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Concepts and Experimental
Protocols of Modelling and
Informatics in Drug Design
Concepts and Experimental
Protocols of Modelling and
Informatics in Drug Design
Om Silakari
Department of Pharmaceutical Sciences and Drug Research,
Punjabi University, Patiala, India
Pankaj Kumar Singh

Department of Chemistry and Pharmacy, University of Sassari,
Sassari, Italy
Academic Press is an imprint of Elsevier
125 London Wall, London EC2Y 5AS, United Kingdom
525 B Street, Suite 1650, San Diego, CA 92101, United States
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Copyright © 2021 Elsevier Inc. All rights reserved.
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Notices
Knowledge and best practice in this field are constantly changing. As new research and experience broaden our
understanding, changes in research methods, professional practices, or medical treatment may become necessary.
Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any
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British Library Cataloguing-in-Publication Data

A catalogue record for this book is available from the British Library
Library of Congress Cataloging-in-Publication Data
A catalog record for this book is available from the Library of Congress
ISBN: 978-0-12-820546-4
For Information on all Academic Press publications

visit our website at https://www.elsevier.com/books-and-journals
Publisher: Stacy Masucci

Senior Acquisitions Editor: Rafael E. Teixeira
Editorial Project Manager: Sam W. Young
Production Project Manager: Niranjan Bhaskaran
Senior Cover Designer: Mark Rogers
Typeset by MPS Limited, Chennai, India
Contents
Preface................................................................................................................ xiii
Acknowledgment ................................................................................................... xv
Chapter 1: Fundamentals of molecular modeling ...................................................... 1

1.1 Molecular modeling ............................................................................................. 1
1.2 Molecular representation...................................................................................... 1
1.2.1 Cartesian coordinate ................................................................................... 2
1.2.2 Polar coordinate ......................................................................................... 3
1.2.3 Internal coordinate...................................................................................... 3
1.3 Computer graphics ............................................................................................... 3
1.4 Molecular models................................................................................................. 4
1.4.1 CPK models ............................................................................................... 4
1.4.2 Dreiding models ......................................................................................... 5
1.4.3 Computer models ....................................................................................... 6
1.5 Molecular surfaces ............................................................................................... 7
1.5.1 Van der Waals surface (VWS) ................................................................... 8
1.5.2 Solvent accessible surface .......................................................................... 8
1.5.3 Solvent excluded surface ............................................................................ 9
1.5.4 Charged partial surface area (CPSA) ........................................................ 10
1.6 Workstations....................................................................................................... 11
1.6.1 GPU hardware .......................................................................................... 11
1.7 Principles of molecular modeling...................................................................... 12
1.7.1 Molecular mechanics ................................................................................ 12
1.7.2 Molecular dynamics ................................................................................. 18
1.7.3 Quantum mechanics ................................................................................. 22
References .................................................................................................................. 25
Chapter 2: QSAR: Descriptor calculations, model generation,

validation and their application ............................................................ 29
2.1 Introduction ...................................................................................................... 29
v
vi Contents
2.2 Fundamental principle of QSAR ..................................................................... 31

2.3 QSAR methodology ......................................................................................... 32
2.3.1 Data preparation ..................................................................................... 34
2.3.2 Data analysis .......................................................................................... 37
2.3.3 Validation ............................................................................................... 39
2.4 Descriptor calculations for QSAR models ...................................................... 41
2.4.1 Types of QSAR descriptors .................................................................... 41
2.5 Development of Hansch models and their validation ..................................... 45
2.5.1 General guidelines for derivation of Hansch QSAR model ..................... 46
2.6 QSAR model generation using Free Wilson approach ................................... 47
2.6.1 Limitations.............................................................................................. 48
2.7 QSAR model generation using mixed approach ............................................. 48
2.8 3D QSAR analyses........................................................................................... 49
2.8.1 Comparative molecular field analysis (CoMFA) ..................................... 49
2.8.2 Comparative molecular similarity indices analysis, (CoMSIA) ............... 52
2.9 Conventional QSAR versus 3D-QSAR ........................................................... 54
2.10 Conclusion........................................................................................................ 54
References .................................................................................................................. 61
Chapter 3: Small molecule databases: A collection of promising

bioactive molecules .............................................................................. 65
3.1 Introduction ........................................................................................................ 65
3.2 BindingDB.......................................................................................................... 65
3.2.1 Description ............................................................................................... 66
3.2.2 Details ...................................................................................................... 66
3.3 ChEBI ................................................................................................................. 68
3.3.1 Description ............................................................................................... 69
3.3.2 Details ...................................................................................................... 69
3.4 ChemSpider ........................................................................................................ 72
3.4.1 Description ............................................................................................... 72
3.5 ChEMBL ............................................................................................................ 73
3.5.1 Description ............................................................................................... 74
3.6 ZINC................................................................................................................... 77
3.6.1 Description ............................................................................................... 77
3.6.2 Details ...................................................................................................... 78
3.7 PubChem ............................................................................................................ 79
3.7.1 Description ............................................................................................... 81
3.8 DrugBank ........................................................................................................... 82
3.8.1 Description ............................................................................................... 83
References .................................................................................................................. 86
Contents vii
Chapter 4: Database exploration: Selection and analysis of

target protein structures ..................................................................... 89
4.1 Introduction ........................................................................................................ 89
4.2 Protein databases ................................................................................................ 89
4.2.1 UniProt: the Universal Protein knowledgebase ......................................... 89
4.2.2 Research Collaboratory for Structural Bioinformatics
Protein Data Bank (RCSB PDB) .............................................................. 95
4.2.3 Binding database .................................................................................... 100
4.2.4 Therapeutic target database .................................................................... 101
References ................................................................................................................ 104
Chapter 5: Homology modeling: Developing 3D structures of target

proteins missing in databases ..............................................................107
5.1 Introduction ...................................................................................................... 107
5.2 Methodology of homology modeling .............................................................. 110
5.2.1 Template recognition and initial alignment ............................................ 111
5.2.2 Alignment correction .............................................................................. 113
5.2.3 Step 3: Backbone building ..................................................................... 113
5.2.4 Loop modeling ....................................................................................... 114
5.2.5 Side-chain modeling ............................................................................... 116
5.2.6 Ligand modeling .................................................................................... 116
5.2.7 Model optimization ................................................................................ 116
5.2.8 Model validation .................................................................................... 117
5.3 Software for homology modeling .................................................................... 118
5.3.1 Robetta ................................................................................................... 118
5.3.2 Modeller ................................................................................................. 119
5.3.3 3D-JURY ............................................................................................... 120
5.3.4 Swiss-model ........................................................................................... 120
5.4 Conclusion........................................................................................................ 121
References ................................................................................................................ 126
Chapter 6: Molecular docking analysis: Basic technique to predict

drug-receptor interactions ...................................................................131
6.1 Introduction: what is molecular docking? ....................................................... 131
6.2 Theory of docking ............................................................................................ 132
6.2.1 Sampling algorithms............................................................................... 132
6.2.2 Scoring functions ................................................................................... 135
6.3 Types of molecular docking ............................................................................ 137
6.3.1 Rigid docking: rigid ligand and rigid receptor docking .......................... 137
6.3.2 Constrained docking: flexible ligand and rigid receptor ......................... 137
viii Contents
6.3.3 Flexible docking: flexible ligand and flexible receptor docking ............. 138
6.4 Standard methodology for molecular docking ................................................ 139
6.5 Softwares available for molecular docking ..................................................... 143
6.6 Conclusion........................................................................................................ 145
References ................................................................................................................ 152
Chapter 7: Molecular dynamic simulations: Technique to analyze real-time

interactions of drug-receptor complexes ...............................................157
7.1 Introduction ...................................................................................................... 157
7.2 Principles of MD simulations .......................................................................... 158
7.2.1 Definitions.............................................................................................. 158
7.2.2 Calculating averages from a MD simulation .......................................... 159
7.2.3 Classical mechanics................................................................................ 160
7.2.4 Algorithms ............................................................................................. 163
7.3 Steps of MD simulations.................................................................................. 165
7.3.1 Initialization ........................................................................................... 165
7.3.2 Energy minimization .............................................................................. 167
7.3.3 Heating the simulation system ................................................................ 168
7.3.4 Equilibration at a constant temperature .................................................. 168
7.3.5 Production stage of MD trajectory (NVE ensemble) .............................. 168
7.4 Applications of MD simulations in drug discovery ........................................ 168
7.4.1 Identifying cryptic and allosteric binding sites ....................................... 169
7.4.2 Improving the computational identification of
small-molecule binders ........................................................................... 169
7.4.3 Advanced free-energy calculations using MD simulations ..................... 170
7.5 MD simulations: Current limitations ............................................................... 172
References ................................................................................................................ 177
Chapter 8: Water mapping: Analysis of binding site spaces

to enhance binding .............................................................................179
8.1 Introduction ...................................................................................................... 179
8.2 Thermodynamics .............................................................................................. 181
8.3 Predicting location and nature of water molecule: To be or
not to be replaced? ........................................................................................... 183
8.4 Strategies to identify cavity “waters” .............................................................. 187
8.4.1 Molecular docking.................................................................................. 187
8.4.2 Molecular dynamics ............................................................................... 189
8.4.3 Free energy calculations ......................................................................... 190
8.5 Loopholes and limitations................................................................................ 192
Contents ix
8.6 Conclusion........................................................................................................ 193

References ................................................................................................................ 197
Chapter 9: Ligand-based pharmacophore modeling: A technique utilized for

virtual screening of commercial databases ...........................................203
9.1 Introduction ...................................................................................................... 203
9.2 Methodology of pharmacophore modeling or mapping.................................. 205
9.2.1 Input: Data set preparation and conformational search ........................... 205
9.2.2 Conformational search............................................................................ 206
9.2.3 Feature extraction ................................................................................... 207
9.2.4 Pattern identification .............................................................................. 208
9.2.5 Scoring of the model .............................................................................. 209
9.2.6 Validation of pharmacophore ................................................................. 210
9.2.7 Applications of pharmacophore modeling .............................................. 211
9.3 In process determinants for quality pharmacophore modeling....................... 213
9.3.1 Molecular alignments ............................................................................. 213
9.3.2 Handling flexibility ................................................................................ 214
9.3.3 Alignment algorithms ............................................................................. 214
9.3.4 Key aspects of scoring and optimization ................................................ 215
9.4 Automated pharmacophore generation methods ............................................. 216
9.4.1 Geometry- and feature-based methods.................................................... 216
9.4.2 Field-based methods ............................................................................... 225
9.4.3 Pharmacophore fingerprints .................................................................... 226
9.4.4 ChemX/Chem Diverse, PharmPrint, OSPPREYS,
3D keys, Tuplets .................................................................................... 226
9.4.5 Other methods ........................................................................................ 227
9.5 Conclusion........................................................................................................ 230
References ................................................................................................................ 232
Chapter 10: Fragment based drug design: Connecting small substructures

for a bioactive lead .........................................................................235
10.1 Introduction .................................................................................................... 235
10.2 General strategy for fragment based drug design ......................................... 236
10.2.1 Techniques for finding fragments ....................................................... 236
10.2.2 Converting fragments into hits and leads ............................................ 239
10.2.3 Hit identification and validation.......................................................... 241
10.3 Recent advancements in FBDD techniques .................................................. 241
10.3.1 Fragment-based molecular evolutionary approach .............................. 242
10.3.2 Construction and deconstruction approach .......................................... 243
10.3.3 Computational functional group mapping ........................................... 243
x Contents
10.3.4 Multitasking computational model approach....................................... 244

10.4 Limitations...................................................................................................... 245
10.5 Conclusion...................................................................................................... 246
References ................................................................................................................ 251
Chapter 11: Scaffold hopping: An approach to improve the existing

pharmacological profile of NCEs ......................................................255
11.1 Introduction .................................................................................................... 255
11.2 Computational approaches of scaffold hopping ............................................ 256
11.2.1 Pharmacophore searching ................................................................... 257
11.2.2 Recombination of ligand fragments .................................................... 258
11.2.3 Molecular similarity method ............................................................... 260
11.3 Conclusion...................................................................................................... 261
References ................................................................................................................ 264
Chapter 12: Hotspot and binding site prediction: Strategy to target

protein protein interactions ............................................................267
12.1 Introduction .................................................................................................... 267
12.2 Protein protein binding sites ........................................................................ 268
12.3 Types of protein protein interaction regions ............................................... 269
12.4 Computational prediction of protein binding sites........................................ 269
12.4.1 Protein protein docking ..................................................................... 269
12.4.2 Binding site prediction based on the protein sequence ........................ 271
12.4.3 Binding site prediction based on the protein structure ........................ 271
12.4.4 Energy-based methods ........................................................................ 274
12.5 Hot-spot residues at protein interfaces .......................................................... 275
12.6 Prediction of hot spots in protein protein interactions ................................ 276
12.6.1 Hot-spot prediction based on the sequence ......................................... 276
12.6.2 Hot-spot prediction based on the structure .......................................... 276
12.6.3 Hot-spot prediction based on the unbound protein structure ............... 277
12.7 Conclusion...................................................................................................... 278
References ................................................................................................................ 281
Chapter 13: In-silico SNP analysis: An aid to identify novel potential

deleterious SNPs in drug targets ......................................................285
13.1 Introduction .................................................................................................... 285
13.2 Sequence-based approaches to SNP analysis ................................................ 286
13.3 Structure-based approaches to SNP analysis................................................. 286
13.4 Sequence-based prediction tools.................................................................... 287
Contents xi
13.4.1 SIFT ................................................................................................... 287

13.4.2 MAPP ................................................................................................. 288
13.4.3 PANTHER .......................................................................................... 288
13.4.4 Parepro ............................................................................................... 289
13.4.5 PhD-SNP ............................................................................................ 289
13.4.6 SNPs&GO .......................................................................................... 289
13.5 Structure-based prediction tools .................................................................... 290
13.5.1 PolyPhen............................................................................................. 290
13.5.2 SNPs3D .............................................................................................. 290
13.5.3 LS-SNP............................................................................................... 291
13.5.4 SNPeffect ........................................................................................... 292
13.5.5 SNAP.................................................................................................. 292
13.5.6 PMUT ................................................................................................. 293
13.5.7 SAPRED............................................................................................. 293
13.5.8 MutPred .............................................................................................. 294
13.5.9 MuD ................................................................................................... 294
13.6 Conclusion...................................................................................................... 295
References ................................................................................................................ 297
Chapter 14: ADMET tools: Prediction and assessment of chemical ADMET

properties of NCEs .........................................................................299
14.1 Introduction .................................................................................................... 299
14.2 Prediction of physicochemical properties...................................................... 301
14.2.1 Solubility and solubilization ............................................................... 301
14.2.2 Permeability and active transporters ................................................... 302
14.2.3 Hydrogen bonding .............................................................................. 302
14.2.4 Ionization constant (or dissociation constant)...................................... 303
14.2.5 Lipophilicity ....................................................................................... 303
14.3 Prediction of ADME and related properties.................................................. 304
14.3.1 Absorption.......................................................................................... 305
14.3.2 Bioavailability .................................................................................... 306
14.3.3 Blood brain barrier penetration ......................................................... 306
14.3.4 Transporters ....................................................................................... 307
14.3.5 Dermal and ocular penetration ........................................................... 309
14.3.6 Plasma-protein binding ....................................................................... 309
14.3.7 Volume of distribution ....................................................................... 309
14.3.8 Clearance ........................................................................................... 310
14.3.9 Metabolism ........................................................................................ 310
14.3.10 Toxicity .............................................................................................. 312
14.4 Computational tools for ADMET prediction ................................................ 314
14.5 Conclusion...................................................................................................... 315
References ................................................................................................................ 318
xii Contents
Chapter 15: Cheminformatic tools: Identify suitable synthesis procedures

to realize designed molecules ...........................................................321
15.1 Introduction .................................................................................................... 321
15.2 Strategies for computer assisted prediction of synthetic schemes ................ 322
15.2.1 Template library-based ....................................................................... 322
15.2.2 Template-free ..................................................................................... 322
15.2.3 Focused template application .............................................................. 323
15.3 Approaches to validate selected synthetic route ........................................... 324
15.3.1 Classifying reaction feasibility ............................................................ 324
15.3.2 Predicting mechanistic steps ............................................................... 325
15.3.3 Ranking templates .............................................................................. 325
15.3.4 Ranking products ................................................................................ 325
15.3.5 Generating products ............................................................................ 325
15.4 Tools developed so-far................................................................................... 326
15.5 Conclusion...................................................................................................... 330
References ................................................................................................................ 330
Chapter 16: Statistical methods and parameters: Tools to generate and

evaluate theoretical in silico models .................................................333
16.1 Introduction .................................................................................................... 333
16.2 Data analysis methods.................................................................................... 334
16.2.1 Principal components analysis (PCA) ................................................. 334
16.2.2 Cluster analysis ................................................................................... 334
16.3 Regression methods........................................................................................ 334
16.3.1 Simple regression analysis .................................................................. 335
16.3.2 Multiple linear regressions .................................................................. 336
16.3.3 Stepwise multiple linear regression ..................................................... 336
16.3.4 Principal components regression (PCR) .............................................. 336
16.3.5 Partial least square regression analysis................................................ 337
16.3.6 Genetic function approximation (GFA)............................................... 340
16.3.7 Genetic partial least squares (G/PLS) ................................................. 340
16.4 Evaluation of in silico models ....................................................................... 341
16.4.1 Internal validation ............................................................................... 341
16.4.2 External validation .............................................................................. 345
16.4.3 Virtual screening validation ................................................................ 348
16.5 Conclusion...................................................................................................... 348
References ................................................................................................................ 349
Glossary .............................................................................................................351
Index ..................................................................................................................367
Preface
The main reason for proposing a new book in the field of CADD is increasing focus of
educational institution towards molecular modeling as a key and rational approach for drug
discovery. Research scholars, undergrad students and sometimes even teachers of drug
design and medicinal chemistry do not readily find books to guide their research ideas and
CADD-based experiments. Students as well as teachers usually gain theoretical knowledge
via various books available in the market but they lack proper experimental application of
these tools. Most of the books available in libraries focus on the theoretical concepts of
computer-aided drug design and use of molecular modeling in general. Thorough
examination of such books disappoint scholars and teachers as they do not provide any
insight into the actual application of these theoretical concepts into solving research
problems. Even the books providing discussion about different softwares utilized in in-silico
analysis fail in providing the clear guidelines to a “lay-man”, to utilize them. Therefore, we
wanted to write a book that reflects on the issues faced by researchers in the practical
application of concepts of CADD, rather than a theory book on definitions and explanations
of CADD. This book will be a handbook for practical applications of different in-silico
tools available today along with various information about hardware as well as list of
softwares commonly employed in CAMM.
Of all the current trends in medicinal chemistry, CADD based studies are most common
and rationale approach. More importantly the correct utilization of such tools is important
to obtain reliable results and therefore the user, which could be anyone from an undergrad
student to a doctoral fellow, should be well-versed about the application of such tools and
techniques. Additionally, experience in solving the problem arising during performing an
analysis is necessary. We were greatly intrigued by the vast application offered by this field
and believe that researchers would benefit more from a book that provide sample exercises
in each chapter to guide an end user in practising a CAMM exercise on any and every
software package/online servers. Users can re-perform the given exercises which will help
them in understanding the correct interpretation in context of their study.
xiii
xiv Preface
Such a book can facilitate the actual application of multiple CAMM based approaches
employed in the process of drug designing. Each user who utilize a CAMM based tools do
not actually have set standard to compare his/her obtained results. This book will provide
users with a standard protocol and results which can be utilized to validate their own results
and will aid in building confidence over the obtained results.
We also kept in mind that information regarding the general principles associated with the
basic concepts of molecular modeling is also imperative for the book to become a
significant piece of literature. We aimed at an approach that would make sense and appeal
to today’s research scholars. Thus we incorporated a subsection in each chapter that
specifically understated the update in the current knowledge in each tools and technique of
this field. To avoid complexity in discussions, we have provided graphical representations
of general protocol followed in each in-silico technique for drug designing. We have
deliberately omitted detailed discussion of obscure theoretical principles and have only
focussed on simple explanations and information on how to utilize computers and artificial
intelligence in the process of drug design. This book will also help the readers in
understanding the utility of freely available software tools for the purpose of understanding
the complex process of identification of a suitable drug for a pathological condition and
their development.
Each chapter will discuss the basic protocols utilized in the process of lead identification to
optimization and finally prediction of its mechanism of action. The book will provide a set
exercise which could be utilized by the researcher to optimize and validate the tool
employed by him. Additionally this book will provide good number of exercises to UG
students (B.Pharm, B.Tech (bioinformatics), BSc (bioinformatics), BSc (biotechnology),
BSc (biochemistry)) and PG students (M.Pharm (all streams), MSc (bioinformatics)),
valuable to train them for their practical applications. Thus, this book may serve well to the
beginners of molecular modeling. It may be followed by the graduate student to gain basic
knowledge about the tools and route exercises of molecular modeling.
Acknowledgment
Authors would like to thank Dr. Bhawna Vyas, Research Associate, Department of
Chemistry, Punjabi University, Patiala, Ms. Shalki Choudhary, Senior Research Fellow,
DPSDR, Punjabi University, Patiala and Ms. Himanshu Verma, Senior Research Fellow,
DPSDR, Punjabi University, Patiala, for their providing assistance and suggestions while
compiling this book. Authors are also indebted to the supportive, and at the same time
critical, faculty members of the department of Pharmaceutical Sciences and Drug Research.
Authors would also like to acknowledge the support and guidance from Samuel Young,
Editorial Project Manager, Elsevier and Rafael Teixeira, Acquisitions Editor, Cancer
Research/Oncology, Medical Informatics/Bioinformatics, Systems Biology and Biostatistics,
Elsevier, along with other members of the editorial team at Elsevier. Finally, the time spent
on the preparation of this book was made available only with the forbearance of our
families, friends, and research groups, and we thank all of them for their patience and
understanding.
A special mention to Prof. Mario Sechi, Department of Chemistry and Pharmacy,
University of Sassari, Sassari, Italy, for his constant guidance, support and for providing an
excellent environment during the execution of this work.
xv
CHAPTER 1
Fundamentals of molecular modeling
1.1 Molecular modeling

Molecular modeling describes the generation, representation and/or manipulation of 3-D
structure of chemical and biological molecules, along with determination of physicochemical
properties that can help to interpret structural activity relationship (SAR) of the biological
molecules. Molecular modeling provides scientist with five major types of information.
a. The 3D structure of molecules
b. The chemical and physical characteristics of the molecules
c. Comparison of structure of a molecule with other different molecules
d. Visualization of complexes formed between different molecules/macromolecules
e. Prediction about how new related molecules might look
For the analysis of exponentially increasing data obtained through the introduction of automated
whole genome and protein sequencing techniques, in the early 2000s, the field of bioinformatics
emerged rapidly [1]. From the pioneering laborious mapping and comparison of protein and
gene sequences in molecular biology, via an intense phase, which to a large extent can be
viewed as ‘database mining’ and the development of efficient computer based algorithms, into a
science of its own, which today has reached a high level of maturity and sophistication. Tools
in bioinformatics are nowadays used with great success in structural biology, computational
chemistry, genetics, molecular biology, pharmaceutical industry, pharmacology and more. In
this chapter, a brief outline of the basics of molecular modeling is given, focusing on the
interfaces between medicinal chemistry, pharmacology, computational chemistry, informatics,
artificial intelligence and machine learning. This includes molecular representations, computer
graphics, molecular surfaces and their principles such as molecular mechanics/quantum
mechanics/molecular dynamics [2]. The aim is to provide a brief introduction to a vast and
rapidly growing field. In subsequent chapters, more specialized drug designing tools and
techniques are presented, that build upon the foundations given herein.
1.2 Molecular representation

One of the most basic and usually ignored component of molecular modeling study is
representation of the molecules. Since the beginning of the molecular modeling studies
Concepts and Experimental Protocols of Modelling and Informatics in Drug Design.

DOI: https://doi.org/10.1016/B978-0-12-820546-4.00001-5 1
© 2021 Elsevier Inc. All rights reserved.
2 Chapter 1
there have been several refinement in the methods utilized to represent molecules in in-
silico studies. To represent 3D structure of a molecule and electronic properties associated
with it, certain coordinate systems are required. Following coordinate system are generally
used for molecular representation.
1.2.1 Cartesian coordinate
In Cartesian coordinate system, two perpendicular lines are chosen in the plane and the
coordinates of a point are taken to be assigned as distances to the lines (Fig. 1.1A).
Similarly for 3-D representation of molecules, three perpendicular planes are chosen and
three coordinates of a point are assigned as distances to each of the planes (Fig. 1.1B).
Depending on the direction and order of the coordinate axis the system may be a right hand
or a left hand system (Fig. 1.1C) [3]. This coordinate system is important to understand the
orientation of the molecules in molecular space on computer as in Fig. 1.1B and 1.1C.
orientations of chair conformations of cyclohexane are different as their Cartesian
coordinate are different.
Figure 1.1
Coordinate system for representation of a molecule: Cartesian (A) 2D, (B) & (C) 3D and (D)
polar coordinate.
Fundamentals of molecular modeling 3
1.2.2 Polar coordinate
In this system, a point is chosen as the pole and a ray from this point is taken as
the polar axis. For a given angle θ, there is a single line through the pole whose
angle with the polar axis is θ. Then there is unique point on this line whose signed
distance from the origin is r for given number r. For a given pair of coordinates
(r, θ) there is a single point, but any point is represented by many pairs of
coordinates. For example, (r, θ), (r, θ 1 2π) and (-r, θ 1 π) are all polar coordinates
for the same point (Fig. 1.1D) [1].
1.2.3 Internal coordinate
A more chemically intuitive way of writing the coordinates is to use the internal
coordinates of a molecule (i.e. bond lengths, bond angles and torsion angles). Internal
coordinates are usually written as a Z-matrix [1]. Here is an example of a Z-matrix, for
ethene (C2H4):
Atom number Atom type Distance (Å) Bond angle ( ) Torsion angle ( )
1 C
2 C 1 1.31
3 H 1 1.07 2 121.5
4 H 1 1.07 2 121.5 3 180.0
5 H 2 1.07 1 121.5 3 180.0
6 H 2 1.07 1 121.5 4 180.0
The first line of the Z-matrix defines atom number 1 (carbon). Atom 2 is also a
carbon atom, and is at a distance of 1.31 Å from atom 1 (the approximate length of
a carbon-carbon double bond). The third column defines the atom to which the
distance in column 4 refers, i.e. atom 3 (a hydrogen) is 1.07 Å from atom 1 (the
length of the C-H bond). Similarly the atom numbers in columns 5 and 7 define
which atoms are involved in the bond angle and torsion angle (values given in
columns 6 and 8 respectively). So, for example, atom number 6 is a hydrogen. It is
1.07 Å from atom 2, the bond angle involves atoms 6-2-1, and the torsion angle is
for atoms 6-2-14. All the torsion angles are 180 , showing that the molecule is
planar. This system of coordinate is required to generate unique conformation of a
molecular system on computer screen.
1.3 Computer graphics

Computer graphics display are either vector or raster. Raster images, also known as
bitmaps, are comprised of individual pixels of color. Each color pixel contributes to the
4 Chapter 1
overall image. Raster images might be compared to pointillist paintings, which are
composed with a series of individually-colored dots of paint. Each paint dot in a pointillist
painting might represent a single pixel in a raster image. When viewed as an individual dot,
it’s just a color; but when viewed as a whole, the colored dots make up a vivid and detailed
painting. The pixels in a raster image work in the same manner, which provides rich details
and pixel-by-pixel editing. Unlike raster graphics, which are comprised of colored pixels
arranged to display an image, vector graphics are made up of paths, each with a
mathematical formula (vector) that tells the path how it is shaped and what color it is
bordered with or filled by. Since mathematical formulas dictate how the image is rendered,
vector images retain their appearance regardless of size. They can be scaled infinitely.
Vector images can be created and edited in programs such as Illustrator, CorelDraw, and
InkScape [4].
On vector displays the lines making up the image are traced on the face of the CRT. The
lines are continuous strokes and appear very straight and smooth. However only lines and
dots can be drawn on vector systems. Filled areas such as molecular surfaces, must be
represented by many closely spaced lines or dots, which adds greatly to the complexity of
the image. On raster displays, the CRT is repeatedly horizontally scanned, as on a television
screen. The image is made up of discrete pixels. Lines can appear jagged, depending on the
resolution of the CRT being used. Because of the pixels method used in raster system, filled
areas are more readily drawn on these systems than on vector systems [5].
1.4 Molecular models

The simplest types of models are CPK, dreiding models and computer models, which
provide a better way to represent molecules.
1.4.1 CPK models
CPK models are physical models in which a color coded molecular model assembly kit is
provided for representing organic molecular structures (Fig. 1.2) [6]. These models consist
of shapes comprising two basic and complementary construction units capable of being
interlocked. The basic construction units are color coded plastic tubes which can be coupled
to second basic construction units, representing the bonds between adjacent atoms. The
second basic construction units are color coded coupling spheres, according to the valency
of the atoms to be joined, the center of said coupling sphere represent atom centers. These
coupling spheres have radial arms substantially located on the surface of a sphere with the
center of the coupling unit being the center of the sphere. These units are made up of
plastic and are of two types, one type adapted for planar-trigonal coupling of three said
tubes separated by angles of about 120 and the other type adapted for tetrahedral coupling
Figure 1.2
CPK model representation of quinazoline molecule.
of four said tubes separated by angles of about 109 . Said first and second construction
units are capable of being joined together and held immobile by friction by having said
radial arms and/or the cavities of said tubes tapered so that skeletal models of complex
organic macromolecules may be assembled such that the distance between the centers of
two directly connected coupling means represents the distance between joined atoms [7].
These models give a good representation of the shape of a molecule. They can be
manipulated to produce various conformations of the molecule. But they cannot be used to
present electronic properties of molecules and they cannot be superimposed upon one
another to compare molecular conformation and shape. The bond lengths and angles cannot
be adjusted in these models.
1.4.2 Dreiding models
Dreiding models are physical models that use thin metal or plastic rods to represent
bonds [8]. Bond lengths and angles are fixed, although rotations around bonds can be easily
done. One can also demonstrate the ready conversion of one boat form into another and
then stop halfway between the two and preserve the twist form. Selection of appropriate
balls and use of rubber tubing connectors to form double bonds and C3-C4 cycloalkanes
permits construction of numerous interesting cis and trans olefins, optically active allenes,
and small ring-compounds, in some of which optical isomerism is superimposed on
geometrical isomerism. However, they give a poor representation of molecular volume and
cannot be used to show electronic properties. Depending on the complexity of the model,
they could possibly be superimposed upon one another for comparison of molecular
conformation (Fig. 1.3).
6 Chapter 1
Figure 1.3
Dreiding model representation of quinazoline molecule.
Figure 1.4
Computer model representation of ligand protein complex.
1.4.3 Computer models
Computer models can be used to draw a virtually limitless variety of molecular

representations from stick figures to molecular surfaces (Fig. 1.4). Computer graphics
models can also very readily be used to represent electronic properties of molecules. These
models can be easily superimposed and accurately constructed using any bond lengths,
angles and torsion angles. Elements are color coded and can easily be recognized on the
basis of color assignment to that particular element (Fig. 1.5).
Figure 1.5
Filled color coded computer model representation of ligand.
A disadvantage of computer models is that they are not physical, three dimensional models.
Thus computer molecular modeling tools portray images in a way that seems three
dimensional. Initially the models were drawn on cathode ray tubes (CRTs) using special
purpose computer hardware. In CRTs the images were limited to two dimension. The third
dimension was realized by rapidly displaying slightly different two dimensional images. In
this method, time was used as a parameter to represent third Cartesian dimension. This
technique is referred to as real-time graphics. Another technique used to give graphics a
three dimensional look involved drawing “in front” parts of image more brightly than parts
which are “in back”. More updated computer graphic systems such as PS350 and the silicon
graphics IRIS work station allowed to combine the techniques of real-time graphics,
stereographics and intensity depth cuing to produce a 3-D image with multiple colors.
1.5 Molecular surfaces

Molecular surface is a fundamental aspect of a structure as it is through the complementarity
of shape and chemistry of the surface that molecules interact with each other. The molecular
surface is defined as ‘the surface in contact with a probe sphere while the sphere rolls over
the surface of the molecule. More recently the increasing power of a raster graphics system
allows more complex images to be viewed interactively and this has led to the development
of many techniques for representing solid molecular surfaces (Fig. 1.6).
In modeling of a macromolecule such as protein, DNA, RNA etc. and small molecules with
biological significance, each constituent atom is considered as a simple sphere with its Van
der Waals radius. The visualization or simulations of these overlapping balls can be done
by surface mesh generation technique, where the shape quality of these overlapping balls
has a strong influence on simulation accuracy [9]. There are mainly three type of molecular
8 Chapter 1
Figure 1.6
Representation of different molecular surfaces.
surfaces that plays important role in drug designing process such as van der waals surface
(VWS), solvent-accessible surface (SAS) and solvent excluded surface (SES).
1.5.1 Van der Waals surface (VWS)
VWS simply refer to the union of all possible overlapping balls. The interactions of these
surfaces are important in various chemical and biological processes such as formation of a
tertiary structure of biopolymer, electron tunneling in protein crystals etc. The probable role
of weak VWS interactions on reaction dynamics is an issue of great concern [10]. Usually,
for the macromolecules such as proteins and nucleic acid, VWS may be buried within the
interior of the molecule. van der waal Surface bound molecules are held together by weak
attractive forces like dispersive, electrostatic, charge transfer and hydrogen bond interaction
between closed shell atoms or molecules, and molecules bound to each other by these type
of attractive forces possess low dissociation energies. The understanding of both reactive
and non-reactive dynamics in VWS complexes requires detailed information on potential
energies [11]. The VW radii of each sphere varies slightly with its covalent bonding
environment and these radii are needed for the evaluation of protein volume, interior
packing and also the packing at the protein-water interface [12].
1.5.2 Solvent accessible surface
The solvent accessible surface can be recognized as the surface created by the center of the
solvent that is regarded as a rigid sphere, when it rolls around the van der Waals surface.
This term was initially coined by Richard and Lee, when going through a study on
protein interactions [13]. They were interested in analysing the interaction of protein
with the solvent molecules to determine the hydrophobicity and folding of proteins. In
order to obtain molecular surface that a solvent could access, a probe sphere is made to
roll over the van der Waal surface, and the traces of center of the probe sphere best
describe the SAS [14]. SAS has become a common thread for most of the researchers
especially in the case of the non-polar molecules, as the free energy of aqueous solvent
is proportional to SAS, which in turn proportional to the number of solvent molecules
that are in contact to the solute molecule. Thus, SAS is a central quantity in several
solvation models used in molecular mechanics (MM) [15]. This surface can be used to
determine the amino acid environment energy which depends on an accurate and rapid
estimation of SAS. It can also be used to compute partition coefficient (logP), which is
an important parameter extensively used in studying the structural-biological activity.
Further, in molecular modeling study, the interactions of the compound with non-polar
phase can be determined by utilizing SAS information both in vitro and in vivo [16].
The constructive solid operation geometry operation can be applied for the
representation of SAS and the implicit functions underlying the molecular surface can
be defined through some steps as displayed in Fig. 1.7. The first step is sign change of
these functions, then identification of atoms and definition of function used for the map
evaluation of molecular surface and eventually the clustering of atoms. Function fSAS
(.) can be computed by adding the contribution of those atoms [(C i,Ri)]iεIζI that belong
to the sphere of center x and radius 2r, which is a constructive solid geometry
operation [17].
1.5.3 Solvent excluded surface
Solvent excluded surface (SES) is one of the most popular surface definitions in the
field of biophysics and molecular biology. It is divided into two parts i.e. contact
surface and the reentrant surface. The contact surface, as a part of the van der Waals
surface of each atom is accessible to a probe sphere of a given radius. The reentrant
surface is described as the inward-facing part of the probe sphere, while in contact with
more than one atom [13]. Later, Connolly developed the mathematical representation of
the SES for arbitrary biomolecules in terms of concave patches, saddle patches, and
concex spherical patches [18]. Among these regions, the convex contact surface
segment of the van der Waals surface possess direct contact to the solvent surrounding
the system, and the concave re-entrant surface segment in which solvent sphere has
contact with two or more atoms spheres of the structure. Cannolly representation of SES
is standard tool in molecular modeling that allows quantitative and qualitative
comparison of molecules [14]. The actual representation of solvent excluded surfaces is
displayed in Fig. 1.8.
10 Chapter 1
Figure 1.7
Steps involved defining implicit functions underlying molecular surface.
1.5.4 Charged partial surface area (CPSA)
The physical and chemical properties of charged partial surfaces (CPSAs) play important
role in specificity and selective interactions of ligand with protein. CPSAs were developed
to get the information about the molecular structure that in turn help in determining the
intermolecular interactions for QSAR. Practically, it is useful to ascertain the toxicity and
give description of local and global electrophilicity in non-covalent interactions. CPSA
descriptors have been used in distinguishing the antagonist and agonist that bind to estrogen
receptors. These descriptors also have utility in determining partial charge and
conformational changes [19]. Charged partial surfaces like hydrophilic and hydrophobic
surface area have their utility in various phenomenon related to protein adsorption. Usually,
absorption from hydrophobic surfaces is more effective than hydrophilic surface. Not only
the adsorption, but also some of the protein exchange processes occurs with more ease over
the hydrophobic surfaces than that of hydrophilic surfaces. There is a strong correlation of
Figure 1.8
Representation of molecular/solvent-excluded surface.
target selectivity with physical and chemical properties of these surfaces [20]. The
modulation in hydrophobic surface can be achieved by some of the factors, one of them is
temperature. Temperature, as one of the factor to induce exposure of hydrophobic surface
was identified by studying its effect on the chaperone activity of α-crystallin [21].
1.6 Workstations
Usually vector systems are preferred by molecular modelers because of their speed and high
quality of line drawing. Since these vector systems use special purpose hardware, they have
been more expensive than raster systems and are used as display devices separate from the
host computer which being used to store and modify molecular coordinates. However,
nowadays new computer graphic workstations have been introduced, which include raster
systems having a computer with full operating system and mass storage facility integrated
with the graphic display.
1.6.1 GPU hardware
The general purpose graphics processing unit (GPU) computational resource is very fast and
has also become very popular. It is strongly dependent on the hardware. Many computers
have GPU boards that are used mainly for graphics. To utilize the GPU for an application
program, we must uninstall the GPU graphics driver software and install CUDA, a
computer language for use with GPU. Most of the GPU-MD programs adopt CUDA for
12 Chapter 1
GPU computations. The slot number of each GPU board in the computer must be explicitly
indicated in CUDA. Every year, new GPU hardware has appear in the market with updated
CUDA version. The GPU program should be tuned up for each GPU, since the performance
of GPU programs depends on the balance of the number of GPU cores and memory-band
width. In contrast to CPUs, which are used for all application programs, the application of
GPU is quite limited. This means that the GPU is used only when the GPU programs are
available.
GPU computing is particularly suitable to run molecular dynamics simulation programs like
AMBER, Gromacs, NAMD and psygene-G/myPresto. Some of these GPU programs are
freely available. However, one of the most serious problems for end users is how to set up
the GPU machine for these MD programs. The other problem is that the system size for the
GPU computation must be larger than the minimum size that is determined by the program.
Since most GPU programs adopt a space-decomposition method for parallel computing, the
system must be decomposed into sub systems. This means that the MD of a small system
(like a single molecule) is not suitable for GPU computing.
1.7 Principles of molecular modeling

Modeling of molecules for understanding various types of molecular phenomenon related to
chemistry, biochemistry, biophysics, molecular biology, drug discovery and drug design,
pharmacogenomics, pharmacology etc. is based on calculation of different kinds of energy
associated with a molecular system. A molecular system is associated with three types of
energies i.e. potential energy, kinetic energy and quantum energy. Calculation and
application of these energies depend upon the type of work to be executed in problems
which are under consideration. Different fundamental principles have been employed to
calculate these three different kinds of molecular energies. Potential energy, kinetic energy
and quantum energy can be calculated by applying the concepts of molecular mechanics
(MM), Molecular Dynamics (MD) and Quantum Mechanics (QM) respectively. Now brief
account about these three concepts are discussed in next sections.
1.7.1 Molecular mechanics
Molecular mechanics treats the molecule as collection of atoms held together by spring.
This assumption is made to apply Newtonian’s mechanics (Huck’s law of mechanics) for
calculating potential energy of molecular system by considering atoms held together by
elastic or harmonic forces. These forces can be described by potential energy functions of
structural features (internal coordinates) like bond-length, bond-angles torsional angle and
non-bonded interactions of a molecule. Non-bonded atoms (greater than two bonds apart)
interact through van der Waals attraction, steric repulsion, and electrostatic attraction/
repulsion. Any deviation from the normal ideal values of internal coordinates while we are
drawing molecules on computer screen, accompanies with strain and leads to increase in the
potential energy. For example ideal value of bond angle of sp3 hybridized carbon in
methane is 109 28v. Deviation from this value leads to angle strain and subsequent
increase in potential energy of methane molecules. Thus every molecular system
experiences different kind of strain viz. bond strain, angle stain torsional strain and strain
due to non-bonding interactions which are contributors of the potential energy of
conformation of that molecular system. The combination of these potential energy functions
is known as ‘force field’ which can be defined as it is a set of rule to parameterize
potential energy functions of molecules. Fig. 1.9 displayed these different kind of strains
along with the formulas used to calculate corresponding energy contributions for potential
Figure 1.9
Components of potential energy in force field arise from different kind of strains produced in a
molecule of four atoms.
14 Chapter 1
energy of conformation in FF. Thus, the energy, E or Etotal of the molecules in the force
field arise due to deviations from ‘ideal’ structural features and can be approximated by a
sum of strain derived energies contributed by these deviation. This can be expressed in the
most general form as
Etotal 5 Es 1 Eb 1 EðWÞ 1 Enb 1 (1.1)
where,
Es 5 energy of a bond being stretched or compressed from its natural bond length;
Eb 5 energy of bending bond angles from their natural values
E(W) 5 torsional energy due to twisting about bonds
Enb5energy of the non-bonded interactions;
Etotal 5 Differences in energy between real molecule and a hypothetical molecule where
all structural values like bond angles, bond length, dihedral angle are exactly at their
ideal value.
The objective of molecular mechanics is to predict the energy associated with a given
conformation of a molecule. However, molecular mechanics energies have no meaning as
absolute quantities. Only differences in energy between two or more conformations have
meaning. MM models predict the energy of a molecule as a function of its conformation.
This allows predictions firstly for the equilibrium geometries and transition states and
secondly for relative energies between conformers or between different molecules.
Different kinds of force-fields have been developed over the years. Some include additional
energy terms that describe other kinds of deformations. Some force-fields account for
coupling between bending and stretching in adjacent bonds in order to improve the
accuracy of the mechanical model [22].
1.7.1.1 Energy minimization

The energy of a system can be calculated by using the molecular mechanics force field.
Most often one is interested in determining minimum energy structures. This can be done
by finding the coordinates at which the first derivatives of the potential function equals to
zero. There are numerous algorithms available for this geometry optimization. The simplest
and most straight-forward of these is the method of steepest descent. In steepest descent we
move down the gradient in a direction parallel to the net force. Steepest descent lead
directly to the nearest local minimum by following a path that is determined by moving
from previous value to a new value by some constant k times the direction in which the
energy is decreasing.
Another method is conjugate gradient method, unlike steepest descent, it utilizes
information from the previous gradients along with the current gradient to locate the
minimum. Conjugate gradient methods take the second search direction to be a linear
combination of the current gradients and the previous one. Conjugate gradient methods are
more efficient than steepest descent and require fewer energy evaluations and gradient
calculations. Conjugate gradient methods can also induce large changes in the coordinates
while searching for a minimum but the convergence characteristics are better than with
steepest descent.
Next method is the newton-raphson procedure, it is a powerful, convergent minimization
procedure. In the newton-raphson algorithm, one needs to have the second derivative matrix
available. This method is based on the assumption that the energy is quadratically
dependent i.e., it behaves like a classical spring. If the energy function were quadratic, the
increments x would lead directly to the minimum in one step. This is of course almost
never the case for the potential surface of complex biomolecules. Newton Raphson methods
do not need to do linear interpolations like conjugate gradient, so energy evaluations can be
speeded up by a factor of about 23.
The best compromise is to use the method of fletcher and powell. This algorithm combines
the advantages of steepest descent with newton-raphson and requires only the first
derivatives, but builds up the second derivatives by successive approximations. This method
is both quadratically convergent and efficient [23].
1.7.1.2 Classes of force field methods

Class I Methods: Higher order terms and cross terms. Higher accuracy, used for small or
medium sized molecules. Examples: Allinger’s MM14, EFF, and CFF.
Class II Methods: For very large molecules (e.g., proteins). Made cheaper by using only
quadratic Taylor expansions and neglecting cross terms. Examples: AMBER, CHARMM,
GROMOS, etc. Made even cheaper by using “united atoms.”
1.7.1.3 List of some important common force fields

AMBER: Assisted model building refinement, it is designated for the simulation of
peptide and nucleic acid [24].
CHARMm: Chemistry at Harvard Macromolecular Mechanics. It is used to model
macromolecular structure a protein [25].
CFF92: Consistent force field. Designated for accurate definitions of both small and
large molecules [26].
CVFF: Consistent valence force field. It is parameterized to reproduce peptide and
proteins properties [26].
ESFF: Extensible systematic force field. It is rule based force field, which is currently
under development. The goal of this force field is to provide the widest possible
coverage [27].
16 Chapter 1
MM2: Designated for small molecule and give good result for wide range of system [28].
DREIDING: A simple generic force field predicting structure and dynamics of organic,
biological and main group-inorganic molecules [29].
XED: Extended Electron Distribution. Designed to provide a more sophisticated
description of the charge distribution around a molecule.
OPLS 3: Optimized Potential for Liquid Simulations 3. It is a latest forcefield and is
designed to provide broad coverage of drug-like small molecules and proteins. It
provide nearly 2 orders of magnitude more explicitly fit torsional parameters than other
small molecule force fields.
OPLS3e: It is an improved forcefield of OPLS 3, which provide more accurate and
transferable torsional parametrization. Its performance in predicting protein 2 ligand
binding affinities is better than OPLS 3.
ReaxFF: A reactive forcefield meant for performing molecular dynamic simulations of
large scale reactive chemical system (1000s of atoms). It has Coulomb and Van der
Waal potentials to describe non-bond interactions between atoms.
Parmbsc1: It is refined forcefield for DNA simulations which is parameterized from
high-level quantum mechanical data and has been tested for nearly 100 systems i.e.
covering most of DNA structural space.
CHARMM36m: It is recent and an improved forcefield used for folded and
intrinsically disordered proteins.
AMOEBA polarizable atomic multipole force field: It has parametrization for DNA and
RNA, including the electrostatics, van der Waals, valence, and particularly torsional parameters.
1.7.1.4 List of computer programs that are predominantly used for molecular mechanics
calculations
a. Abalone: Biomolecular simulations, protein folding.
b. ADF: ReaxFF, UFF, QM-MM with Amber and Tripos force fields, DFT and semi-
empirical methods, conformational analysis with RDKit; partly GPU-accelerated.
c. ADUN: QM-MM calculations with empirical valence bond (EVB); framework based
(GNUStep-Cocoa); SCAAS for spherical boundary conditions
d. Ascalaph Designer: Molecular building (DNA, proteins, hydrocarbons, nanotubes),
molecular dynamics, GPU acceleration.
e. Automated Topology Builder (ATB): Automated molecular topology building service
for small molecules (, 99 atoms).
f. Avogadro: Molecule building, editing (peptides, small molecules, crystals),
conformational analysis, 2D/3D conversion; extensible interfaces to other tools
g. COSMOS: Hybrid QM-MM COSMOS-NMR force field with fast semi-empirical calculation
of electrostatic and/or NMR properties; 3-D graphical molecule builder and viewer
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8
In speaking of Doris, Herodotus says: Ή δὲ χώρη αὕτη ἐστὶ
μητρόπολις Δωριέων τῶν ἐν Πελοποννήσῳ. That the land had a
Dorian population in the fifth century b.c. is undoubtedly the case;
but its claim to be metropolis of the Dorians of the south was in all
probability set up by the Spartan authorities, as affording a
convenient pretext for interference in Greek affairs north of Isthmus.
It is probable that this corner of Greece, of which the Malian plain
was the centre, contained patches of various peoples which had in
different ages traversed the peninsula, or which had been driven into
its mountain fastnesses by the passage of invaders:⁠—Dorians,
Œtæans, Trachinians, etc., were probably such remains of larger
tribes.
9
Herodotus seems from his language to assume (viii. 31) that the
whole army had come south by the Dorian route. That is, either a
mistake; or, more probably, the impression his language gives is due
to a mere omission. Few details are given of any part of the route of
the army.
0
The position at Delphi, from a military point of view, is by no means
weak, provided Amphissa be occupied, and the great pass from the
north be thus closed. Under those circumstances, unless the
assailant is in a position to land troops at the head of the Krissæan
gulf, the only line of attack is along this easily defensible path from
the west. It is imaginable that Xerxes, knowing it to be an open town,
under-estimated the difficulty of its capture.
Pogon is an almost land-locked harbour between the island of
Kalauria and the mainland.
2
A Comparison of the Lists of Vessels at Artemisium and

Salamis respectively.
T. = trireme; P. = pentekonters.
Artemisium. Salamis.
{127 T.
Athenians (some Platæans in crews at
53 T. later} 180 T.
Artemisium)
180 T.
Corinthians 40 T. 40 T.
Megareans 20 T. 20 T.
Chalkidians in Athenian ships 20 T. 20 T.
Æginetans 18 T. 30 T.
Sikyonians 12 T. 15 T.
Lacedæmonians 10 T. 16 T.
Epidaurians 8 T. 10 T.
Eretrians 7 T. 7 T.
Trœzenians 5 T. 5 T.
Styreans 2 T. 2 T.
Keians 2 T.; 2 P. 2 T.; 2 P.
Opuntian Locrians 7 P. —
Hermionians — 3 T.
Ambrakiots — 7 T.
Leukadians — 3 T.
Naxians — 4 T.
Kythnians — 1 T.; 1 P.
Krotonians — 1 T.
Malians — 2 P.
Siphnians — 1 P.
Seriphians — 1 P.
366 T.;
324 T.; 9 P.
7 P.
Æschylus gives 310 as the number of the Greek fleet. Valuable as
is the testimony of the poet with regard to those incidents in the
battle which he observed as an eye-witness, his evidence on the dry
question of numbers is not likely to be exact.
3
She did, indeed, send sixty vessels, to observe, so said the patriot
Greeks, how the war went, but not with any intention of taking part
therein. The Corcyræans’ own excuse for their non-participation was
that their fleet had been unable to round Malea.
4
The mistake may be that of a manuscript copyist; but such mistakes
are so common in the text of Herodotus, that they afford strong
ground for supposing that the historian was, like the men of his time,
inaccurate in numerical calculations. The mistake may be in the
Paus. ii. 29. 5. detailed list. Pausanias implies that the Æginetan
contingent was superior in numbers to that of the
Corinthian, that is to say, more than forty. If the number were forty-
two, the total given by Herodotus would be correct; and it is
noticeable in this reference that he himself, in speaking of the
H. viii. 46. number of ships which Ægina supplied, says: “Of the
islanders the Æginetans supplied thirty; they had indeed
other ships manned; but with these they were guarding their own
country; but with the thirty best sailers they fought at Salamis.”
5
By Professor J. W. Bury.
6
Macan, Herod, iv., v., vi., “Athens and Ægina.”
7
Note on the Reference to Siris in Themistocles’ Speech.—The
reference to Siris inevitably suggests that this reported passage in
Themistocles’ speech is an invention of later date arising from the
colonization of Thurii in or about 443. The rapid growth of Athenian
trade in the earlier part of the fifth century, and its peculiar
development along the western route, render it possible, however,
that an idea of settlement on or near the deserted city of Sybaris
may have been long anterior to the actual settlement, and may have
been mooted even before 480. If Plutarch is to be believed,
Themistocles had direct relations with Corcyra, and gave the name
of Sybaris to one, and the name of Italia to the other of his daughters
(Plut. Them. 32).
8
H. viii. 74. τέλος δὲ ἐξερράγη ἐς τὸ μέσον. Cf. also Diod. xi. 16, ad
fin.
9
This Council of War must have been held on the morning of the day
preceding the battle. It lasted, in all probability, several hours, and, if
so, this would indicate the afternoon as the time at which Xerxes
received the message of Themistocles. On this point, then, the
indications in the narrative of Æschylus and Herodotus are in
agreement.
0
Plut. Them. also mentions the same name; but the testimony is
probably dependent on that of Herodotus.
There is a curious triangular concord at this point in the history.
Diodorus says that the Egyptian contingent was sent to block the
strait towards the Megarid (xi. 17).
Plutarch says 200 vessels were sent to close the passage round
Salamis (Them. 12).
Herodotus mentions that the Egyptian contingent numbered 200
(vii. 89).
2
This would account for the fact implied by Æsch. Pers. 400: the two
fleets when they started their movement were not in sight of one
another, though, very shortly after the movement began, the Persian
fleet was visible to the Greeks. The latter would first catch sight of it
after it rounded the Kynosura promontory and the island.
3
Cf. Arist. 8, where the revocation is said to have taken place τρίτῳ
ἔτει after the sentence.
4
Cf. Stein’s brief note on the translation of the words στὰς ἐπὶ τὸ
συνέδριον in H. viii. 79.
5
In so far as I know, this last very important point was first raised by
Prof. J. B. Bury in an article in the Classical Review on “Aristides at
Salamis.”
6
This is Professor Bury’s suggestion. It is open to the objection that
Herodotus expressly mentions the arrival of this vessel (H. viii. 83)
immediately before the battle began. But this objection is not by any
means insuperable. It is much more probable, under the
circumstances, that Herodotus made a mistake as to the time of its
arrival, than that it managed at the time he mentions to force its way
through the blockading fleets at either end of the strait.
7
It would seem as if it were a description of this movement, taken
from his notes on, or sources of information for, the details of the
battle, which Herodotus has used by mistake in describing the
movement of the Persian fleet during the night. He has, of course,
intensely confused the original description by reading into it what he
knew to be the object of that night-movement—the surrounding of
the Greek fleet by blocking the issues both to east and west of it; but,
eliminating this motive from his description, it is possible to see that
in its original form it must have resembled very closely the
description of the advance of the Persian fleet which has been drawn
from the details which Æschylus and Diodorus give.
H. viii. 76. “The west wing put out and made a circling movement
towards Salamis.” It has been already pointed out that by “west
wing” Herodotus evidently means, not the west wing in the original
formation, but the west wing when the fleet had completed the
movement, and had taken up the position which he imagined it to
have assumed when the movement was complete. This “west wing”
would be the east wing in the original position. That it cannot have
been the original west wing has been pointed out in a previous note.
If this correction be made, Herodotus’ language in describing this
movement is peculiarly applicable to the movement of that part of the
Persian fleet which entered the strait by the channel east of
Psyttaleia—ἀνῆγον κυκλούμενοι πρὸς τὴν Σαλαμῖνα; and the
applicability becomes still more striking in view of the evidence,
which will be given later, that this wing of the Persian fleet got in
advance of the other.
The left wing, which would use the channel west of Psyttaleia, is
equally referred to in the words: “Those about Keos and Kynosura
put out in order,” to which he adds, in accordance with his knowledge
that part of the object of the night-movement was the blocking of the
straits, “And they occupied the whole strait as far as Munychia with
their ships.”
8
This phenomenon of the morning wind is very common in the Greek
seas. It will be remembered that Phormio based his tactics in his first
battle with the Corinthian fleet just outside the Corinthian gulf on its
occurrence. I have experienced it there; and on the three occasions
on which I have been through the Strait of Salamis, once in the
summer of 1895, and twice in the summer of 1899, I have
experienced it on each occasion. It began in all three cases quite
suddenly, a little before seven in the morning, blowing from the west,
right down that part of the strait south of Ægaleos. It was extremely
violent while it lasted, though it did not raise a dangerous sea. To the
inexperienced it gave the impression that it meant the beginning of a
very windy day. On two occasions it ceased about 8.30, on the other,
shortly after nine, and the dead calm by which it had been preceded
ensued once more.
9
As is shown by the presence of an Attic vessel opposite the Persian
left, where her ships must almost certainly have been.
0
Cf. Æsch. Pers. 724,—Ναυτικὸς στρατὸς κακωθεὶς πεζὸν ὤλεσε
στρατόν. Thuc. i. 73, 5.—Νικωθεις γὰρ ταῖς ναυσίν ὡς οὐκέτι αὐτῷ
ὁμοίας οὔσης της δυνάμεως κατὰ τάχος τῷ πλέονι τοῦ στρατοῦ
ἀπεχώρησεν.
Modern historians have taken this account of the intended or
attempted construction of the mole too seriously. It has been pointed
out, for instance, that the only point in the strait east of the bay of
Eleusis at which it could possibly be carried out, is at the narrows
where the island of St. George contracts the width of the channel,
and that it is impossible that, under the circumstances as they stood,
Xerxes should have been able to bring vessels to that part of the
strait. But Herodotus never attempts to give the impression that the
operation was ever undertaken seriously; he makes it plain, indeed,
that it was not. If that were so, and it was merely designed to give
the Greeks a wrong impression, it did not in the least matter whether
it was made at a possible or impossible point. Ktesias, Pers. 26, and
Strabo, 395, say that the mole was begun before the battle. This
would imply that a serious attempt was made to construct it. The
notorious unreliability of Ktesias, and the lateness of Strabo’s
evidence, render this account of the matter unworthy of
consideration.
2
H. viii. 103. Λέγουσα γὰρ ἐπετύγχανε τὰ πὲρ᾿ αὐτὸς ἐνόεε.
3
Οὐδεμία συμφορὴ μεγάλη ἔσται σεό τε περιεόντος καὶ ἐκείνων τῶν
πρηγμάτων περὶ οἶκον τὸν σόν.
4
It has been suggested that the real intention was to induce the
Ionians to revolt. The behaviour of this contingent in the recent battle
was not calculated to encourage such a plan, conceived within a few
days of the actual fight.
5
Ἐπείτε οὐκ ἐπαύετο λέγων ταῦτα ὁ Τιμόδημος, etc.
6
May it not be suggested that some archæologist acquainted with the
extant remains of Phœnician Carthage might confer a distinct
service on history by examining the structures at Agrigentum which
date from this period? The workman as well as the designer must
have set his mark there.
7
It has already been remarked that his description of Thermopylæ is
that of a traveller coming from the north—“from Achaia”—as he
himself says.
8
Herodotus himself (ix. 8) takes this view of the matter. He implies
that the Spartans did not care whether the Athenians medized or not
after the wall was completed. It is quite out of the question, however,
to suppose that the Spartans could have regarded with equanimity
the possible transference of the Athenian fleet to the Persian side.
They had the experience of Artemisium and Salamis to guide them.
9
It is sometimes assumed from H. vii. 229, that the usual quota was
one helot to each hoplite; but a more probable interpretation of that
passage is that the reference is to the personal armed servant who
accompanied each hoplite to war, and that it cannot be deduced
therefrom that the body of these formed the whole number of the
helots present on an ordinary occasion.
Modern criticism of the impossibility of despatching so large a
force unknown to the Athenian embassy is not convincing. We do
not know the place at which it gathered. It is extremely likely that a
large number of helots were drawn from Messenia, and joined the
army at Orestheion, where the great route from Messenia meets the
route from Sparta by way of the valley of the Eurotas.
0
His departure from the Isthmus is ascribed by Herodotus to the fact
that when he was sacrificing ἐπὶ τῷ Πέρσῃ an eclipse of the sun took
place. This eclipse has been calculated to have occurred on the 2nd
of October, 480. If so, it would be about the time of the Persian
retreat from Attica after Salamis, and Stein’s conjecture that the
sacrifice had something to do with a plan to harass the Persian
retreat, has a certain amount of probability in its favour.
If Sparta had been careless as to whether Athens medized or not,
she might, probably would, have despatched troops to the Isthmus at
an earlier date. But if she was waiting until pressure of
circumstances forced Athens to adopt Peloponnesian views as to the
line of defence, then the delay is accounted for. Had her army been
at the Isthmus when Mardonius advanced into Bœotia, the
Athenians would certainly have called upon it to carry out the
agreement, and march to the northward of Kithæron. In that case the
Spartan government would have been obliged either to comply, or,
by a refusal, to show in the most unmistakeable manner possible the
war policy which it intended to adopt.
2
I was, I confess, surprised to find in August, 1899, that, in spite of
the excellent road to Megara from Bœotia by the way of Eleusis, the
track on the old line of the Platæa-Megara road is still largely used.
3
A road has been constructed through it in recent years, running from
Kriekouki on the Bœotian side to Villa on the south of the range.
4
I am inclined to think that the site of Skolos is that which Leake, and
others following him, have identified with Erythræ. Paus. ix. 4, 3,
says that if before crossing the Asopos river on the road from Platæa
to Thebes, you turned off down the stream, and went about forty
stades, i.e. four and three-quarter miles, you came to the ruins of
Skolos. This would place it not far east of the road from Thebes to
Dryoskephalæ. He speaks of Skolos in another passage as a village
of Parasopia beneath Kithæron, a rugged place, and δυσοικητός.
That seems to preclude the idea of its being near the river, which
traverses alluvial lands at this part of its course. The ruins identified
by Leake as Erythræ cannot belong to that town if the testimony of
Herodotus and Pausanias is accurately worded. This point will be
discussed in a later note. In actual fact, however, the exact site of
Skolos is very difficult to determine. My main reason for suggesting
that it stood where Leake places Erythræ is that those ruins are the
only ruins in the neighbourhood indicated by Pausanias, and are
certainly not the ruins of Erythræ.
5
It is necessary to pursue so obvious a line of argument, because, for
some incomprehensible reason, modern historians have thought it
right to judge of the plans of these able Persian commanders as
though they were dictated by no higher considerations than such as
might occur to an untutored savage.
6
The weakness of this line in case of attack from the north was
conclusively shown twenty years later in the manœuvres which led
to the battle of Tanagra.
7
It is almost certain that an ancient road from Eleusis followed the
eminently natural line taken by the modern road from Eleusis to
Eleutheræ. There was also, in all probability, a route from Athens to
Eleutheræ which did not enter Eleusis at all, but, branching from the
Sacred Way near the Rheitoi after traversing the low pass through
Mount Ægaleos, went up the Thriasian plain and joined the road
from Eleusis among the low hills of Western Attica.
8
These ridges will be found numbered 1, 2, 3, 4, 5, 6, in the
accompanying map.
9
Marked A 6 in the map.
0
Called in the map, for purposes of distinction, the Asopos ridge, the
Long ridge, and the Plateau.
Those of the streams marked A 4 and A 5 on the map.
2
During my stay at Kriekouki, in December ’92–January ’93, the
rainfall was at times extraordinarily heavy. Nevertheless, I had not on
any occasion the slightest difficulty in crossing any of the streams,
and it was not even necessary to get wet in so doing. On one
occasion also I happened to be following the line of one of the
watercourses leading to the Œroë amid a downpour of rain such as
we rarely see in England, which had been going on with more or less
continuity for the previous fourteen hours; and yet, as I descended
the brook towards the plain the water became less and less until, on
the plain, there was no water running in the stream bed.
3
Pausanias knew the roads through these two passes.
(1) Platæa-Athens road.
He says (xi. 1, 6) that Neokles, the Bœotarch, in his surprise of
Platæa in the year 374, led the Thebans οὐ τὴν εὐθεῖαν ἀπὸ τῶν
Θηβῶν τὴν πεδιάδα, τὴν δὲ ἐπὶ Ὑσιὰς ἦγε πρὸς Ἐλευθερῶν τε καὶ
τῆς Ἀττικῆς.
There will be occasion to show that Hysiæ was in all probability a
small place, on a site just outside the southernmost end of the village
of Kriekouki. It was therefore at the eastern side of the opening of
the valley through which the road from Platæa to Athens passed.
The remains of that ancient road are, however, at the other side of
the valley opening; and, therefore, Hysiæ was not upon it. Probably,
however, down the valley came a track which is still used, and which,
after passing through the village of Kriekouki, goes due north to
Thebes in a line parallel to the main road from Dryoskephalæ. This
would be the road which Pausanias here mention. It would, in
entering the valley to the pass, go close to this site of Hysiæ. Of the
identity of this site it will be necessary to speak in a later note.
In 379, after the revolution in Thebes (X. H. v. 4, 14), the Spartans
despatched Kleombrotos with a force to Bœotia. As Chabrias, with
Athenian peltasts, was guarding “the road through Eleutheræ,” he
went, κατὰ τὴν εἰς Πλαταιὰς φέρουσαν.
This is almost certainly the Platæa-Athens pass. Kleombrotos
probably did not discover that the Dryoskephalæ pass was guarded
until he got to Eleutheræ. After doing so he turned to the left and
made his way through the Platæa-Athens pass, exterminating a
small body of troops which attempted to defend it.
(2) The Platæa-Megara road.
Pausanias (ix. 2, 3) says, Τοῖς δὲ ἐκ Μεγάρων ἰοῦσι πηγή τέ ἐστιν
ἐν δεξιᾷ καὶ προελθοῦσιν ὀλίγον πέτρα· καλοῦσι δὲ τὴν μὲν
Ἀκταίωνος κοίτην.
In the previous sentence he has expressly spoken of the road from
Eleutheræ to Platæa. The Megara road is therefore a different road.
The κοὶτη Ἀκταίωνος can, I think, be determined with sufficient
certainty at the present day. It is on the top of a low cliff, probably the
πέτρα mentioned, overhanging the sources of the stream O 3. Near
the foot of the cliff is an ancient well, known in Leake’s time as the
Vergutiani Spring.
4
Ἐπὶ τῆς ὑπωρέης τοῦ Κιθαιρῶνος.
5
The site of Erythræ.
Colonel Leake identified it with certain ruins which are found at the
foot of the mountain slope several miles east of the road from
Dryoskephalæ to Thebes. The available evidence seems to me to be
strongly against this view.
(1) The traditional site is where I have placed it, though I am afraid
that but little stress can be laid on traditions in modern Greece.
(2) Its comparatively frequent mention by Greek writers seems to
indicate that, though a small place, its position was of some
importance. If Leake’s view be correct this cannot have been the
case. If it were where I believe it to have been, it would be at the
northern exit of one of the most important passes in Greece. There is
an ancient φρουρίον on the bastion of Kithæron to the east of the
site. Its remains are so scanty, however, that they do not afford any
clue as to its date.
(3) There are remains of ancient buildings on the site. There are
also remains of an ancient well, besides which is a heap of stones,
from which two stones were obtained a few years ago with
inscriptions showing them to have belonged to a temple of
Eleusinian Demeter. Pausanias mentions so many temples in the
neighbourhood dedicated to that deity, that the discovery contributes
but little to the identification of the site. I was informed at Kriekouki
last year (August, 1899) that those particular stones were known to
have been originally discovered on another site. As neither my
informant nor any one else could tell me whence, why, or by whom
they were removed, I did not place much credence in the report.
(4) Pausanias says (ix. 2, 1), Γῆς δὲ τῆς Πλαταιίδος ἐν τῶ
Κιθαιρῶνι ὀλίγον τῆς εὐθείας ἐκτραπεῖσιν ἐς δεξιὰν Ὑσιῶν καὶ
Ἐρυθρῶν ἐρείπιά ἐστι; and further on (ix. 2, 2), he says, referring to
the road of which he is speaking: αὕτη μὲν (i.e. ὅδος) ἀπ’
Ἐλευθερῶν ἐς Πλάταιαν ἄγει. The road referred to is of course the
Athens-Platæa road, on which he is travelling towards Platæa. Can
any one suppose that Pausanias would have used the expression
quoted, especially the word ὀλίγον, had the ruins of Erythræ, as
Leake conjectured, lain some three and a half miles away from the
nearest point of this road, and hidden from it, moreover, by the great
projecting bastion of Kithæron, which is shown at the south-east
corner of the accompanying map?
Leake quotes Thucydides (iii. 24), who says that the two hundred
and twelve fugitives from Platæa first took the Thebes road in order
to put their pursuers off the scent, and then turning, ᾔεσαν τὴν πρὸς
τὸ ὄρος φέρουσαν ὁδόν ἐς Ἐρύθρας καὶ Ὑσιάς, καὶ λαβόμενοι τῶν
ὀρῶν διαφεύγουσιν ἐς τὰς Ἀθήνας. Meanwhile the pursuers were
searching the road along the ὐπωρέη. This last road would lead the
pursuers near the site where I conjecture Hysiæ to have stood, and
the objection may be raised that it is unlikely that the fugitives would
have gone to a place close to the road along which they could see
the pursuers were searching for them. It is, however, to be remarked
that Thucydides does not say that they went to either Erythræ or
Hysiæ. Had he intended to imply this he would have mentioned
those places in their proper order, Hysiæ first and Erythræ second.
Whenever he refers to the actual course taken by a body of men, or
by a fleet, he invariably mentions the places touched at or arrived at
in their geographical order. Vide Th. ii. 48, 1; ii. 56, 5; ii. 69, 1; iv. 5,
2; vii. 2, 2; vii. 31, 2.
The passage seems perfectly comprehensible and in accord with
the hypothesis which I put forward with respect to the positions of
Hysiæ and Erythræ. These fugitives, turning from the Platæa-
Thebes road, took the track which in modern times leads from
Pyrgos to Kriekouki, and which in ancient times would be the road
from Thespiæ to Hysiæ, Erythræ, and the passes. They did not go to
but towards those places, making in reality for those high rugged
bastions to the north-east of the pass of Dryoskephalæ.
But, after all, Pausanias’ words in the passage quoted dispose
effectively of Colonel Leake’s site. He would not have described a
place twenty-five stades away from the road as a short distance to
the right of it.
(5) Herodotus (ix. 15) speaks of the Persian camp as ἀρξάμενον
ἀπὸ Ἐρυθρέων παρὰ Ὑσιάς, κατέτεινε δὲ ἐς τὴν Πλαταίιδα γῆν.
These words merely show that Erythræ was east of Hysiæ.
(6) Perhaps one of the strongest pieces of evidence is Herodotus’
statement that the first Greek position was “at Erythræ.” Is it
conceivable that the Greek force, especially in its then state of
feeling with regard to the Persians, would be likely, after issuing from
the pass of Dryoskephalæ, to turn east along Kithæron, leave the
pass open, and take up a position with their backs to a part of the
range through which there was no passage of retreat?
(7) We are told later that their reason for moving to their second
position was the question of water-supply. This accords with the
present state of the locality about the traditional Erythræ. The
streams in that neighbourhood have but little water in them in the dry
season.
(8) The ground in this neighbourhood accords peculiarly with the
description given by Herodotus of the first engagement.
6
Marked ridges 1, 2, 3, 4, in the map.
7
These positions will be found marked upon the accompanying map.
It is necessary, however, to explain the evidence on which they are
determined.
8
The details of the contingents given by Herodotus are:⁠—
Lacedæmonians—
Spartans 5000
Periœki 5000
Helots 35,000
Tegeans 1500
Corinthians 5000
Potidæans 300
Orchomenians (Arcadia) 600
Sikyonians 3000
Epidaurians 800
Trœzenians 1000
Lepreans 200
Mykenæans and Tirynthians 400
Phliasians 1000
Hermionians 300
Eretrians and Styreans 600
Chalkidians 400
Ambrakiots 500
Leukadians and Anaktorians 800
Paleans from Kephallenia 200
Æginetans 500
Megareans 3000
Platæans 600
Athenians 8000
Miscellaneous light-armed troops 34,500
Total 108,200
9
I.e. A 1. In the days before scientific survey there was frequently the
utmost confusion with regard to the application of names to the head
streams of main rivers. This generally took the form of applying the
name of the main stream to several of its feeders. The tendency of
the local population was to apply the well-known name to that upper
tributary which was in their immediate neighbourhood, and was
therefore best known to them. Examples of this are frequent in
England; the upper waters of the Thames are a case in point. In
early sketch maps it will be found that the name Thames is applied
with the utmost diversity to the head streams of the river, and even a
tributary so far down as the Evenlode is sometimes given the name
of the main river. This is, I fancy, what has taken place with regard to
the Asopos. The Platæans, with whom Herodotus must have come
in contact in the course of his visit to the region, called this stream, A
1, by the name of the main river, and consequently “Asopos” in
Herodotus is to be understood to mean this stream up to its junction
with the stream which comes from the west, rising not far from
Leuktra, and, after that, to refer to what is really the main river. From
Platæa itself the course of this stream is plainly traceable in the
plain, running along the western base of the Asopos ridge. The
stream coming from Leuktra is not visible, and it is quite conceivable
that Herodotus never had any definite knowledge of its existence. In
Leake’s time (vide his sketch map) the inhabitants of Kriekouki seem
to have called the stream, A 6, Asopos. It is not so called at the
present day. My own impression is, however, that Herodotus,
although he heard the Platæans speak of A 1 as the Asopos, may in
one passage refer to the stream from Leuktra with a special attribute:
τὸν Ἀσωπὸν τὸν ταύτῃ ῥέοντα (H. ix. 31). A sentence previously, at
the end of Chapter 30, he has a reference to the Asopos without any
qualification, οὗτοι μὲν νὺν ταχθέντες ἐπὶ τῷ Ἀσωπῷ
ἐστρατοπεδἐυοντο, and this reference is undoubtedly to A 1, which is
to him, as other references in his narrative show, the upper Asopos
“ordinarily so called.”
0
H. ix. 31, ad init., πυθόμενοι τοὺς Ἕλληνας εἶναι ἐν Πλαταιῇσι.
Cf. especially the mention of the Asopos and its context in Chapter
40.
2
It will be remarked that Artabazos’ statement on this point is in direct
conflict with that reported by Herodotus to have been made at the
same time by Alexander of Macedon to the Greeks.
3
It appears later (Chap. 46, ad init.) that it was to the Athenian
generals alone that Alexander’s story was in the first instance
imparted. That tends to confirm, what the lie of the ground would
suggest, that the Greek left was nearer the Asopos than the right
wing.
4
This is one of the most important passages in Herodotus’ description
of the battle. It indicates more clearly than has been hitherto
indicated, the position of the Greeks in their second position.
In the first place, if we remember that the Lacedæmonians were
on the Greek right, it will be seen that it forms a very strong
argument in favour of the identification of Gargaphia which has been
adopted. Had it been at Apotripi it would certainly have been near
the Greek centre. It also shows the obliquity of the Greek line with
respect to the course of the Asopos; in other words, that it was, as
might be expected, extended along the Asopos ridge.
5
This is shown still more clearly in the account of the withdrawal from
this position.
6
The three developments of the Greek second position may be
summed up as follows:⁠—
1. The Greek right was near the spring of Gargaphia, not on the
Asopos ridge, while the left was near the Heroön of Androkrates.
2. After a forward movement of the whole line, the right took up
position on the Asopos ridge, while the line extended along the
course of that ridge, until the left was actually on the Asopos.
3. The left, when its position on the plain became untenable, took
to the higher ground of the north extension of the Asopos ridge.
7
It would seem as if this determination were not come to at the
morning council. Their idea at that time appears to have been to
move during the night, in case the enemy did not renew their attack.
As the attack was renewed, the movement was deferred until the
following night.
8
The members of the American school at Athens who excavated
parts of the site of Platæa some years ago were inclined to believe
that at the time of the battle the town stood on the higher or southern
end of the bastion which is now strewn with the traces of the
successive towns which have occupied the site; and that it did not
extend northward to the point where the bastion sinks more or less
abruptly into the plain. They also believed that they discovered the
foundations of the temple of Hera on this north extension of the
bastion. I am disposed to think that their conjecture as to the position
of the contemporary town is correct, though the question is not of
sufficient importance with respect to this particular passage in Greek
history to render it desirable or necessary to quote the mass of
evidence on which the opinion is founded. The position of the temple
of Hera as determined by them agrees with the brief mention of it in
this passage of Herodotus.
9
Herodotus, in words already quoted, says that it was the intention of
the Greeks, on moving to the “Island,” to detach a part of the army to
relieve the attendants who were blocked in the pass. This is certainly
the Dryoskephalæ or the Platæa-Athens pass, probably the latter,
which they were attempting to use as an alternative way, after the
fearful disaster which had befallen the former provision train in the
exit of the Dryoskephalæ pass. Herodotus shows, too, that this relief
was urgently required, since the Greek army was running short of
provisions; for, although the Platæa-Megara pass must have been
open, it is of such a character as to render it impossible that the
commissariat for a force of 100,000 men could be adequately
maintained through its channel. It is therefore in the very highest
degree probable that an attempt, at any rate, was made to carry out
this part of the arrangement between the generals. Now, the Spartan
force on the right of the Greek line would be, in so far as position
was concerned, that portion of the Greek army on which this duty
would naturally devolve. The mission of this force for the relief of the
pass was one of extreme danger and difficulty, and it would be
natural that the service should devolve on that part of the army which
enjoyed the highest military reputation. It was, I venture to think,
while carrying out this movement that the Spartans became involved
in that series of events which led to the last catastrophe in the great
tragedy.
0
Thucydides (i. 20) denies that such a division or regiment existed in
the Spartan army.
Even in the Spartan army indiscipline was apt to make its
appearance without the existence of such a substantial motive as in
the present instance. Cf. the insubordination of the Spartan officers
at the battle of Mantinea in 418 b.c. (Thuc. v. 72).
2
That they never reached the rocky ὑπωρέη is plain from the
incidents of the battle that followed.
3
Of A 4 and A 5.
4
The ὑπωρέη of Herodotus.
5
Cf. the tale H. ix. 58.
6
Δρόμῳ διαβάντας τὸν Ἀσωπὸν (H. ix. 59).
7
It will be seen, when the details of the Athenian retreat come to be
examined, how noticeably this detail accords with the account which
Herodotus gives of that retreat.
8
Some modern commentators have regarded this detail mentioned by
Herodotus as a convincing proof of the Athenian bias in his narrative.
To me it seems eminently natural, after the experience of the
previous days, that Pausanias or any other commander should have
summoned help under the circumstances. I shall, moreover, have
occasion to show that the Athenians did undoubtedly diverge from
their march to the Island in the direction in which the Spartan battle
with the Persians took place.
9
It is clear from Herodotus’ subsequent account of the proceedings of
the Greek centre that this battle took place out of sight of that part of
the army which had retired to Platæa.
0
H. ix. 62: Ἤδη ἐγίνετο ἡ μάχη ἰσχυρὴ παρ’ αὐτὸ τὸ Δημήτριον.
This incidental detail mentioned by Herodotus peculiarly supports
the view that the temple must have stood on the site of the church of
St. Demetrion.
2
This is clearly shown in Herodotus’ narrative. He distinctly speaks of
the Athenians as having at the beginning of the movement “turned
down towards the plain” (H. ix. 56, κάτω τραφθέντες ἐς τὸ πεδίον);
and in a still more remarkable passage he says that, when
Mardonius led his Persians across the Asopos in pursuit of the
Greeks, “he did not see the Athenians, who had turned down
towards the plain, by reason of the (intervening) hills” (H. ix. 59). The
hills mentioned are evidently the northern extension of the Asopos
ridge.
3
A 1 in the map.
4
Ridge 5.
5
Thus far διὰ τῆς ὑπωρέης (H. ix. 69).
6
I.e. ridges 3 and 2; cf. H. ix. 69, διὰ ... τῶν κολωνῶν.
7
Ridge 5.
8
I confess I cannot understand the argument of those who regard
Herodotus’ account of Platæa as being tainted throughout with a
lying Athenian tradition. In so far as the narrative provides evidence
of its source or sources, there is at least as much matter in it which
may be attributed to Spartan as to Athenian origin.
9
The Asopos ridge, the Long ridge, and the Plateau.
0
The treatment meted out to the Æginetans in the narrative of
Platæa, as contrasted with the account which Herodotus gives of
their conduct at Salamis, points to the very various character of the
sources from which he drew his history. This part of the Platæan
narrative is undoubtedly drawn from a tradition highly coloured by
the relations which existed between Athens and Ægina twenty years
after Platæa was fought.
Xen. Anab. iii. 2, 27. The striking words are μὴ τὰ ζεύγη ἡμῶν
στρατηγῇ.
2
I have had occasion to speak of the Thermopylæ narrative under
various aspects in relation to the sources from which it is derived.
To prevent any misconception, I should like to sum up briefly my
conclusions.
(1) The whole “motivation” of the story is derived from a
version of official origin at Sparta.
(2) The incidents of the actual fighting may be derived partly
from a Spartan source, probably of an unofficial character. The
description of some of them, however, rests on information
picked up by Herodotus at Thermopylæ itself from natives of the
region.

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Concepts and Experimental Protocols

of Modelling and Informatics in Drug

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British Library Cataloguing-in-Publication Data

For Information on all Academic Press publications

Publisher: Stacy Masucci

Chapter 1: Fundamentals of molecular modeling ...................................................... 1

Chapter 2: QSAR: Descriptor calculations, model generation,

2.2 Fundamental principle of QSAR ..................................................................... 31

Chapter 3: Small molecule databases: A collection of promising

Chapter 4: Database exploration: Selection and analysis of

Chapter 5: Homology modeling: Developing 3D structures of target

Chapter 6: Molecular docking analysis: Basic technique to predict

Chapter 7: Molecular dynamic simulations: Technique to analyze real-time

Chapter 8: Water mapping: Analysis of binding site spaces

8.6 Conclusion........................................................................................................ 193

Chapter 9: Ligand-based pharmacophore modeling: A technique utilized for

Chapter 10: Fragment based drug design: Connecting small substructures

10.3.4 Multitasking computational model approach....................................... 244

Chapter 11: Scaffold hopping: An approach to improve the existing

Chapter 12: Hotspot and binding site prediction: Strategy to target

Chapter 13: In-silico SNP analysis: An aid to identify novel potential

13.4.1 SIFT ................................................................................................... 287

Chapter 14: ADMET tools: Prediction and assessment of chemical ADMET

Chapter 15: Cheminformatic tools: Identify suitable synthesis procedures

Chapter 16: Statistical methods and parameters: Tools to generate and

Fundamentals of molecular modeling

1.1 Molecular modeling

1.2 Molecular representation

Concepts and Experimental Protocols of Modelling and Informatics in Drug Design.

1.2.1 Cartesian coordinate

1.2.2 Polar coordinate

1.2.3 Internal coordinate

1.3 Computer graphics

1.4 Molecular models

1.4.1 CPK models

1.4.2 Dreiding models

1.4.3 Computer models

Computer models can be used to draw a virtually limitless variety of molecular

1.5 Molecular surfaces

1.5.1 Van der Waals surface (VWS)

1.5.2 Solvent accessible surface

1.5.3 Solvent excluded surface

1.5.4 Charged partial surface area (CPSA)

1.6.1 GPU hardware

1.7 Principles of molecular modeling

1.7.1 Molecular mechanics

1.7.1.1 Energy minimization

1.7.1.2 Classes of force field methods

1.7.1.3 List of some important common force fields

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