Synopsis and assignments
ƒ Synopsis:
Chemistry 494
Unit 1 Physics of nanoscopic systems
Molecular interactions and dynamics
Coulomb and ion-dipole interactions
ƒ Coulomb potential energy:
EP(r) ∝ q1q2/r
ƒ Almost all intermolecular interactions can be
traced back to Coulomb interactions.
ƒ The interaction between an ion with charge |z|
and a polar molecule with dipole moment µ at a
distance r is
EP(r) ∝ -|z|µ/r 2
ƒ The interaction is attractive for proper alignment
of the ion and the dipole: cations attract the
partial negative charges on the polar molecule
and anions attract the partial positive charges on
the polar molecule.
ƒ The interaction has a shorter range than the
Coulomb interaction: polar molecules need to be
almost in contact with the ion.
If we are to learn how to manipulate atoms and molecules into clusters with a
desired function, we must know a great deal about the interactions that give rise
to three-dimensional structures of molecules and to cohesion in condensed
phases. We should also know how to simulate these interactions, so we can
design new constructs before going on to synthesize them. To make progress, it
suffices to apply the concepts of classical physics to molecular systems.
ƒ Required reading:
ƒ Atkins & de Paula, Physical chemistry, Chapters 21 (Sections 21.5-21.8) and
22 (Sections 21.1-22.5).
ƒ Voet & Voet, Biochemistry, Chapter 7.
ƒ Further reading:
ƒ K.E. Drexler, Nanosystems. J. Wiley & Sons, New York (1992)
A classic text with a sophisticated treatment of the physics of nanoscopic
materials.
ƒ C.R. Cantor and P.R. Schimmel, Biophysical chemistry, part I: the
conformation of biological macromolecules. W.H. Freeman and Company,
San Francisco (1980).
Intermediate treatment of protein structure, including a thorough discussion of
molecular interactions.
Dipole-dipole interactions in solids
ƒ In solids, molecules with dipole moments tend to
align with each other, with the partial positive
charge on one molecule attracted to the partial
negative charge on another.
ƒ The interaction between polar molecules with
dipole moments µ1 and µ2 at a distance r, when
the dipoles are aligned, is
EP(r) ∝ -µ1 µ2/r 3
ƒ The interaction is attractive in solids for
alignment of dipoles.
ƒ The interaction has a shorter range than the ion-
dipole or Coulomb interaction. Polar molecules
need to be almost in contact with each other.
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 Dipole-dipole interactions in gases and liquids
ƒ In gases, the molecules are in constant motion.
ƒ The interaction between polar molecules with
dipole moments µ1 and µ2 at a distance r, when
the dipoles are rotating, is
EP(r) ∝ -µ12 µ22/r 6
ƒ The interaction is attractive, but weaker in gases
than in solids.
ƒ In liquids, the molecules also move.
ƒ The interaction is attractive, but stronger in
liquids than in gases because in liquids the
molecules are closer to each other.
Dipole-induced dipole interactions
ƒ The interaction between a polar molecule
with dipole moment µ1 and a nonpolar
molecule with polarizability α2 at a distance
r, is
EP(r) ∝ -µ12 α2/r 6
ƒ The expression above also applies to
molecules that are both polar, with each one
inducing a dipole in the other.
ƒ The interaction is weaker than dipole-dipole
interactions.
London interactions
ƒ The London interaction:
ƒ accounts for the attraction between any
pair of ground-state molecules (polar or
nonpolar).
ƒ arises from instantaneous partial charges
(instantaneous dipole moment) in one
molecule inducing partial charges
(induced dipole moment) in a neighboring
molecule.
ƒ The polarizability α of a molecule is related to
the ease of deformation of its electron cloud.
ƒ Polarizability is proportional to the total
number of electrons in the molecule.
ƒ The number of electrons in a molecule is
proportional to the molar mass, so the
polarizability is proportional to molecular
mass and size.
ƒ The interaction between molecules with
polarizabilities α1 and α2 at a distance r, is
EP(r) ∝ -α12 α22/r 6
Hydrogen bonding
ƒ A H atom, covalently bonded to either
an N, O, or F atom in one molecule, is
strongly attracted to the lone pair of
electrons on an N, O, or F atom in
another molecule.
ƒ Hydrogen bonds are strongest when
the three atoms are in a straight line.
ƒ Hydrogen bonds can exist in gases
(acetic acid), liquids (water), and solids
(ice).
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 The strengths of molecular interactions Molecular mechanics

ƒ Steric energy: the energy of interaction

between different atoms in a molecule.
ƒ Force field: a description of all
interactions that contribute to the steric
energy.
ƒ Goal of a molecular mechanics
simulation: minimize the steric energy
of the molecule.
ƒ Molecular mechanics:
ƒ gives a snapshot of the lowest
energy form of the molecule at 0 K
in vacuo,
ƒ helps in the visualization of the
conformational space of large
molecules, such as biopolymers,
ƒ is computationally “inexpensive”.
ƒ is the most limited of all computer-
aided molecular modeling routines.

The force field The force field

ƒ Bond stretching (harmonic oscillator): ƒ Bond stretching (harmonic oscillator):
Vstretch = ½ kstretch(r - re)2 Vstretch = ½ kstretch(r - re)2
r
ƒ Bond bending: ƒ Bond bending:
Vbend = ½ kbend(θ -θe)2 Vbend = ½ kbend(θ -θe)2 φ
q iq j
ƒ Bond torsion: VCoulomb = ƒ Bond torsion:
4π εr
Vtorsion = A(1 + cos nφ) Vtorsion = A(1 + cos nφ)
ƒ Electrostatic interaction: ƒ Electrostatic interaction:
q iq j q iq j
VCoulomb = VCoulomb = Vtorsion = A (1 + cos nφ)
4π εr 4π εr
ƒ Dispersive interactions ƒ Dispersive interactions
(Lennard-Jones): (Lennard-Jones):
C D C D
VLJ = 12 − 6 VLJ = 12 − 6
r r r r
ƒ Hydrogen-bonding: ƒ Hydrogen-bonding:
E F E F
VH bonding = 12 − 10 VH bonding = 12 − 10
r r r r
ƒ Steric energy: ƒ Steric energy:
V = Vstretch + Vbend + Vtorsion + VCoulomb V = Vstretch + Vbend + Vtorsion + VCoulomb φ
+ VLJ + VHbonding + VLJ + VHbonding

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 The force field The force field
ƒ Bond stretching (harmonic oscillator): ƒ Bond stretching (harmonic oscillator):
Vstretch = ½ kstretch(r - re)2 Vstretch = ½ kstretch(r - re)2
ƒ Bond bending: ƒ Bond bending:
Vbend = ½ kbend(θ -θe)2 Vbend = ½ kbend(θ -θe)2
ƒ Bond torsion: ƒ Bond torsion:
Vtorsion = A(1 + cos nφ) Vtorsion = A(1 + cos nφ)
ƒ Electrostatic interaction: ƒ Electrostatic interaction:
q iq j q iq j
VCoulomb = VCoulomb =
4π εr 4π εr
ƒ Dispersive interactions ƒ Dispersive interactions
(Lennard-Jones): (Lennard-Jones):
C D r C D
VLJ = 12 − 6 VLJ = 12 − 6
r r r r
ƒ Hydrogen-bonding: ƒ Hydrogen-bonding:
E F E F
VH bonding = 12 − 10 VH bonding = 12 − 10
r r r r
ƒ Steric energy: ƒ Steric energy:
V = Vstretch + Vbend + Vtorsion + VCoulomb V = Vstretch + Vbend + Vtorsion + VCoulomb
+ VLJ + VHbonding + VLJ + VHbonding

Polypeptides Conformational analysis of polypeptides

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 Helices Sheets

Molecular dynamics Principles of molecular dynamics calculations

ƒ Molecular mechanics freezes the molecule at 0 K, an unrealistic situation.
ƒ For very complex molecules the optimization algorithm may yield only a local ƒ In general,
minimum of the potential energy surface. dV dv
ƒ Molecular dynamics: − = F = ma = m
dx dt
ƒ calculates motions of atoms at T > 0 K by integrating Newton’s equations of
motion. ƒ At time t,
ƒ estimates “best structures” sampled by the molecule at a given temperature. ∆x ∆v
v1 = , a1 = = m −1F1
ƒ Molecular motions: ∆t ∆t
ƒ Local motions (0.001 to 0.5 nm, 10-15 to 10-1 s):
ƒ atomic fluctuations, ƒ The particle continues to move:
ƒ sidechain motions, x 2 = x1 + v1∆t
ƒ loop motions, dV ( x )
ƒ terminal arm motions. v 2 = v1 + a1∆t = v1 + m −1F1∆t = v1 − m −1 ∆t
ƒ Rigid body motions (0.1 to 1 nm, 10-9 to 1 s): dx x1
ƒ helix motions, ƒ In general,
ƒ domain motions,
dV ( x )
ƒ subunit motions. xi = xi−1 + v i−1∆t v i = v i−1 − m −1 ∆t
ƒ Large scale motions (> 0.5 nm, 10-7 to 104 s): d x x i −1
ƒ folding/unfolding transitions,
ƒ dissociation/association of large structures.

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 Molecular dynamics calculations Special techniques in molecular dynamics simulations

ƒ The initial positions result from a molecular mechanics calculation
(T = 0 K).
ƒ The initial velocities are selected randomly from the Maxwell-Boltzmann
distribution.
ƒ Heating times of 1 ps are appropriate.
ƒ The potential energy function V(x) is given by the force field also used in
molecular mechanics calculations.
ƒ The procedure discussed above is used to integrate the equations of motion by
one of many numerical methods.
ƒ Simulation:
ƒ A time step of 0.5-2.0 fs ascertains that all aspects of molecular motion are
sampled correctly.
ƒ Large molecules have a broad range of vibrational frequencies. To make
sure that at least one full period of low-frequency oscillations is sampled,
the simulation time should be at least 10 ps.
ƒ Quenched dynamics:
ƒ Supply enough thermal energy to overcome conformational barriers,
thereby breaking away from local minima.
ƒ The molecule can "visit" many low-energy conformations that are
indicative of the structures available to the molecule at a given
temperature.
ƒ A collection of these low-energy structures is called the conformational
space of the molecule. One of the structures in this space corresponds to
the global minimum.
ƒ Annealing:
ƒ To determine accurate geometries in the conformational space, it is
typical to cool high-temperature structures back to 0 K at the end of the
simulation.
ƒ In many cases, this procedure leads to the discovery of even more low-
energy structures.

Ethane Alanine dipeptide

Alanine dipeptide (heated to 500 K

then cooled to 0 K)
φ = -144o, ψ = +66o

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 Monte Carlo simulations

ƒ Atoms are moved through small but otherwise random distances, and the change
in steric energy, ∆V, is calculated.
ƒ If the steric energy is not greater than before the change, then the conformation
is accepted.
ƒ If the steric energy is greater than before the change, check if the new
conformation is reasonable and can exist in equilibrium with structures of lower
conformational energy at the temperature of the simulation.
ƒ Use the Boltzmann distribution:
ratio of populations of two states ∝ e-∆V/kT
ƒ Because in this case ∆V > 0, the exponential factor varies between 0 and 1
and is compared with a random number between 0 and 1:
ƒ if the factor is larger than the random number, the conformation is
accepted;
ƒ if the factor is not larger, the conformation is rejected.
ƒ Molecular dynamics and Monte Carlo simulations are fast.