoms,
which turns out to be less than 1 kJmol-1 (chemical accuracy) for 80% of a thousand test configurations of that
molecule. One should note that this Kriging training is occurring in a 60D space of features or coordinates (i.e.
Kriging input). So, in the key formula shown in Figure 3, the parameter d is set to 60. The fact that Kriging can cope
with such high-dimensional and complex spaces is pivotal in using this machine method as an instrument to study
transferability. A proper assessment of transferability will necessarily introduce large atomic environments, whose
influence will have to be studied.
In early work36 on intramolecular polarisation in doubly capped alanine, absolute total energy errors were also
assessed. These errors are severe measures of the performance all Kriging models generated for this molecule, that
is, for all the multipole moments (up to quadrupole) of all its atoms. The Kriging models for all multipole moments
of a central atom collectively predict the electrostatic interaction energy between this atom and the exact (i.e. not
predicted) multipole moments of the surrounding atoms. This is the predicted energy, which needs to be compared
with the exact energy. The latter is calculated from the exact moments of the central atom interacting with the exact
moments of the surrounding atoms. The absolute energy difference is added for each atom in the molecule. This
total error is a strict gauge because the absolute value prevents that errors can cancel each other out.
In total, 29 minima were found for the molecule on the HF/6-31G** potential energy surface. The Hartree-Fock
level was used for exploratory purposes, later to be replaced by B3LYP basis set of at least double-zeta and
augmented quality. Hartree-Fock electron densities are known to lead to bonds that are too polar. This leads in turn
to atomic charges that are too large. One can prove36 that this inadequacy exaggerates the difference between
predicted and exact energies. One thousand distorted geometries were generated over all minima together and a set
of 100 geometries was kept behind for external testing. The average absolute error in the total 14 and higher (1n,
n4) electrostatic interaction energy when predicting is 7 kJmol-1, with a maximum of 26 kJmol-1 and a minimum of
0.1 kJmol-1. The standard deviation over the test cases is 6 kJmol-1. The absolute interaction energies corresponding
to these errors range from 0.04 to 248 kJmol-1, with an average value of 83.3 kJmol-1. For the calculations described
herein, the average time to produce (22l9=198) atomic multipole moments was 140 milliseconds.
An alternative generator for a training set is sampling local environments, directly from the Protein Databank
(PDB). This provides (experimentally determined) distorted geometries. Figure 4 shows preliminary work on the
test error distribution for doubly capped serines as they occur in the PDB. A sphere centered at C and with a radius
of 3 yields 17 atoms surrounding the central carbon atom of interest. A few thousand ab initio wave functions
were obtained. The sigmoidal or S curves mark which cumulative percentage of the test geometries has an energy
error corresponding to the value where the percentile intersects the S curve. Of the three levels of theory shown
(HF/6-31G(d,p); B3LYP/apc-1 and MP2/cc-pVDZ), the MP2 level performs the best. As expected, the HF level is
the worst for the reason explained above. For MP2, 70% of the atoms are within 4 kJ mol-1, which is already quite
accurate at this preliminary stage. The very few structures with very high errors are a cause of concern and more
research is underway to attempt to move the S-curves to the left.

FIGURE 4. S curves for a test set of doubly capped serines occurring in protein crystal structures (PDB).

267
 The in-house Kriging code EREBUS, with which these results were generated, has been replaced by a new in-
house Kriging code called FEREBUS, written in FORTRAN and using the powerful NAG library for matrix
inversion and related tasks. FEREBUS operates a particle swarm algorithm37 by default, which helps in finding
selects the best possible Kriging model, according to objective of maximum likelihood. An initial test focused on N-
methylacetamide (NMA), which serves as a popular model molecule for the peptide bond. For a training set of three
hundred normal-mode-distorted geometries, 270 unseen geometries were held back for external testing. In this
problem, there are 12 atoms and hence 3l12-6=30 features. Wave functions were obtained at B3LYP/apc-1 level,
which is an excellent compromise between speed and accuracy (ignoring dispersion of course, for now).
Figure 5 shows the summary of the energy errors, which are most encouraging. The Kriging parameters p were
optimised (rather than fixed to 1 or 2), the particle swarm size was 12 and the inertia weight was set to 0.729. The
inertia weight was updated as inertia weight = (0.729/(a+1)) where a is the number of iterations where the global
best likelihood has not increased. The cognitive and social learning factors were both set to 1.494. The Kriging
parameters  were initialised in the range [0,1] for d dimensions, while the p parameters were initialised in the range
]0,2], again for d dimensions. The initial  and p velocities were set to 1.0. Some of these factors will be more
important than others, depending on the system being investigated. Systematic research on the influence of these
settings on the S-curves is in progress.
Let us note that the mean energy error was 1.5 kJmol-1, the minimum error 0.03 kJmol-1, and the maximum error
7.8 kJmol-1. Encouraging error estimates such as these inspire confidence in using the qualifier knowledgeable in
front of a topological atom equipped with Kriging models. Such a trained atom knows which multipole moments to
adopt when surrounding by a considerable number (here 11) of atoms, the exact configuration of which this atom
has never encountered before.

FIGURE 5. S curve for normal mode distorted geometries of N-methylacetamide at B3LYP/apc-1 level.

CONCLUSION
The true predictive power of a force field depends on the reliability of the information transfer of small
molecules (or molecular clusters) to large molecules. Only if this transferability is high, a force field will make
reliable predictions. The main idea behind our force field, called QCTFF, is to construct "knowledgeable" atoms.
These atoms are drawn from small molecules and made to interact in order to predict properties of large molecules.
They are 3D fragments of electron density, with a finite volume. These atoms have sharp boundaries, which endows
them with a "malleable" character. Their precise shape responds to the immediate environment of the molecule they
are part of. The powerful machine learning method Kriging then captures how these atoms change their multipole
moments in response to the positions of their neighbours. We have successfully reached the proof-of-concept stage
of this novel idea, as illustrated by the case studies discussed here.

268
 ACKNOWLEDGMENTS
Gratitude is due to present and past group members for their sustained work in the development of QCTFF. Based
on more recent contributions I thank Dr Matthew Mills for his work on the in-house energy assessment code called
NYX, Shaun Kandathil and Tim Fletcher for preparing the latest Kriging predictions for N-methylacetamide, Maria
Bailey for using the in-house software and GUI for creating the topological atoms in histidine, and Dr Yongna Yuan
for her preliminary PDB work on serine.

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269
OBITUARY
 Remembering Cesare Pisani

Born in 1938, he graduated in Physics at the University of Milano in 1963. He

spent a few years studying gas-surface interactions in ultra high vacuum both
experimentally and theoretically, rst at a company (SAES Getters), next
at the University of Torino under the direction of Prof. Franco Ricca. Since
1970, his interests moved towards the semi-empirical and ab initio simulation
of the properties of crystalline surfaces and bulk materials. His whole career
has taken place at the University of Torino, where he became full professor in
Quantum Chemistry in 1981 and was awarded the title of Emeritus Professor
in 2009.
He has always been working for promoting the ex-
tension of the powerful quantum mechanical (QM)
techniques employed in molecular quantum chem-
istry to the study of the electronic structure of solids.
Accordingly, in the mid seventies, he started with R.
Dovesi, C. Roetti and V. R. Saunders the pioneering
CRYSTAL project. The CRYSTAL computer pro-
gram, published in 1988, was for many years the only
ab initio code for periodic structures distributed to
the scientic community, and it is still one of the
most popular codes in this area of research.
The availability of a powerful tool for the solu-
tion of the Schrodinger equation for periodic systems
was also instrumental, in Pisanis scientic strategy,
for tackling the problem of local defects in crystals.
After his collaboration with Tom Grimley on this
subject he devised an original technique, based on
a combination of Green function and standard QM approach, which were
implemented by him and his collaborators in the public computer program
EMBED [6].
In the last years, he has promoted, with the group of Martin Sch utz of
the Regensburg University, the CRYSCOR project, aiming at implement-
ing rigorous post-HF treatments of electron correlation in CRYSTAL, based
on a localized representation of the HF manifold [7]. This eort represents
in a sense the completion of Pisanis career, intended to provide the scien-
tic community with computational tools for the rigorous theoretical study
of problems in solid state chemistry. His scientic contribution to compu-
tational quantum chemistry and physics is invaluable. In addition to his
outstanding professional qualities, Cesare has been a wonderful and caring
person. We owe him a debt of gratitude for his friendship and patient guid-
ance.
Roberto Dovesi
Theory and Applications in Computational Chemistry: The First Decade of the Second Millennium
AIP Conf. Proc. 1456, 273-273 (2012); doi: 10.1063/1.4730668
2012 American Institute of Physics 978-0-7354-1057-2/$30.00

273
 Remembering Bjrn O. Roos
Bjorn O. Roos was born June 28, 1937 in Malm, Sweden, and died in Lund,
Sweden, in Februry 22, 2010. He was a student of late professor Inga Fischer-
Hjalmars; in 1968 he was at the IBM Research Laboratory in San Jose California,
one of the first post-doctoral associate to Professor Enrico Clementi; in 1983 he was
named professor at the Department of Theoretical Chemistry, at the University of
Lund, Sweden. He is the author of over 300
scientific articles. Among the many honors
we recall his nomination as Member of the
Royal Swedish Academy of Science (1984)
and member of the Nobel Committee for
Chemistry (19922000). A study on the p-
electron theory is his earliest contribution to
quantum chemistry. The ab initio work
started in 1968 in California and this led in
1970 to the development of the direct
configuration interaction method (direct CI).
Early applications of the new approach
included hydrogen bonded systems (the
water dimer, malondialdehyde, etc) and
weak interactions. In 1980 the complete
active space (CAS) SCF method was
presented. Development of the methodology and computer software led to a powerful
technique for calculations on systems with a complex electronic structure. Early
applications included studies of transition metal complexes, excited states of
molecules, transition states for chemical reactions, etc. The CASSCF approach was
later extended to RASSCF (restricted active space) and was complemented with a
state interaction (RASSI) approach for the calculation of transition properties. The
CASSCF method was in 1989 supplemented with a second order perturbation
treatment of remaining electron correlation effects. Extended curriculum vitae is in
available from the International Journal Quantum Chemistry, November 2011,
Volume 111. Quoting directly from Prof. Roos, we recall that his approach has been
successfully applied to such different properties as: molecular structure,
polarisabilities and other physical properties, electronic spectroscopy of organic, bio-
organic molecules and transition metal complexes, electron affinities, etc., in most
cases yielding results of high accuracy.The computational chemistry community
always has regarded Bjrn Ross as one of his most prominent promoters and
representative leader, highly motivated, determined, tireless worker, and for many of
us a most competent collaborator and colleague, and for me a very dear friend.

Enrico Clementi
Theory and Applications in Computational Chemistry: The First Decade of the Second Millennium
AIP Conf. Proc. 1456, 274-274 (2012); doi: 10.1063/1.4730669
2012 American Institute of Physics 978-0-7354-1057-2/$30.00

274
 Remembering Eolo Scrocco
Eolo Scrocco, Emeritus Professor of Physical Chemistry
at the University of Pisa, Italy, member of the IAQMS
and of the Accademia dei Lincei was born on May 23,
1916 in Tivoli (Roma) and died in Roma on January 25,
2012. Scrocco was a student at the celebrated school of
Enrico Fermi at the University of Roma and, after world
war II, moved to Bologna where he began to work in
Molecular Physics. Professor of Physical Chemistry at the
University of Pisa since 1955, Scrocco was a prominent
scholar in the development of Physical Chemistry and, in
particular, in the application of Theoretical Chemistry to many problems of
spectroscopy, thermodynamics, and chemical reactivity. Scrocco's scientific activity
in those years coincided with the introduction of the quantum approach Physical
Chemistry in Italy as well as in the most advanced research groups all over the world.
The first calculations of Raman intensities, the prediction of vibrational frequencies
in conjugated carbonyl compounds, the definition of molecular valence, the
calculation of hydration enthalpy of metallic ions, the proposal of new Slater orbitals,
and the calculation of nuclear quadrupole coupling constants were the main
achievements of Scrocco in that time. In most of his studies he coupled theoretical
and computational approaches with experimental techniques at the state of the art
level. Later on Scrocco and his coworkers1 developed important, highly renowned,
and still topical theoretical methods and concepts, such as the electrostatic molecular
potential for predicting chemical reactivity, the demonstration of the transferability of
functional group potentials, and the electrostatic interaction model between a solute
and a solvent, describing the latter as a continuum dielectric medium. After his early
and voluntary retirement in 1979, Scrocco resumed his studies of biological
problems, a juvenile passion, merging once again theories and experiments, and
publishing papers on the structural deformation of the DNA double helix during the
first transcription stages and on plant physiology. His students and coworkers
remember him as a scientist with far reaching views, and a gifted teacher who
infected his students with his passion for science.
1
G. Alagona, R. Bonaccorsi, R. Cimiraglia, C. Ghio, M. Persico, C. Petrongolo, and J. Tomasi.

Caterina Ghio, Maurizio Persico, Carlo Petrongolo, and Jacopo Tomasi

Theory and Applications in Computational Chemistry: The First Decade of the Second Millennium
AIP Conf. Proc. 1456, 275-275 (2012); doi: 10.1063/1.4730670
2012 American Institute of Physics 978-0-7354-1057-2/$30.00

275
 AUTHOR INDEX

A F
Ferrari, A. M. 249
Adda, A. 215 Francardi, M. 241
Al-Badri, N. 223
Al-Farhan, K. 223 G
Al-Jallal, N. 223
Al-Kahtani, A. 223 Ghio, Caterina 275
Al-Qunaibit, M. 223 Gilis, Dimitri 139
Andr, Jean-Marie 1, 109 Guo, Hong 180

B H

Bellotti, Vittorio 257 Hasegawa, J. 101

Belmiloud, Y. 230 Heidarsson, Ptur O. 201
Bessrour, R. 230 Heimel, Georg 148
Businaro, L. 241 Hosni, Z. 230

C K

Cecconi, Ciro 201 Koch, Norbert 148

Clementi, Enrico 1, 5, 274 Krallafa, A. 215

D L

Dauchez, M. 215 Lazzarino, M. 241

De Angelis, F. 241 Lazzeretti, Paolo 114
De La Pierre, M. 249 Li, Xiaohu 131
Dehouck, Yves 139 Lin, Sheng H. 119
Di Fabrizio, E. 241 Liu, Wenjian 62
Diraviyam, Karthikeyan 173
Dovesi, R. 249 M
Dovesi, Roberto 273
Maitra, Rahul 81
E McCammon, J. Andrew 1, 165
Miyahara, T. 101
El-Azhary, A. A. 223 Monaco, Guglielmo 114

277
Mukherjee, Debashis 81
N Sen, Sangita 81
Nakamura, Hiroki 119
Nakashima, H. 101
Nakatsuji, H. 101
Nol, Y. 249
O T
hrn, Yngve 67
Ohtsuka, Yuhki 97
Orlando, R. 249
Ortiz, J. V. 73
P Tozzini, Valentina 187
Panecka, Joanna 207
Patrini, M. 241
Pelloni, Stefano 114
Persico, Maurizio 275
Petrongolo, Carlo 275
Popelier, Paul L. A. 262
R
Rognan, Didier 157
Rooman, Marianne 139
Salzmann, Ingo 148
Saxena, Akansha 173
278
Schatz, George C. 131
Seddiki, A. 215
Sept, David 173
Shee, Avijit 81
Sim, Hoon 173
Sinha, Debalina 81
Stoppini, Monica 257
Tangour, B. 230
Taylor, Greg 55
Ten-no, Seiichiro 97
Teranishi, Yoshiaki 119
Tomasi, Jacopo 275
Trovato, Fabio 187
Trylska, Joanna 207
W
Wang, Yi 165
Z
Zaccaria, R. Proietti 241
Zanasi, Riccardo 114
Zicovich-Wilson, C. M. 249