Kenny B. Lipkowitz, PhD, is a retired Professor of Chemistry from North Dakota State University.Donald B. Boyd was apponted Research Professor of Chemistry at Indiana University - Purdue University Indianapolis in 1994. He has published over 100 refereed journal papers and book chapters.

• 1. Basis Sets for Ab Initio Molecular Orbital Calculations and Intermolecular Interactions 1David Feller and Ernest R. DavidsonIntroduction 1Some Terminology 4Gaussian Compared to Exponential Functions 4Contracted Gaussians 4Polarization Functions 7Complete Sets 8The Basis Set Superposition Error 9Choosing a Basis Set 10Molecular Geometries 11Energy Differences 15One-Electron Properties 20In-Depth Discussion 20Sources of Gaussian Primitives and Contraction Coefficients 20Even-Tempered Gaussians 21Well-Tempered Gaussians 22MINI-/, MIDI-/ and MAXI-/ etc. 26Still Others 27Atomic Natural Orbitals 27Functions for Augmenting Basis Sets 29Weak Interactions 34Conclusion 36References 372. Semiempirical Molecular Orbital Methods 45James J. P. StewartIntroduction 45History of Semiempirical Methods 46Complete Neglect of Differential Overlap 47Complete Neglect of Differential Overlap Version 2 50Intermediate Neglect of Differential Overlap 51Neglect of Diatomic Differential Overlap (NDDO) 52Modified Neglect of Diatomic Overlap 55Austin Model 1 57Parametric Method Number 3 58Self-Consistent Field Convergers 58Strong and Weak Points of NDDO Semiempirical Methods 61MINDO/3 62MNDO, AMI, and PM3 62Theoretical Experiments 73Stationary Points 74General Procedure for Characterizing a Reaction 74Reaction Path 75Time-Dependent Phenomena 76Future of Semiempirical Methods 77Summary 78References 783. Properties of Molecules by Direct Calculation 83Clifford E. Dykstra, Joseph D. Augspurger, Bernard Kirtman, and David J. MalikIntroduction 83Overview of Quantum Mechanical Properties 84Correspondence between Energy Derivatives and Properties 84Differentiation of the Schrodinger Equation 85The Development of Methods for Property Determinations 87Semiempirical Approaches 87Ab Initio Methods 89Detailed View of Ab Initio Methods 92Hamiltonians and Operators 92Computational Organization of the Differentiation Process 95Derivatives of Electronic Wavefunctions 97Local Space Concepts for Extended Systems 99Vibrations and Rotations 100Direct Property Calculations 103Electrical Properties 103Magnetic Properties 107Force Constants 109Transition Probabilities and Optical Properties 110Summary 111References 1124. The Application of Quantitative Design Strategies in Pesticide Discovery 119Ernest L. PlummerIntroduction 119The Selection of a Strategy 122The Well-Designed Substituent Set 126The Ideal Substituent Set Should Cover All Factors That Control Activity 127The Ideal Substituent Set Should Cover the Selected Factor Space as Completely as Possible 128The Ideal Substituent Set Should Span Orthogonal Dimensions of Parameter Space 129The Ideal Set Should Contain the Minimum Number of Substituents Necessary to Avoid Chance Correlations and Still Meet the Desired Goal 130Target Compounds Should Be Chosen to Preserve Synthetic Resources But Should Not Be Chosen Just Because They Are Easy to Synthesize 131The Derivatives Must Be Stable under the Conditions of Bioevaluation 131Analysis Strategies 132The Topliss Tree 132Free-Wilson Analysis 135A Strategy for Lead Optimization Using Multiple Linear Regression Analysis 138Choose the Optimal Pattern for Substitution 139Choose the Factors (Parameters) That Are Likely to Be Important 142Select a Substituent Set 143Synthesize and Submit for Biological Evaluation 152Plot Each Parameter versus Activity 154Generate Squared Terms if Justified by the Single Parameter Plots 157Run All Combinations of the Chosen Parameters through Linear Regression Analysis to the Limits of Statistical Significance 158Repeat the Process Until the QSAR Is Stable 160Sequential Simplex Optimization (SSO) 161Conclusion 164References 1655. Chemometrics and Multivariate Analysis in Analytical Chemistry 169Peter C. JursIntroduction 169Response Surfaces, Sampling, and Optimization 170Signal Processing 173Principal Components Analysis and Factor Analysis 175Calibration and Mixture Analysis 178Classification and Clustering 182Classification 183Clustering 184Library Searching 186Molecular Structure-Property Relationships 188Gas Chromatographic Retention Indices for Diverse Drug Compounds 192Simulation of Carbon-13 Nuclear Magnetic Resonance Spectra of Methyl-Substituted Norbornan-2-ols 198Summary and Conclusions 207References 2086. Searching Databases of Three-Dimensional Structures 213Yvonne C. Martin, Mark G. Bures, and Peter WilletWhy Are Such Methods Needed? 213Tools for Searching Two-Dimensional Chemical Structures of Small Molecules 217Computer Representation of Two-Dimensional Chemical Structures 218Searching Files of Two-Dimensional Chemical Structures 220 Languages for Chemical Programming 222System Design for Chemical Information Systems 224Similarity of Small Molecules Based on Two-Dimensional Structure 225Substituent Effects on Molecular Properties 225Two-Dimensional Topological Descriptors of Molecular Shape 226Similarity of Small Molecules Based on Three-Dimensional Structure 226Three-Dimensional Similarity Based on Geometric Properties 227Three-Dimensional Similarity Based on Steric Properties 231Databases of Three-Dimensional Structures of Molecules 234Searching Files of Three-Dimensional Structures of Small Molecules 236Programs from the Cambridge Crystallographic Data Centre 236Searching Based Principally on Shape Properties 237Strategies Based on Screen Searching 238Strategies Based on a Substructure Specification Language 243Databases and Searching of Multiple Three-Dimensional Pharmacophoric Patterns 248Searching Files of Three-Dimensional Protein Structures 249The Protein Data Bank 249Identification of Patterns of Atoms 249Identification of Secondary Structure Motifs 252Conclusions 253Appendix: Sources of Databases and Programs 255References 2567. Molecular Surfaces 265Paul G. MezeyIntroduction 265Molecular Body and Molecular Surface 266Classical Models for Molecular Surfaces: Hard Spheres and van der Waals Surfaces (VDWSs) 267Electron Density Contour Surfaces 269The Density Domain Approach to Chemical Bonding (DDA) 271Molecular Electrostatic Potential 274Molecular Orbitals 276Solvent Accessible Surfaces 278Union Surfaces 279Interpenetration of Molecular Contour Surfaces 281Shape Analysis of Molecular Surfaces 282Conclusions 288References 2898. Computer Simulation of Biomolecular Systems Using Molecular Dynamics and Free Energy Peturbation Methods 295Terry P. LybrandIntroduction 295Models 296Methods 297Energy Minimization 298Normal Mode Analysis 298Monte Carlo 299Molecular Dynamics 300Free Energy Pertubation Methods 308Summary 314References 3159. Aspects of Molecular Modeling 321Donald B. BoydIntroduction 321Quantum Mechanics 323Why Use Quantum Mechanics? 323Theory 325Approximations 326Comparison of Ab Initio and Semiempirical MO Methods 328Input 329Output 331Basis Sets for Ab Initio Calculations 332Caveats on Basis Sets 334Post-Hartree-Fock Treatments 334Selection of an MO Method 336Numerical Sensitivity of Geometry Optimization Procedures 337Quality of Results from Quantum Mechanical Methods 339Information from X-Ray Databases for Molecular Modeling 341Standard Geometries 345Distance Geometry 345Summary 348References 35110. Successes of Computer-Assisted Molecular Design 355Donald B. BoydLevels of Success 355Norfloxacin 359Metamitron 360Bromobutide 361Myclobutanil 362Conclusion 364References 36511. Perspectives on Ab Initio Calculations 373Ernest R. DavidsonAtomic Orbitals Do Not Work 375The Error in 'P Is Largest Where 'P Is Largest 376The Number of Electron Pairs Is N(N - l)/2 377The Computer Cost, at Fixed Accuracy, Grows Like N! 378Computers Do Not Solve Problems, People Do 379Appendix: Compendium of Software for Molecular Modeling 383Donald B. BoydPersonal Computers 384Minicomputers-Superminicomputers-Workstations 387Supercomputers 392Subject Index 393

Kenny B. Lipkowitz, PhD, is a retired Professor of Chemistry from North Dakota State University.Donald B. Boyd was apponted Research Professor of Chemistry at Indiana University - Purdue University Indianapolis in 1994. He has published over 100 refereed journal papers and book chapters.

• 1. Basis Sets for Ab Initio Molecular Orbital Calculations and Intermolecular Interactions 1David Feller and Ernest R. DavidsonIntroduction 1Some Terminology 4Gaussian Compared to Exponential Functions 4Contracted Gaussians 4Polarization Functions 7Complete Sets 8The Basis Set Superposition Error 9Choosing a Basis Set 10Molecular Geometries 11Energy Differences 15One-Electron Properties 20In-Depth Discussion 20Sources of Gaussian Primitives and Contraction Coefficients 20Even-Tempered Gaussians 21Well-Tempered Gaussians 22MINI-/, MIDI-/ and MAXI-/ etc. 26Still Others 27Atomic Natural Orbitals 27Functions for Augmenting Basis Sets 29Weak Interactions 34Conclusion 36References 372. Semiempirical Molecular Orbital Methods 45James J. P. StewartIntroduction 45History of Semiempirical Methods 46Complete Neglect of Differential Overlap 47Complete Neglect of Differential Overlap Version 2 50Intermediate Neglect of Differential Overlap 51Neglect of Diatomic Differential Overlap (NDDO) 52Modified Neglect of Diatomic Overlap 55Austin Model 1 57Parametric Method Number 3 58Self-Consistent Field Convergers 58Strong and Weak Points of NDDO Semiempirical Methods 61MINDO/3 62MNDO, AMI, and PM3 62Theoretical Experiments 73Stationary Points 74General Procedure for Characterizing a Reaction 74Reaction Path 75Time-Dependent Phenomena 76Future of Semiempirical Methods 77Summary 78References 783. Properties of Molecules by Direct Calculation 83Clifford E. Dykstra, Joseph D. Augspurger, Bernard Kirtman, and David J. MalikIntroduction 83Overview of Quantum Mechanical Properties 84Correspondence between Energy Derivatives and Properties 84Differentiation of the Schrodinger Equation 85The Development of Methods for Property Determinations 87Semiempirical Approaches 87Ab Initio Methods 89Detailed View of Ab Initio Methods 92Hamiltonians and Operators 92Computational Organization of the Differentiation Process 95Derivatives of Electronic Wavefunctions 97Local Space Concepts for Extended Systems 99Vibrations and Rotations 100Direct Property Calculations 103Electrical Properties 103Magnetic Properties 107Force Constants 109Transition Probabilities and Optical Properties 110Summary 111References 1124. The Application of Quantitative Design Strategies in Pesticide Discovery 119Ernest L. PlummerIntroduction 119The Selection of a Strategy 122The Well-Designed Substituent Set 126The Ideal Substituent Set Should Cover All Factors That Control Activity 127The Ideal Substituent Set Should Cover the Selected Factor Space as Completely as Possible 128The Ideal Substituent Set Should Span Orthogonal Dimensions of Parameter Space 129The Ideal Set Should Contain the Minimum Number of Substituents Necessary to Avoid Chance Correlations and Still Meet the Desired Goal 130Target Compounds Should Be Chosen to Preserve Synthetic Resources But Should Not Be Chosen Just Because They Are Easy to Synthesize 131The Derivatives Must Be Stable under the Conditions of Bioevaluation 131Analysis Strategies 132The Topliss Tree 132Free-Wilson Analysis 135A Strategy for Lead Optimization Using Multiple Linear Regression Analysis 138Choose the Optimal Pattern for Substitution 139Choose the Factors (Parameters) That Are Likely to Be Important 142Select a Substituent Set 143Synthesize and Submit for Biological Evaluation 152Plot Each Parameter versus Activity 154Generate Squared Terms if Justified by the Single Parameter Plots 157Run All Combinations of the Chosen Parameters through Linear Regression Analysis to the Limits of Statistical Significance 158Repeat the Process Until the QSAR Is Stable 160Sequential Simplex Optimization (SSO) 161Conclusion 164References 1655. Chemometrics and Multivariate Analysis in Analytical Chemistry 169Peter C. JursIntroduction 169Response Surfaces, Sampling, and Optimization 170Signal Processing 173Principal Components Analysis and Factor Analysis 175Calibration and Mixture Analysis 178Classification and Clustering 182Classification 183Clustering 184Library Searching 186Molecular Structure-Property Relationships 188Gas Chromatographic Retention Indices for Diverse Drug Compounds 192Simulation of Carbon-13 Nuclear Magnetic Resonance Spectra of Methyl-Substituted Norbornan-2-ols 198Summary and Conclusions 207References 2086. Searching Databases of Three-Dimensional Structures 213Yvonne C. Martin, Mark G. Bures, and Peter WilletWhy Are Such Methods Needed? 213Tools for Searching Two-Dimensional Chemical Structures of Small Molecules 217Computer Representation of Two-Dimensional Chemical Structures 218Searching Files of Two-Dimensional Chemical Structures 220 Languages for Chemical Programming 222System Design for Chemical Information Systems 224Similarity of Small Molecules Based on Two-Dimensional Structure 225Substituent Effects on Molecular Properties 225Two-Dimensional Topological Descriptors of Molecular Shape 226Similarity of Small Molecules Based on Three-Dimensional Structure 226Three-Dimensional Similarity Based on Geometric Properties 227Three-Dimensional Similarity Based on Steric Properties 231Databases of Three-Dimensional Structures of Molecules 234Searching Files of Three-Dimensional Structures of Small Molecules 236Programs from the Cambridge Crystallographic Data Centre 236Searching Based Principally on Shape Properties 237Strategies Based on Screen Searching 238Strategies Based on a Substructure Specification Language 243Databases and Searching of Multiple Three-Dimensional Pharmacophoric Patterns 248Searching Files of Three-Dimensional Protein Structures 249The Protein Data Bank 249Identification of Patterns of Atoms 249Identification of Secondary Structure Motifs 252Conclusions 253Appendix: Sources of Databases and Programs 255References 2567. Molecular Surfaces 265Paul G. MezeyIntroduction 265Molecular Body and Molecular Surface 266Classical Models for Molecular Surfaces: Hard Spheres and van der Waals Surfaces (VDWSs) 267Electron Density Contour Surfaces 269The Density Domain Approach to Chemical Bonding (DDA) 271Molecular Electrostatic Potential 274Molecular Orbitals 276Solvent Accessible Surfaces 278Union Surfaces 279Interpenetration of Molecular Contour Surfaces 281Shape Analysis of Molecular Surfaces 282Conclusions 288References 2898. Computer Simulation of Biomolecular Systems Using Molecular Dynamics and Free Energy Peturbation Methods 295Terry P. LybrandIntroduction 295Models 296Methods 297Energy Minimization 298Normal Mode Analysis 298Monte Carlo 299Molecular Dynamics 300Free Energy Pertubation Methods 308Summary 314References 3159. Aspects of Molecular Modeling 321Donald B. BoydIntroduction 321Quantum Mechanics 323Why Use Quantum Mechanics? 323Theory 325Approximations 326Comparison of Ab Initio and Semiempirical MO Methods 328Input 329Output 331Basis Sets for Ab Initio Calculations 332Caveats on Basis Sets 334Post-Hartree-Fock Treatments 334Selection of an MO Method 336Numerical Sensitivity of Geometry Optimization Procedures 337Quality of Results from Quantum Mechanical Methods 339Information from X-Ray Databases for Molecular Modeling 341Standard Geometries 345Distance Geometry 345Summary 348References 35110. Successes of Computer-Assisted Molecular Design 355Donald B. BoydLevels of Success 355Norfloxacin 359Metamitron 360Bromobutide 361Myclobutanil 362Conclusion 364References 36511. Perspectives on Ab Initio Calculations 373Ernest R. DavidsonAtomic Orbitals Do Not Work 375The Error in 'P Is Largest Where 'P Is Largest 376The Number of Electron Pairs Is N(N - l)/2 377The Computer Cost, at Fixed Accuracy, Grows Like N! 378Computers Do Not Solve Problems, People Do 379Appendix: Compendium of Software for Molecular Modeling 383Donald B. BoydPersonal Computers 384Minicomputers-Superminicomputers-Workstations 387Supercomputers 392Subject Index 393

Kenny B. Lipkowitz, PhD, is a retired Professor of Chemistry from North Dakota State University.Donald B. Boyd was apponted Research Professor of Chemistry at Indiana University - Purdue University Indianapolis in 1994. He has published over 100 refereed journal papers and book chapters.

• 1. Basis Sets for Ab Initio Molecular Orbital Calculations and Intermolecular Interactions 1David Feller and Ernest R. DavidsonIntroduction 1Some Terminology 4Gaussian Compared to Exponential Functions 4Contracted Gaussians 4Polarization Functions 7Complete Sets 8The Basis Set Superposition Error 9Choosing a Basis Set 10Molecular Geometries 11Energy Differences 15One-Electron Properties 20In-Depth Discussion 20Sources of Gaussian Primitives and Contraction Coefficients 20Even-Tempered Gaussians 21Well-Tempered Gaussians 22MINI-/, MIDI-/ and MAXI-/ etc. 26Still Others 27Atomic Natural Orbitals 27Functions for Augmenting Basis Sets 29Weak Interactions 34Conclusion 36References 372. Semiempirical Molecular Orbital Methods 45James J. P. StewartIntroduction 45History of Semiempirical Methods 46Complete Neglect of Differential Overlap 47Complete Neglect of Differential Overlap Version 2 50Intermediate Neglect of Differential Overlap 51Neglect of Diatomic Differential Overlap (NDDO) 52Modified Neglect of Diatomic Overlap 55Austin Model 1 57Parametric Method Number 3 58Self-Consistent Field Convergers 58Strong and Weak Points of NDDO Semiempirical Methods 61MINDO/3 62MNDO, AMI, and PM3 62Theoretical Experiments 73Stationary Points 74General Procedure for Characterizing a Reaction 74Reaction Path 75Time-Dependent Phenomena 76Future of Semiempirical Methods 77Summary 78References 783. Properties of Molecules by Direct Calculation 83Clifford E. Dykstra, Joseph D. Augspurger, Bernard Kirtman, and David J. MalikIntroduction 83Overview of Quantum Mechanical Properties 84Correspondence between Energy Derivatives and Properties 84Differentiation of the Schrodinger Equation 85The Development of Methods for Property Determinations 87Semiempirical Approaches 87Ab Initio Methods 89Detailed View of Ab Initio Methods 92Hamiltonians and Operators 92Computational Organization of the Differentiation Process 95Derivatives of Electronic Wavefunctions 97Local Space Concepts for Extended Systems 99Vibrations and Rotations 100Direct Property Calculations 103Electrical Properties 103Magnetic Properties 107Force Constants 109Transition Probabilities and Optical Properties 110Summary 111References 1124. The Application of Quantitative Design Strategies in Pesticide Discovery 119Ernest L. PlummerIntroduction 119The Selection of a Strategy 122The Well-Designed Substituent Set 126The Ideal Substituent Set Should Cover All Factors That Control Activity 127The Ideal Substituent Set Should Cover the Selected Factor Space as Completely as Possible 128The Ideal Substituent Set Should Span Orthogonal Dimensions of Parameter Space 129The Ideal Set Should Contain the Minimum Number of Substituents Necessary to Avoid Chance Correlations and Still Meet the Desired Goal 130Target Compounds Should Be Chosen to Preserve Synthetic Resources But Should Not Be Chosen Just Because They Are Easy to Synthesize 131The Derivatives Must Be Stable under the Conditions of Bioevaluation 131Analysis Strategies 132The Topliss Tree 132Free-Wilson Analysis 135A Strategy for Lead Optimization Using Multiple Linear Regression Analysis 138Choose the Optimal Pattern for Substitution 139Choose the Factors (Parameters) That Are Likely to Be Important 142Select a Substituent Set 143Synthesize and Submit for Biological Evaluation 152Plot Each Parameter versus Activity 154Generate Squared Terms if Justified by the Single Parameter Plots 157Run All Combinations of the Chosen Parameters through Linear Regression Analysis to the Limits of Statistical Significance 158Repeat the Process Until the QSAR Is Stable 160Sequential Simplex Optimization (SSO) 161Conclusion 164References 1655. Chemometrics and Multivariate Analysis in Analytical Chemistry 169Peter C. JursIntroduction 169Response Surfaces, Sampling, and Optimization 170Signal Processing 173Principal Components Analysis and Factor Analysis 175Calibration and Mixture Analysis 178Classification and Clustering 182Classification 183Clustering 184Library Searching 186Molecular Structure-Property Relationships 188Gas Chromatographic Retention Indices for Diverse Drug Compounds 192Simulation of Carbon-13 Nuclear Magnetic Resonance Spectra of Methyl-Substituted Norbornan-2-ols 198Summary and Conclusions 207References 2086. Searching Databases of Three-Dimensional Structures 213Yvonne C. Martin, Mark G. Bures, and Peter WilletWhy Are Such Methods Needed? 213Tools for Searching Two-Dimensional Chemical Structures of Small Molecules 217Computer Representation of Two-Dimensional Chemical Structures 218Searching Files of Two-Dimensional Chemical Structures 220 Languages for Chemical Programming 222System Design for Chemical Information Systems 224Similarity of Small Molecules Based on Two-Dimensional Structure 225Substituent Effects on Molecular Properties 225Two-Dimensional Topological Descriptors of Molecular Shape 226Similarity of Small Molecules Based on Three-Dimensional Structure 226Three-Dimensional Similarity Based on Geometric Properties 227Three-Dimensional Similarity Based on Steric Properties 231Databases of Three-Dimensional Structures of Molecules 234Searching Files of Three-Dimensional Structures of Small Molecules 236Programs from the Cambridge Crystallographic Data Centre 236Searching Based Principally on Shape Properties 237Strategies Based on Screen Searching 238Strategies Based on a Substructure Specification Language 243Databases and Searching of Multiple Three-Dimensional Pharmacophoric Patterns 248Searching Files of Three-Dimensional Protein Structures 249The Protein Data Bank 249Identification of Patterns of Atoms 249Identification of Secondary Structure Motifs 252Conclusions 253Appendix: Sources of Databases and Programs 255References 2567. Molecular Surfaces 265Paul G. MezeyIntroduction 265Molecular Body and Molecular Surface 266Classical Models for Molecular Surfaces: Hard Spheres and van der Waals Surfaces (VDWSs) 267Electron Density Contour Surfaces 269The Density Domain Approach to Chemical Bonding (DDA) 271Molecular Electrostatic Potential 274Molecular Orbitals 276Solvent Accessible Surfaces 278Union Surfaces 279Interpenetration of Molecular Contour Surfaces 281Shape Analysis of Molecular Surfaces 282Conclusions 288References 2898. Computer Simulation of Biomolecular Systems Using Molecular Dynamics and Free Energy Peturbation Methods 295Terry P. LybrandIntroduction 295Models 296Methods 297Energy Minimization 298Normal Mode Analysis 298Monte Carlo 299Molecular Dynamics 300Free Energy Pertubation Methods 308Summary 314References 3159. Aspects of Molecular Modeling 321Donald B. BoydIntroduction 321Quantum Mechanics 323Why Use Quantum Mechanics? 323Theory 325Approximations 326Comparison of Ab Initio and Semiempirical MO Methods 328Input 329Output 331Basis Sets for Ab Initio Calculations 332Caveats on Basis Sets 334Post-Hartree-Fock Treatments 334Selection of an MO Method 336Numerical Sensitivity of Geometry Optimization Procedures 337Quality of Results from Quantum Mechanical Methods 339Information from X-Ray Databases for Molecular Modeling 341Standard Geometries 345Distance Geometry 345Summary 348References 35110. Successes of Computer-Assisted Molecular Design 355Donald B. BoydLevels of Success 355Norfloxacin 359Metamitron 360Bromobutide 361Myclobutanil 362Conclusion 364References 36511. Perspectives on Ab Initio Calculations 373Ernest R. DavidsonAtomic Orbitals Do Not Work 375The Error in 'P Is Largest Where 'P Is Largest 376The Number of Electron Pairs Is N(N - l)/2 377The Computer Cost, at Fixed Accuracy, Grows Like N! 378Computers Do Not Solve Problems, People Do 379Appendix: Compendium of Software for Molecular Modeling 383Donald B. BoydPersonal Computers 384Minicomputers-Superminicomputers-Workstations 387Supercomputers 392Subject Index 393