Molecular Modelling PRINCIPLES AND APPLICATIONS Second edition Andrew R. Leach Glaxo Wellcome Research and Development An ingnt of Pearson Education Harlow, Engiand Londen New York Reading, Massachusetts San Francisco Toronto Don Mills, Ontano Sydney Tokyo Singapore Hong Kang Seoul Taipe! Cape Town Madiid Mexico City Amsterdam « Munich Paris MianPearson Education Limited Edinburgh Gate Harlow Essex CM20 2)E England and Associated Companies around the world Visit us om the World Wide Web at owe poarsoneduc com First published under the Longman imprint 1996 Second edition 2001 © Pearson Education Limited 1996, 2001 The right of Andrew R Leach to be identified as the author of this Work has been asserted by him in accordance with the Copyright, Designs and Patents Act 1988 Allrights reserved. No part of this publication may be reproduced, stored ina retrieval system, or transmitted in any form or by any means, electronic, mechaneal, photocopying, recording or otherwise without either the prior written permission of the publisher or a licence permitting restricted copying in the United Kingdom issued by the Copyright Licensing Agency Ltd, 90 Tottenham Court Road, London W1P OLP. ISBN 0-582-38210-6 British Library Cataloguing-in-Publication Data ‘A catalogue record for this book can be obtained from the British Library Library of Congress Cataioging-in-Publication Data Leach, Andrew R, Molecular modelling principles and applications / Andrew R. Leach. - 2nd ed pcm. Includes bibliographical references and index ISBN 0-582-38210-6 1 Molecular structure-Computer simulation 2 Molecuies-Models-Computer simulation |. Title Q1480,L43 2001 541 2'0113-de21 987654321 05 04 03 02 OL ‘Top righthand cover image © American Institute of Physics ‘Typeset by 60 Printed in Great Britain by Henry Ling Ltd, at the Dorset Press, Dorchester, DorsetContents Preface to the Second Edition Preface to the First Edition Symbols and Physical Constants Acknowledgements 1 Useful Concepts in Molecular Modeling 1.1 Intreduction 1.2 Coordinate Systems 13 Potential Energy Surfaces 1.4 Molecular Graphics 15 Surfaces 1.6 Computer Hardware and Software 17 Units of Length and Energy 18 The Molecular Modelling Literature 1.9 The Internet 110 Mathematical Concepts Further Reading References 2 An Introduction to Computational Quantum Mechanics 21 22 23 Introduction One-electron Atoms Polyelectronic Atoms and Molecules Molecular Orbital Calculations The Hartree-Fock Equations Basis Sets Calculating Molecular Properties Using ab initio Quantum Mechanics Approximate Molecular Orbital Theories Semi-empirical Methods Hiickel Theory Performance of Semi-empirical Methods Appendix 2.1 Some Common Acronyms Used in Computational Quantum Chemistry Further Reading References Seoomauenee 24 24vill 3 Advanced ab initio Methods, Density Functional Theory and Solid-state Quantum Mechanics 31 3.2 33 B34 3.5 3.6 37 38 39 Introduction Open-shell Systems Electron Correlation Practical Considerations When Performing ab initio Calculations Energy Component Analysis Valence Bond Theories Density Functional Theory Quantum Mechanical Methods for Studying the Solid State The Future Role of Quantum Mechanics: Theory and Experiment Working Together Appendix 3.1 Altemative Expression for a Wavefunction Satisfying Bloch’s Function Further Reading References 4 Empirical Force Field Models: Molecular Mechanics 4A 42 43 44 45 4.23 Introduction Some General Features of Molecular Mechanics Force Fields Bond Stretching Angle Bending Torsional Terms Improper Torsions and Out-of-plane Bending Motions Cross Terms: Class 1, 2 and 3 Force Fields Introduction to Non-bonded Interactions Electrostatic Interactions Van der Waals Interactions Many-body Effects in Empirical Potentials Effective Pair Potentials Hydrogen Bonding in Molecular Mechanics Force Field Models for the Simulation of Liquid Water United Atom Force Fields and Reduced Representations Derivatives of the Mclecular Mechanics Energy Function Calculating Thermodynamic Properties Using a Force Field Force Field Parametrisation ‘Transferability of Force Field Parameters The Treatment of Delocalised Systems Force Fields for Inorganic Molecules Force Fields for Solid-state Systems Empirical Potentials for Metals and Semiconductors Appendix 4.1 The Interaction Between Two Drude Molecules Further Reading References Contents 160 lel 161 162 216 231 233 236 240 246 247 247Contents 5 Energy Minimisation and Related Methods for Exploring the Energy Surface 5.1 introduction 5.2 Non-derivative Minimisation Methods 5.3 Introduction to Derivative Minimisation Methods 54 First-order Minimisation Methods 55 Second Derivative Methods: The Newton-Raphson Method 5.6 Quasi-Newton Methods 5.7 Which Minimisation Method Should | Use? 5.8 Applications of Energy Minimisation 5.9 Determination of Transition Structures and Reaction Pathways 5.10 Solid-state Systems: Lattice Statics and Lattice Dynamics Further Reading References 6 Computer Simulation Methods 6.1 Introduction 6.2 Calculation of Simple Thermodynamic Properties 6.3 Phase Space 64 Practical Aspects of Computer Simulation 6.5 Boundaries 6.6 — Monitoring the Equilibration 67 Trancating the Potential and the Minimum Image Convention 68 — Long-range Forces 69 — Analysing the Results of a Simulation and Estimating Errors Appendix 6.1 Basic Statistical Mechanics Appendix 6.2. Heat Capacity and Energy Fluctuations Appendix 6.3 The Real Gas Contribution to the Virial Appendix 6.4 Translating Particle Back into Central Box for Three Box Shapes Farther Reading References 7 Molecular Dynamics Simulation Methods 7.1 Introduction 72 Molecular Dynamics Using Simple Models 7.3 Molecular Dynamics with Continuous Potentials 74 — Setting up and Running a Molecular Dynamics Simulation 75 Constraint Dynamics 7.6 Time-dependent Properties 77 — Molecular Dynamics at Constant Temperature and Pressure 7.8 — incorporating Solvent Effects into Molecular Dynamics: Potentials of Mean Force and Stochastic Dynamics 7.9 — Conformational Changes from Molecular Dynamics Simulations 710 Molecular Dynamics Simulations of Chain Amphiphiles 253 253, 258, 261 262 267 270 273 279 295 300 301 303 307 312 315 317 324Contents ‘Appendix 7.1. Energy Conservation in Molecular Dynamics Further Reading References Monte Carlo Simulation Methods 8.1 82 83 B84 8.5 8.6 87 88 8.9 8.10 8.11 8.12 813 Introduction. Calculating Properties by Integration Some Theoretical Background to the Metropolis Method Implementation of the Metropolis Monte Carlo Method Monte Carlo Simulation of Molecules Models Used in Monte Carlo Simulations of Polymers ‘Biased’ Monte Carlo Methods Tackling the Problem of Quasi-ergodicity: J-walking and Multicanonical Monte Carlo Monte Carlo Sampling from Different Ensembles Calculating the Chemical Potential The Configurational Bias Monte Carlo Method Simulating Phase Equilibria by the Gibbs Ensemble Monte Carlo Method Monte Carlo or Molecular Dynamics? Appendix 8.1. The Marsaglia Random Number Generator Further Reading References Conformational Analysis 91 9.2 93 94 95 96 97 98 99 910 911 912 913 914 9.15 9.16 Introduction Systematic Methods for Exploring Conformational Space Model-building Approaches Random Search Methods Distance Geometry Exploring Conformational Space Using Simulation Methods Which Conformational Search Method Should I Use? A Comparison of Different Approaches Variations on the Standard Methods Finding the Global Energy Minimum: Evolutionary Algorithms and Simulated Annealing Solving Protein Structures Using Restrained Molecular Dynamics and Simulated Annealing Structural Databases Molecular Fitting Clustering Algorithms and Pattern Recognition Techniques Reducing the Dimensionality of a Data Set Covering Conformational Space: Poling A ‘Classic’ Optimisation Problem: Predicting Crystal Structures 405 406 406 467 475 476 477 479 483 489 490 491 497 499 501Contents 10 i Farther Reading References Protein Structure Prediction, Sequence Analysis and Protein Folding 10.1 10.2 10.3 104 10.5 10.6 10.7 10.8 109 introduction Some Basic Principles of Protein Structure First-principles Methods for Predicting Protein Structure Introduction te Comparative Modelling Sequence Alignment Constructing and Evaluating a Comparative Model Predicting Protein Structures by ‘Threading’ A Comparison of Protein Structure Prediction Methods: CASP Protein Folding and Unfolding Appendix 10.1 Some Common Abbreviations and Acronyms Used in Bioinformatics Appendix 10.2 Some of the Most Common Sequence and Structural Databases Used in Bioinformatics Appendix 10.3 Mutation Probability Matrix for 1 PAM Appendix 10.4 Mutation Probability Matrix for 250 PAM Further Reading References Four Challenges in Molecular Modelling: Free Energies, Solvation, Reactions and Solid-state Defects ih. 412 11.3 114 115 11.6 11.7 8 9 11.10 init 11.12 11.13 1114 Free Energy Calculations ‘The Calculation of Free Energy Differences Applications of Methods for Calculating Free Energy Differences The Calculation of Enthalpy and Entropy Differences Partitioning the Free Energy Potential Pitfalls with Free Energy Calculations Potentials of Mean Force Approximate/‘Rapid’ Free Energy Methods Continuum Representations of the Solvent The Electrostatic Contribution to the Free Energy of Solvation: The Born and Onsager Models Non-electrosiatic Contributions to the Solvation Free Energy Very Simple Solvation Models Modelling Chemical Reactions Modelling Solid-state Defects Appendix 11.1 Calculating Free Energy Differences Using Thermodynamic Integration Appendix 11.2 Using the Slow Growth Method for Calculating Free Energy Differences xi 505 506 509 513 517 522 522 539 545 547 549 553 563 563 564 569 574 574 577 580 592 593 608 610 630 631xi Contents Appendix 11.3 Expansion of Zwanzig Expression for the Free Energy Difference for the Linear Response Method Further Reading References 42. The Use of Molecular Modelling and Chemoinformatics to Discover and Design New Molecules 12.1 12.2 D3 124 125 12.6 12.7 Rs 129 12.40 1211 12.12 12.13 12.14 Molecular Modelling in Drug Discovery Computer Representations of Molecules, Chemical Databases and 2D Substructure Searching 3D Database Searching Deriving and Using Three-dimensional Pharmacophores Sources of Data for 3D Databases Molecular Docking Applications of 3D Database Searching and Docking Molecular Similarity and Similarity Searching Molecular Descriptors Selecting ‘Diverse’ Sets of Compounds Structure-based De Novo Ligand Design Quantitative Structure~Activity Relationships Partial Least Squares Combinatorial Libraries Further Reading References Index 631 632 633 640 647 659 661 668 687 695, 706 7 719 720Preface to the Second Edition ‘The impetus for this second edition is a desire to include some of the new ‘techniques that have emerged in recent years and also extend the scope of the book to cover certain areas that were under-represented (even neglected) in the first edition. In this second volume there are three topics that fall into the first category (density functional theory, bioinformatics/ protein structure analysis and chemoinformatics) and one main area in the second category (modelling of the solid state). In addition, of course, a new edition provides an opportunity to take a critical view of the text and to re-organise and update the material. Thus whilst much remains from the first edition, and this second book follows much the same path through the subject, readers familiar with the first edition will find some changes which 1 hope they will agree are for the better. As with the first edition we initially consider quantum mechanics, but this is now split into two chapters, Thus Chapter 2 provides an introduction to the ab initio and semi-empirical approaches together with some examples of the uses of quantum mechanics. Chapier 3 covers more advanced aspects of the ab initio approach, density functional theory and the particular problems of the solid state. Molecular mechanics is the subject of Chapter 4 and then in Chapter 5 we consider energy minimisation and other ‘static’ techniques. Chapters 6, 7 and 8 deal with the two main simulation methods (molecular dynamics and Monte Carlo). Chapter 9 is devoted to the conformational analysis of ‘small’ molecules but also includes some topics (e.g. cluster analysis, principal components analysis) that are widely used in informatics. In Chapter 10 the problems of protein structure prediction and protein folding are considered; this chapter also contains an introduction to some of the more widely used methods in bioinformatics. In Chapter 11 we draw upon material from the previous chapters in a discussion of free energy calculations, continuum solvent models, and methods for simulating chemical reactions and defects in solids. Finally, Chapter 12 is concerned with modelling and chemoinformatics techniques for discovering and designing new molecules, including database searching, docking, de novo design, quantitative structure-activity relationships and combinatorial library design. As in the first edition, the inexorable pace of change means that what is currently considered ‘cutting edge’ will soon become routine. The examples are thus chosen primarily because they illuminate the underlying theory rather than because they are the first application of @ particular technique or are the most recent available. In a similar vein, it is impossible ina volume such as this to even attempt to cover everything and so there are undoubtedly areas which are under-represented. This is not intended to be a definitive historical account or a review of the current state-of-the-art. Thus, whilst I have tried to include many literature references it is possible that the invention of some technique may appear to be incorrectly attributed or a ‘classic’ application may be missing, A general guiding principle has beenxiv Preface to the Secand Edition to focus on those techniques that are in widespread use rather than those which are the province of one particular research group. Despite these caveats I hope that the coverage is sufficient to provide a solid introduction to the main areas and also that those readers who ate ‘experts’ will find something new to interest them. A Companion Web Site accompanies Molecular Modelling: Principles and Applications, Second Edition by Andrew Leach Visit the Molecular Modelling Companion Web Site at wure.booksites.net/leach ‘The website contains general information about the book, up-to-date hyperlinks to related chemistry sources on the web, reference copies of appendices of relevant acronyms, and twenty-six full screen, full-colour graphical representations of molecular structures.Preface to the First Edition Molecular modelling used to be restricted to a small number of scientists who had access to the necessary computer hardware and software. Its practitioners wrote their own programs, managed their own computer systems and mended them when they broke down. Today’s computer workstations are much more powerful than the mainframe computers of even a few years ago and can be purchased relatively cheaply. It is no longer necessary for the modeller to write computer programs as software can be obtained from commercial soft- ware companies and academic laboratories. Molecular modelling can now be performed in any laboratory or classroom. This book is intended to provide an introduction to some of the techniques used in molecular modelling and computational chemistry, and to illustrate how these techniques can be used to study physical, chemical and biological phenomena. A major objective is to provide, in one volume, some of the theoretical background to the vast array of methods available to the molecular modeller. I also hope that the book will help the reader to select the most appropriate method for a problem and so make the most of his or her modelling, hardware and software. Many modelling programs are extremely simple to use and are often supplied with seductive graphical interfaces, which obviously helps to make modelling techniques more accessible, but it can also be very easy fo select a wholly inappropriate technique or method. Most molecular modelling studies involve three stages. In the first stage a model is selected to describe the intra- and inter-molecular interactions in the system. The two most common models that are used in molecular modelling are quantum mechanics and molecular mechanics. These models enable the energy of any arrangement of the atoms and molecules in the system to be calculated, and allow the modeller to determine how the energy of the system varies as the positions of the atoms and molecules change. The second stage of a molecular modelling study is the calculation itself, such as an energy minimisation, a molecular dynamics or Monte Carlo simulation, or a confermational search. Finally, the calculation must be analysed, not only to calculate properties but also to check that it has been performed properly. The book is organised so that some of the techniques discussed in later chapters refer to material discussed earlier, though I have tried to make each chapter as independent of the others as possible. Some readers may therefore be pleased to know that it is not essential to completely digest the chapters on quantum mechanics and molecular mechanics in order to read about methods for searching conformational space! Readers with experience in one of more areas may, of course, wish to be more selective. J have tried to provide as much of the underlying theory as seems appropriate to enable the reader to understand the fundamentals of each method, In doing so I have assumed some background knowledge of quantum mechanics, statistical mechanics, conformational analysis and mathematics, A reader with an undergraduate degree in chemistry shouldwt Preface to the First Edition have covered this material, which should also be familiar to many undergraduates in the final year of their degree course, Full discussion can be found in the suggestions for further reading at the end of each chapter. I have also attempted to provide a reasonable selection of original references, though in a book of this scope it is obviously impossible to provide a comprehensive coverage of the literature. In this context, ! apologise in advance if any tech- nique is inappropriately attributed. ‘The range of systems that can be considered in molecular modelling is extremely broad, from isolated molecules through simple atomic and molecular liquids to polymers, bio logical macromolecules such as proteins and DNA and solids. Many of the techniques are illustrated with examples chosen to reflect the breadth of applications. It is inevitable that, for reasons of space, some techniques must be dealt with in a rudimentary fashion (or not at all), and that many interesting and important applications cannot be described, Molecular modelling is a rapidly developing discipline and has benefited from the dramatic improve- ments in computer hardware and software of recent years Calculations that were major undertakings only a few years ago can now be performed using personal computing facilities. Thus, examples used to indicate the ‘state of the art’ at the time of writing will invariably. be routine within a short time.Symbols and Physical Constants This list contains the most frequently used symbols and physical constants ordered according to approximate appearance in the text. Xd 7,89 ijk 6,8, We tx) or I wag a et ss des Lagrange multiplier spherical polar coordinates orthogonal unit vectors along x, y, z axes Euler angles arithmetic mean value of x unit matrix square root of ~1 unit vector exponent in Gaussian function (normal distribution) standard deviation variance Planck’s constant (6.626 18 x 10-Js) ifm (1.05459 x 10 Js) particle mass molecular wavefunction & oe + F/07 + P82 (‘del-squared’) Hamiltonian spatial orbital spin functions (‘spin up’ and ‘spin down’) spin orbital (product of spatial orbital and a spin function) basis function/atomic orbital (usually labelled ,,, 6, by, bo) indicates an integral over all spatial coordinates indicates an integral over all spin coordinates indicates an integral over all spatial and spin coordinates distances between two particles iand j (usually electrons in quantum mechanics) distance between two nuclei A and B Kronecker delta (6j = 1 if i = OTF )) exchange operator Coulomb operator core Hamiltonian operator Fock matrix overlap matrix overlap integral between orbitals i and j Fock operator matrix of basis function coefficientsxx QA BATS Symbols and Physical Con: metric matrix (in distance geometry) ith principal component variance-covariance matrix coupling parameter (used in free energy calculations) weighting function used in umbrefla sampling number density (= N/V) similarity coefficient between twe molecules A and B ‘distance’ between two molecules A and B Hammett substitution constant partition coefficient of solute between two solvents log(P,/Pu) for a substituent X relative to a hydrogen substituent squared correlation coefficient squared correlation coefficient in multiple linear regression cross-validated R*Acknowledgements For this second edition I would like to thank Drs Neil Allan, Paul Bamborough, Gianpaolo Bravi, Richard Bryce, Julian Gale, Richard Green, Mike Hann and Alan Lewis, who commen- ted on various parts of the new text. Julian Gale's suggestions were particularly useful for refining the sections concerning materials science and solid-state applications. 1 would also like to record my thanks once more to those who gave their time to read and comment on draft copies of various chapters of the first edition, upon which this second edition is based (in alphabetical order): Dr D B Adolf, Dr J M Blaney, Professor A V Chadwick, Dr P S Charifson, Dr C-W Chung, Dr A Cleasby, Dr A Emerson, Dr J W Essex, Dr D VS Green, Dr | R Gould, Dr M M Hann, Dr C A Leach, Dr M Pass, Dr D A Pearlman, Dr C A Reynolds, Dr D W Salt, Dr M Sagi, Professor J I Siepmann, Dr W C Swope, Dr N R Taylor, Dr P | Thomas, Professor D J Tildesley and Mr O Warschkow. Assistance with the illustrations for the second edition was provided by Drs R Groot, S McGrother and V Milman, Many of the figures from the first edition are also included here and so I would like to thank again Dr S E Greasley, Dr M_M Hann, Dr H Jhoti, DrS N. Jordan, Professor G R Luckhurst, Dr P M McMeekin, Dr A Nicholls, Dr P Popelier, Dr A Robinson and Dr T E Klein. Alexandra Seabrook, Pauline Gillet and Julie Knight at Pearson Education provided the foundation of the publishing team, coping with a steady stream of questions and keeping everyone to schedule. Especial thanks are due to Julie, who did a splendid job as editor. Any errors that remain are of course my own responsibility. If you do find any, I would like to know! I will also be pleased to receive any constructive suggestions, comments or criticisms, We plan to set up a web site that will provide access to various material from the book (such as electronic versions of the colour images) together with email contacts. This can be accessed via www.booksites.net. Molecular modelling would not be what it is today without the efforts of those who develop computer hardware and software and I would like to acknowledge the authors of the follow- ing computer programs which were used to generate figures and/or data described in the text, All calculations were performed using Silicon Graphics computers. AMBER D A Pearlman, D A Case, JC Caldwell, G L Seibel, U C Singh, PWeiner and P A Kollman 1991 Amber 3 0, University of California, San Francisco. Cambridge Structural Database: F H Allen, $ A Bellard, M D Brice, B A Cartwright, A Doubleday, H Higgs, T Hummelink, B G Humunelink-Peters, O Kennard, W D $ Motherwell, J R Rodgers and D G Watson 1979 The Cambridge Crystallographic Data Centre: Computer-Based Search, Retrieval, Analysis and Display of Information, Acta Crystallographica B35:2331-2339. Cambridge Crystallographic Data Centre, Cambridge, United Kingdom. CASTEP. Molecular Simulations Inc, 9685 Scranton Road, San Diego, California, USA. Catalyst. Molecular Simulations Inc , 9685 Scranton Road, San Diego, Califomia, USA. Cerius2, Molecular Simulations Inc., 9685 Scranton Road, San Diego, California, USA.xii Acknowledgements COSMIC: J G Vinter, A Davis, M R Saunders 1987, Strategic approaches to drug design. |. An integrated software framework for molecular modeling, Jounal of Computer-Aided Molecular Design. 1(1)31-51. Dials and Windows. G Ravishanker, § Swaminathan, D L Beveridge, R Lavery and H Sklenar 1989, Journal of Biomolecular Structure ant Dynamics 6:669-699. Wesleyan University, USA Gaussian 92: M J Frisch, G W Trucks, M Head-Gordon, P MW Gill, M W Weng, J B Foresman, BG Johnson, H B Schlegel, M A Robb, E $ Replogle, R Gomperts, J L, Andres, K Raghavachari, | S Binkley, C Gonzalez, R L Martin, D J Fox, D J DeFrees, J Baker, J J P Stewart and } A Pople. Gaussian Inc, Pittsburgh, Pennsylvania, USA GCG: Genetics Computer Group, Inc., University Research Park, 575 Science Drive, Suite B, Madison, Wisconsin 53711, USA, GRASP (Graphical Representation and Analysis of Surface Properties): A Nicholls, Columbia University, New York, USA GRID: P | Goodford 1985 A Computational Procedure for Determining Energetically Favorable Binding Sites on Biologically Important Macromolecules. Journal of Medicinal Chemistry 28:849- 857. Molecular Discovery Ltd, Oxford, United Kingdom. Insightlf: Molecular Simulations inc., 9685 Scranton Road, San Diego, California, USA. IsoStar: | j Bruno, j C Cole, J P M Lommerse, RS Rowland, R Taylor and M L Verdonk 1997. Isostar: a library of information about nonbonded interactions. Jourstal of Computer-Aided Molecular Design 11:525-337. Cambridge Crystallographic Data Centre, Cambridge, United Kingdom, Micromo}- § M Colwell, A R Marshall, RD Amos and N C Handy 1985. Quantum chemistry on microcomputers, Chemistry in Britain 21:655~659 Molscript: P J Kraulis 1991, Molscript ~ A program to produce both detailed and schematic plots of protein structures, Journal of Applied Crystallography 24:946-950. PROCHECK. R Laskowski, MW MacAsthur, DS Moss and J M Thornton 1993, Procheck - A program to check the stereochemical quality of protein structures. Journal of Applied Crystallography 26°283- 291. Quanta: Molecular Simulations Inc., 9685 Scranton Road, San Diego, California, USA. Spartan: Wavefunction inc, 18401 Von Karman, Suite 370, Irvine, California, USA. SPASMS (San Francisco Package of Applications for the Simulation of Molecular Systems). D A Spellmeyer, W C Swope, E-R Evensen, T Cheatham, D M Ferguson and P A Kollman. University of California, San Francisco, USA. Sybyl: ‘Tripos Inc,, 1699 South Hanley Road, St. Louis, Missouri, USA. The following programs were used to produce draft copies of the manusenpt and diagrams: Microsoft Word (Microsoft Corp.), Gnuplot (T Williams and C Kelley), Kaleidagraph (Abelbeck Software), Chem3D (CambridgeSoft Corp ) and Microsoft Excel (Microsoft Corp.). We are grateful to the following for permission to reproduce copyright material: Figure 1.11 from Mathematical Methods in the Physical Sciences, 2nd edn, Boas M 1, 1983. Reprinted by permission of John Wiley & Sons, Inc. Figure 1.14 from The FFT Fundamentals aut Concepts by Ramirez ©1985. Reprinted by permission of Prentice-Hall, Inc,, Upper Saddle River, Nj. Figures 27 and 33 from Ab initio Molecular Orbital Theory, Hebre W J, L Radom, P v R Schleyer, J A Hehre €1986 Reprinted with permission by John Wiley & Sons, Ine, Figure 3 5 fromm Gerratt J, D 1, Cooper, P B Karadakov and M Raimondi 1997, Modern valence bond theory. Chemical Society Revirws 87-100. Reproduced by permission of The Royal Society of Chemusiry Figure 3.22 from Needs RJ and Mujica 1995. First-principles pseudopotential study of the structural phases of silicon. Physical Review B 51-9652-9660Acknowledgements Xxili Figure 4.18 from Buckingham A D 1959, Molecular Quadrupole Moments Quarterly Reviews of the Chemical Society 13:183-214. Reproduced by permission of ‘The Royal Society of Chemistry. Figure 4.29 trom Computer Simulation in Chemical Physics, edited by Allen MP and D J Tildesley, 1993. Effective Pair Potentials and Beyond, Sprik M, with kind permission from Kluwer Academic Publishers Figure 4 49 reprinted with permission from Pranata J and W L Jorgensen. Computational Studies on ¥K506; Conformational Search and Molecular Dynamucs Simulations in Water, The Journal of the America Chemical Society 113:9483-9293 ©1991 American Chemical Society. Figue 450 from Molecular Parameters for Organosilicon Compounds Calculated from Ab Initio Computations, Grigoras $ and T H Lane, Journal of Computational Chemistry 9:25-39, ©1988 Reprinted by permission of John Wiley & Sons, Inc. Figures 5 4 and 58 Press W H, BP Flannery, § A Teukolsky and W T Veiterling, Numerical Recipes in Fortran. 1992, Cambridge University Press, Figure 5 21 reprinted with permission from Chandrasekhar J, $F Smith and W I. Jorgensen. Theoretical Examination of the Sx2 Reaction Involving Chloride Ion and Methy! Chloride in the Gas Phase and Aqueous Solution, The Journal of the American Chemical Society 107:154-163, ©1985 American Chemical Society. Figure 523 reprinted with permission from Doubleday C, J Melver, M Page and T Zielinski ‘Temperature Dependence of the Transition-State Structure for the Disproportionation of Hydrogen Atom with Ethyl Radical, The Journal of the American Chentical Society 107-5800-5801 €:1985 American Chemical Society. Figure 529 from Gonzalez C and H B Schleget 1988 An Improved Algorithm for Reaction Path Following. The Journal of Chemical Physics 90-2154-2161, Figure 530 reprinted from Chemical Physicul Letters, 194, Fischer § and M Karplus. Conjugate Peak Refinement: An Algorithm for Finding Reaction Paths and Accurate Transition States in Systems with Many Degrees of Freedom. 252-261, ©1992, with permission from Elsevier Science Figure 535 reprinted with permission from Houk K N, J Gonzélez and Y Li. Pericyclic Reaction Transition States. Passions and Punctilios 1935~1995. Accounts of Chemical Research 28:81-90. ©1995 American Chemical Society. Figure 6.25 reprinted from Chernical Physics Letters, 196, Ding H-Q, N Karasawa and W A Goddard III, The Reduced Cell Multipole Method for Coulomb Interactions in Periodic Systems with Million- Atom Unit Cells, 6-10, 1992, with permission of Elsevier Science Figure 72 from Alder BJ and TE Wainwright 1959, Studies in Molecular Dynamics. I. General Method. ‘The Journal of Chemicat Physics 31:459-466, Figure 7 11 from Alder BJ and T B Wainwright 1970. Decay of the Velocity Autocorrelation Function, Physical Review A 1:18-21, Figure 7 12 from Guillot B 1991 A Molecular Dynamics Study of the Infrared Spectrum of Water. The Journal of Chemical Physics 95:1543~1551. Figure 7 13 reprinted with permission from Jorgensen W L, KC Binning Jr and B Bigot Structures and Properties of Organic Liquids: n-Butane and 1,2-Dichloroethane and Their Conformational Equilibria. The Journal of the American Chemical Society 103:4393-4399. ©1981 American Chemical Society. Figure 7.24 (and on cover) from Groot R D and T J Madden 1998, Dynamic simulation of diblock copolymer microphase separation The Journal of Chemical Physics 108:8713-8724. (© American Institute of Physics Figure 8 16 from Frantz, DD, D L Freeman and J D Doll 1990. Reducing quasi-ergodic behavior in Monte Carlo simulations by J-walking: applications to atomic clusters. The Journal of Chentical Physics 93:2769-2784xxiv Acknowledgements Figure 8.17 from Cracknell R F, D Nicholson and N Quirke 1994. A Grand Canonical Monte Carlo Study of Lennard-Jones Mixtures in Slit Pores; 2: Mixtures of Two-Centre Ethane with Methane, Molecular Simulation 13:161-175. ©1994 OPA (Overseas Publishers Association) N.V. Permission to reproduce granted by Gordon and Breach Publishers. Figure 8.22 reprinted with permission from Smit B and } | Siepmann. Simulating the Adsorption of Alkanes in Zeolites Science 264 1118-1120 ©1994 American Association for the Advancement of Science. Figure 9.34 from Poling Promoting Conformational Variation, Smellie A §, $ L Teig and P Towbin Journal of Computational Chemistry 16:171-187, (1995. Reprinted by permission of John Wiley & Sons, Inc. Figure 10.18 from Pearson W R and D J Lipman 1988 Improved wols for biological sequence comparison Proceedings of the National Academy of Sciences USA 85 2444-2448, Figure 10.21 reprinted from Current Opinion in Structural Biology, 6, Eddy $ R, Hidden Markov Models, 361-365 ©1996, with permission from Elsevier Science Figure 10.26 Reprinted with permission from Liithy R, J U Bowie and D Fisenberg Assessment of Protein Models with Three-Dimensional Profiles Nature 356:83-85. ©1992 Macmillan Magazines Lirmted. Figure 11.6 from Lybrand TP, ] A McCammon and G Wipif 1986 Theoretical Calculation of Relative Binding Affinity in Host-Cuest Systems. Proceedings of the National Academy of Sciences USA 83:833- 835 Figure 11.18 reprinted with permission from Guo Z and C L Brooks III. Rapid Screening of Binding Affiruties. Application of the Dynamics Method to a Trypsin-Inhubitor System. The Journal of the American Chemical Society 120:1920-1921. ©1998 American Chemical Society. Figure 11 24 reprinted with permission from Still WC, A Tempezyrk, R C Hawley and T Hendrickson Semianalytical Treatment of Solvation for Molecular Mechanics and Dynamics. The Journal of the American Chemical Society 112 6127-6129 (©1990 American Chemical Society. Figure 11 35 reprinted with permission from Chandrasekhar J and W L jorgensen 1985, Energy Profile for a Nonconcerted §y:2 Reaction in Solution. The Journal of the American Chemical Society 107.2974— 2975. (©1985 American Chemical Society. Figure 11.37 reprinted with permission from Agvist J, M Fothergill and A Warshel. Computer Sinwulation of the CO2/HCO; interconversion Step in Human Carboric Anhydrase I. The Journal of the Arterican Chentical Society 115:631-635 ©1993 American Chemucal Society Figure 11.40 reprinted with permussion from Saitta A M, P D Sooper, E Wasserman and M L Klein 1999. Influence of a knot on the strength of a polymer strand. Nature 399:46-48. ©)1999 Macmillan Magazines Limited. Figure 11 42 from NATO ASI Series C498 (New Trends in Materials Chemistry), 1997, 285-318, Defects and ‘Matter Transport in Solid Materials, Chadwick A V and J Corish, with kind permission of Kluwer Academic Publishers Whilst every effort has been made to trace the owners of copyright material, we take this opportunity to offer our apologies to any copyright holders whose rights we may have unwittingly infringed.Mite Useful Concepts in Molecular Modelling 4.1 Introduction What is molecular modelling? ‘Molecular’ clearly implies some connection with molecules. The Oxford English Dictionary defines ‘model’ as ‘a simplified or idealised description of a system or process, often in mathematical terms, devised to facilitate calculations and predic- tions’. Molecular modelling would therefore appear to be concerned with ways to mimic the behaviour of molecules and molecular systems. Today, molecular modelling is invariably associated with computer modelling, but it is quite feasible to perform some simple molecular modelling studies using mechanical models or a pencil, paper and hand calcula- tor, Nevertheless, computational techniques have revolutionised molecular modelling to the extent that most calculations could not be performed without the use of a computer. This is not fo imply that a more sophisticated model is necessarily any better than a simple one, but computers have certainly extended the range of models that can be considered and the systems to which they can be applied. ‘The ‘models’ that most chemists first encounter are molecular models such as the ‘stick’ models devised by Dreiding or the ‘space filling’ models of Corey, Pauling and Keltun (commonly referred to as CPK models). These models enable three-dimensional represen- tations of the structures of molecules fo be constructed. An important advantage of these models is that they are interactive, enabling the user to pose ‘what if ...’ or ‘is it possible to -. ‘questions. These structural models continue to play an important role both in teaching and in research, but molecular modelling is also concerned with more abstract models, many of which have a distinguished history. An obvious example is quantum mechanics, the foundations of which were laid many years before the first computers were constructed, There is a lot of confusion over the meaning of the terms ‘theoretical chemistry’, ‘computa- tional chemistry’ and ‘molecular modelling’. Indeed, many practitioners use ail three labels to describe aspects of their research, as the occasion demands! ‘Theoretical chemistry’ is often considered synonymous with quantum mechanics, whereas computational chemistry encompasses not only quantum mechanics but also molecular mechanics, minimisation, simulations, conformational analysis and other computer-based methods for understanding and predicting the behaviour of molecular systems, Molecular modellers use all of these methods and so we shall not concern ourselves with semantics but rather shall consider any theoretical or computational technique that provides insight into the behaviour of molecular systems to be an example of molecular modelling. If a distinction has to be2 Chapter 1 made, it is in the emphasis that molecular modelling places on the representation and manipulation of the structures of molecules, and properties that are dependent upon those three-dimensional structures. The prominent part that computer graphics has played in molecular modelling has led some scientists to consider molecular modelling as little more than a method for generating ‘pretty pictures’, but the technique is now firmly established, widely used and accepted as a discipline in its own right. A closely related subject is molecular informatics. This is a rather new term, making a precise definition difficult, but it is usually considered to encompass two disciplines: chemoinfor- matics and bioinformatics. Of these twe areas, chemoinformatics (also written cheminfor- matics) is the newer name but the older discipline; chemists have been using computers to store, retrieve and manipulate information about molecules almost since computers were invented. Both chemoinformatics and bioinformatics have risen to prominence primar- ily as a consequence of the introduction of new experimental techniques. For the chemist these experimental techniques are combinatorial library synthesis and high-throughput screening, which enable very large numbers of molecules to be synthesised and tested; for the biologist they are the automated sequencing machines that are being used to determine the human genome. A characteristic feature of molecular informatics is that it is concerned with information about large numbers of molecules, much larger than is typically the case for a traditional molecular modelling study. For this reason, informatics was initially more concerned with less complex representations of molecules that did not fully represent their three-dimensional properties. However, even this distinction is now being eroded and there is increasing use made of more traditional molecular modelling techniques within informatics. In the rest of this chapter we shall discuss a number of concepts and techniques that are relevant to many areas of molecular modelling and so do not sit comfortably in any individual chapter. We will also define some of the terms that will be used throughout the book. 1.2 Coordinate Systems It is obviously important to be able to specify the positions of the atoms and/or molecules in the system to a modelling program’. There are two common ways in which this can be done. The most straightforward approach is to specify the Cartesian (x,y,z) coordinates of all the atoms present. The alternative is to use internal coordinates, in which the position ‘of each atom is described relative to other atoms in the system. Internal coordinates are usually written as a Z-matrix. The Z-matrix contains one line for each atom in the system. A sample Z-matrix for the staggered conformation of ethane (see Figure 1.1) is “For a system containing a large number of independent molecules it is common to use the term ‘configuration’ to refer to each arrangement; this use of the word ‘configuration’ is not to be con- fused with its standard chemical meaning as a different bonding arrangement of the atoms in a moleculeUseful Concepts in Molecular Modelling 3 Fig 11 The staggered conformation of ethane as follows: 1 Cc 2 Cc 15401 3 H 16 1 10950 2 4 H 10 2 10.5 1 1300 3 5 H 10 1 1095 2 600 4 6 H 10 2 109.5 1 60.0 5 7 #H 10 1 1095 2 180.0 6 8 H 1.0 2 1095 2 60.0 7 Inthe first line of the Z-matrix we define atom 1, which is a carbon atom, Atom number 2 is also a carbon atom that is a distance of 154A from atom 1 (columns 3 and 4). Atom 3 is a hydrogen. atom that is bonded to atom 1 with a bond length of 1.0 A. The angle formed by atoms 2-1-3 is 109.5°, information that is specified in columns 5 and 6. The fourth atom is a hydrogen, a distance of 1.0 A from atom 2, the angle 4-2-1 is 109.5°, and the torsion angle (defined in Figure 1.2) for atoms 4-2-1-3 is 180°. Thus for all except the first three atoms, each atom has three internal coordinates: the distance of the atom from one of the atoms previously defined, the angle formed by the atom and two of the previous atoms, and the torsion angle defined by the atom and three of the previous atoms. Fewer internal coordinates are required for the first three atoms because the first atom can be placed anywhere in space (and so it has no internal coordinates); for the second atom it is only necessary to specify its distance from the first atom and then for the third atom only a distance and an angle are required. It is always possible to convert internal to Cartesian coordinates and vice versa. However, one coordinate system is usually preferred for a given application. Internal coordinates can usefully describe the relationship between the atoms in a single molecule, but Cartesian coordinates may be more appropriate when describing a collection of discrete molecules. Internal coordinates are commonly used as input to quantum mechanics programs, whereas calculations using molecular mechanics are usually done in Cartesian coordinates. The total Humber of coordinates that must be specified in the internal coordinate system is six fewer4 Chapter 1 Fig. 1.2 A torsion ungle A-B-C-D is defred as the angle between the planes A, B, Cand B, CD A torsion angie can vary through 360° although the range —180° to +180" és most commonly used We shall adopt the IUPAC ddofinition of a torsion angle in which am eclipsed conformation corresponds fo a torsion angle of 0” and a trans or nti conformation to a torsion angle of 180°. The reaier should note that this may not correspond to some of the definitions used ine the Htersture, where the trans arrangement is defied as a torsion angle of O° {fone looks along the bond B-C, then the torsion angle is the angle through which it is necessary to rotate the bond AB in a clockwise ‘sense in order to superimpose the twoo planes, as sown than the number of Cartesian coordinates for a non-linear molecule. This is because we are at liberty to arbitrarily translate and rotate the system within Cartesian space without changing, the relative positions of the atoms 4.3 Potential Energy Surfaces In molecular modelling the Born-Oppenheimer approximation is invariably assumed to operate. This enables the electronic and nuclear motions to be separated; the much smaller mass of the electrons means that they can rapidly adjust to any change in the nuclear posi- tions, Consequently, the energy of a molecule in its ground electronic state can be considered a function of the nuclear coordinates only. If some or all of the nuclei move then the energy will usually change. The new nuclear positions could be the result of a simple process such as a single bond rotation or it could arise from the concerted movement of a large number of atoms. The magnitude of the accompanying rise or fall in the energy will depend upon the type of change involved. For example, about 3 kcal/mol is required to change the covalent carbon-carbon bond length in ethane by 0.1A away from its equilibrium value, but only about 0.1 kcal/mol is required to increase the non-covalent separation between two argon. atoms by 1A from their minimum energy separation. For small isolated molecules, rotation about single bonds usually involves the smallest changes in energy. For example, if we rotate the carbon-carbon bond in ethane, keeping all of the bond lengths and angles fixed in value, then the energy varies in an approximately sinusoidal fashion as shown in Figure 13, with minima at the three staggered conformations. The energy in this case can be considered a function of a single coordinate only (ie. the torsion angle of the carbon-carbon bond), and as such can be displayed graphically, with energy along one axis and the value of the coordinate along the other.Useful Concepts In Molecular Modelling 5 She Energy (kcal/mol) so ° om 0 60 120 180 240-300” 360 C-Ctorsion angle Fig. 13. Variation in energy with rotation of the carbon-carbon bond in ethane Changes in the energy of a system can be considered as movements on a multidimensional ‘surface’ called the energy surface. We shall be particularly interested in stationary points on the energy surface, where the first derivative of the energy is zero with respect to the internal or Cartesian coordinates. At a stationary point the forces on.all the atoms are zero. Minimum. points are one type of stationary point; these correspond to stable structures. Methods for locating stationary points will be discussed in more detail in Chapter 5, together with a more detailed consideration of the concept of the energy surface. 1.4 Molecular Graphics Computer graphics has had a dramatic impact upon molecular modelling. It should always be remembered, however, that there is much more to molecular modelling than computer graphics. It is the interaction between molecular graphics and the underlying theoretical methods that has enhanced the accessibility of molecalar modelling methods and assisted the analysis and interpretation of such calculations. Molecular graphics systems have evolved from delicate and temperamental pieces of equip- ment that cost hundreds of thousands of pounds and occupied entire rooms, to today’s inexpensive workstations that fit on or under a desk and yet are hundreds of times more powerful Over the years, two different types of molecular graphics display have been used in molecular modelling. First to be developed were vector devices, which construct pictures using an electron gun to draw lines (or dots) on the screen, in a manner similar to an oscilloscope. Vector devices were the mainstay of molecular modelling for almost two decades but have now been largely superseded by raster devices, ‘These divide the screen into a large number of small ‘dots’, called pixels. Each pixel can be set to any of a large number of colours, and so by setting each pixel to the appropriate colour it is possible to generate the desired image. Molecules are most commonly represented on a computer graphics screen using ‘stick’ or ‘space-filling’ representations, which are analogous to the Dreiding and Corey-Pauling- Koltun (CPK) mechanical models. Sophisticated variations on these two basic types have6 Chapter 1 been developed, such as the ability to calour molecules by atomic number and the inclusion of shading and lighting effects, which give ‘solid’ models a more realistic appearance. Some of the commonly used molecular representations are shown in Figure 14 (colour plate section). Computer-generated models do have some advantages when compared with their mechanical counterparts, Of particular importance is the fact that a computer model can be very easily interrogated to provide quantitative information, from simple geometrical measures such as the distance between two atoms to more complex quantities such as the energy or surface area. Quantitative information such as this can be very difficult if not impossible to obtain from a mechanical model. Nevertheless, mechanical models may still be preferred in certain types of situation due to the ease with which they can be manipulated and viewed in three dimensions, A computer screen is inherently two-dimensional, whereas molecules are three-dimensional objects. Nevertheless, some impression of the three-dimensional nature of an object can be represented on a computer screen using techniques such as depth cueing (in which those parts of the object that are further away from the viewer are made less bright) and through the use of perspective. Specialised hardware enables more realistic three-dimensional stereo images to be viewed. In the future ‘virtual reality’ systems may enable a scientist to interact with a computer-generated molecular mode! in much the same way that a mechanical model can be manipulated. Even the most basic computer graphics program provides some standard facilities for the manipulation of models, including the ability to translate, rotate and ‘zoom’ the model towards and away from the viewer. More sophisticated packages can provide the scientist with quantitative feedback on the effect of altering the structure. For example, as a bond is rotated then the energy of each structure could be calculated and displayed interactively. For large molecular systems it may not always be desirable to include every single atom in the computer image; the sheer number of atoms can result in a very confusing and cluttered picture. A clearer picture may be achieved by omitting certain atoms (e.g. hydrogen atoms) or by representing groups of atoms as single ‘pseudo-atoms’ The techniques that have been developed for displaying protein structures nicely illustrate the range of computer graphics representation possible (the use of computational techniques to investigate the structures of proteins is considered in Chapter 10). Proteins are polymers constructed from amino acids, and even a small protein may contain several thousand atoms. One way to produce a clearer picture is to dispense with the explicit representation of any atoms and to represent the protein using a ‘ribbon’. Proteins are also commonly represented using the cartoon drawings developed by } Richardson, an example of which is shown in Figure 1.5 (colour plate section). The cylinders in this figure represent an arrangement of amino acids called an a-helix, and the flat arrows an alternative type of regular structure called a 3-strand. ‘The regions between the cylinders and the strands have no such regular structure and are represented as ‘tubes’. 1.5 Surfaces Many of the problems that are studied using molecular modelling involve the non-covalent interaction between two or more molecules, The study of such interactions is often facilitatedUseful Concepts in Molecular Modelling 7 Solvent-accessible surface Probe sphere Nw sunface ™ Re-entrant surface Molecular Contact surface surface Fig 16° The van der Waals (od) sterface of a molecule corresponds to the oxtward-facing surfaces of the van der Waals spheres of the aionas The molecular surface is generated by rolling a spherical probe (usually of radius 1.4A fo represent a water molecule) on the van der Waals surface The molecular surface is constructed from contact and re-entrant surface elements The centre of the probe traces out the accessible surface by examining the van der Waals, molecular or accessible suxfaces of the molecule. The van der Waals surface is simply constructed from the overlapping van der Waals spheres of the atoms, Figure L6. It corresponds to a CPK or space-filling model. Let us now consider the approach of a small ‘probe’ molecule, represented as a single van der Waals sphere, up to the van der Waals surface of a larger molecule. The finite size of the probe sphere means that there will be regions of ‘dead space’, crevices that are not accessible to the probe as it rolls about on the larger molecule. This is illustrated in Figure 1.6. The amount of dead space increases with the size of the probe; conversely, a probe of zero size would be able to access all of the crevices, The molecular surface [Richards 1977] is traced out by the inward-facing part of the probe sphere as it rolls on the van der Waals surface of the molecule. The molecular surface contains two different types of surface element. The contact surface corresponds to those regions where the probe is actually in contact with the van der Waals surface of the ‘target’, The re-entrant surface regions occur where there are crevices that are too narrow for the probe molecule to penetrate. The molecular surface is usually defined using a water molecule as the probe, represented as a sphere of radius 14 A. ‘The accessible surface is also widely used. As originally defined by Lee and Richards [Lee and Richards 1971] this is the surface that is traced by the centre of the probe molecule as it rolls on the van der Waals surface of the molecule (Figure 1.6). The centre of the probe molecule can thus be placed at any point on the accessible surface and not penetrate the van der Waals spheres of any of the atoms in the molecule. Widely used algorithms for calculating the molecular and accessible surfaces were devel- oped by Connolly [Connolly 1983a,b], and others [e.g. Richmond 1984] have described formulae for the calculation. of exact or approximate values of the surface area. There are many ways to represent surfaces, some of which are illustrated in Figure 1.7 (colour plate section). As shown, it may also be possible to endow a surface with a translucent quality, which enables the molecule inside the surface to be displayed. Clipping can also be used8 Chapter 1 to cut through the suxface to enable the ‘inside’ to be viewed. In addition, properties such as the electrostatic potential can be calculated on the surface and represented using an appro- priate colour scheme. Useful though these representations are, it is important to remember that the electronic distribution in a molecule formally extends to infinity. The ‘hard sphere’ representation is often. very convenient and has certainly proved very valuable, but it may not be appropriate in al! cases [Rouvray 1997, 1999, 2000]. 1.6 Computer Hardware and Software One cannot fail to be amazed at the pace of development in the computer industry, where the ratio of performance-to-price has increased by an order of magnitude every five years or so. The workstations that are commonplace in many laboratories now offer a real alternative to centrally maintained ‘supercomputers’ for molecular modelling calculations, especially as a workstation or even a personal computer can be dedicated to a single task, whereas the super- computer has to be shared with many other users. Nevertheless, in the immediate future there will always be some calculations that require the power that only a supercomputer can offer. The speed of any computer system is ultimately constrained by the speed at which electrical signals can be transmitted. This means that there will come a time when no further enhancements can be made using machines with ‘traditional’ single-processor serial architectures, and parallel computers will play an ever more important role. A parallel computer couples processors together in such a way that a calculation is divided into small pieces with the results being combined at the end. Some calculations are more amenable to parallel processing than others, and a significant amount of effort is being spent converting existing algorithms to run efficiently on parallel arclutectures. In some cases completely new methods have been developed to take maximum advantage of the opportunities of parallel processing. The low cost of personal computer chips means that large ‘farms’ of processors can be constructed to give significant computing power for relatively small outlay. To perform molecular modelling calculations one also requires appropriate programs (the software). The software used by molecular modellers ranges from simple programs that perform just a single task to highly complex packages that integrate many different methods. There is also an extremely wide variation in the price of software! Some programs have been so widely used and tested that they can be considered to have reached the status of a ‘gold standard’ against which similar programs are compared. One hesitates to specify such programs in print, but three items of software have been so widely used and cited that they can safely be afforded the accolade. These are the Gaussian series of programs for per forming ab initio quantum mechanics, the MOPAC/AMPAC programs for semi-empirical quantum mechanics and the MM2 program for molecular mechanics. Various pieces of software were used to generate the data for the examples and illustrations throughout this book. Some of these were written specifically for the task; some were freely available programs; others were commercial packages. I have decided not to describe specific programs in any detail, as such descriptions rapidly become outdated. Nevertheless,