Peptide Solvation and H-bonds (eBook)

Cover page 1
Contents 6
New Directions in the Study of Peptide H-Bonds and.Peptide Solvation 10
Chapter 1: Potential Functions for Hydrogen Bonds in Protein Structure Prediction and Design 14
I. Introduction 15
II. Physical Mechanism of Hydrogen Bond Formation 17
III. Main Approaches to Modeling Hydrogen Bonds in Biomolecular Simulations 19
A. Potentials Derived from Hydrogen Bonding Geometries Observed in Crystal Structures 19
B. Molecular Mechanics: Comparison with the Structure-Derived, Orientation-Dependent Potential 22
C. Quantum Mechanics: Comparison with Molecular Mechanics and the Structure-Derived Potential 25
IV. Applications of Hydrogen Bonding Potentials 33
A. Protein Structure Prediction and Refinement 33
B. Prediction of Protein-Protein Interfaces 37
C. Protein Design 40
V. Conclusions and Perspectives 43
References 45
Chapter 2: Backbone-Backbone H-Bonds Make Context-Dependent Contributions to Protein Folding Kinetics and Thermodynamics: Lessons from Amide-to-Ester Mutations 52
I. Introduction 53
II. Nomenclature and Synthesis of Amide-to-Ester Mutants 55
III. Esters as Amide Replacements 57
A. Geometry and Conformation 57
B. Structural Effects of Amide-to-Ester Mutations 59
IV. Interpretation of Energetic Data from Amide-to-Ester Mutants 61
A. H-Bond Energies and the Thermodynamic Analysis of Amide-to-Ester Mutants 61
B. Kinetic Analysis of Amide-to-Ester Mutants 68
V. Amide-to-Ester Mutations in Studies of Protein Function 69
VI. Amide-to-Ester Mutations in Studies of Protein Folding Thermodynamics 71
VII. Analysis of DeltaDeltaGb and DeltaDeltaGf Values from Amide-to-Ester Mutants 74
A. General Observations 74
B. Quantitative Analysis of DeltaDeltaGf/b Values 77
VIII. Amide-to-Ester Mutations in Studies of Protein Folding Kinetics 81
IX. Conclusions and Future Directions 82
References 83
Chapter 3: Modeling Polarization in Proteins and Protein-ligand Complexes: Methods and Preliminary Results 92
I. Introduction 93
II. Incorporation of Polarization in Molecular Mechanics Models 94
A. Overview 94
B. Development of the OPLS/PFF Force Field 96
C. Simulation Methodology 98
D. Evaluation of the Polarizable Force Field in the Gas Phase and Condensed Phase 98
III. Aqueous Solvation Models for Polarizable Simulations 100
A. Overview 100
B. Polarizable Explicit Water Models 101
IV. Modeling Polarizability with Mixed Quantum Mechanics/Molecular Mechanics Methods 102
A. Overview 102
B. Protein-Ligand Docking Using a Mixed Mixed Quantum Mechanics/Molecular Mechanics Methodology to Compute Ligand Charges 103
V. Protein Simulations in Explicit Solvent Using a Polarizable Force Field 107
A. Overview 107
B. Simulations of BPTI with Polarizable and Fixed Charge Protein and Water Models 109
VI. Conclusion 111
References 112
Chapter 4: Hydrogen Bonds In Molecular Mechanics Force Fields 118
I. Introduction 118
II. Geometric Deformation 119
III. Nonbonded Interactions 124
IV. Conclusion 129
References 130
Chapter 5: Resonance Character of Hydrogen-bonding Interactions in Water and Other H-bonded Species 134
I. Introduction 135
II. Natural Bond Orbital Donor-Acceptor Description of H-Bonding 138
III. Quantum Cluster Equilibrium Theory of H-Bonded Fluids 144
IV. Recent Experimental Advances in Determining Water Coordination Structure 151
V. General Enthalpic and Entropic Principles of H-Bonding 154
A. Torsional, Angular, and Dissociative Entropic Contributions 154
B. Binary and Cooperative Enthalpic Contributions 156
VI. Hydrophobic Solvation: A Cluster Equilibrium View 158
VII. Summary and Conclusions: The Importance of Resonance in H-Bonding and Its Possible Representation by Molecular Dynamics Simulations 162
References 163
Chapter 6: How hydrogen bonds shape membrane protein structure 170
I. Introduction 170
II. Structure of Fluid Lipid Bilayers 172
III. Energetics of Peptides in Bilayers 173
A. Folding in the Membrane Interface 174
B. Transmembrane Helices 176
IV. Helix-Helix Interactions in Bilayers 178
V. Perspectives 180
References 180
Chapter 7: Peptide and Protein Folding and Conformational Equilibria: Theoretical Treatment of Electrostatics and Hydrogen Bonding with Implicit Solvent Models 186
I. Introduction 187
II. Generalized Born (GB) Models 189
A. GB Electrostatics Theory 189
B. Advances and Achievements 192
C. Remaining Opportunities for Continued Improvement 195
III. Peptide Folding and Conformational Equilibria 197
A. Influence of Backbone H-Bond Strength on Conformational Equilibria 197
B. Influence of Backbone Dihedral Energetics on Conformational Equilibria 202
IV. Concluding Discussion 203
References 205
Chapter 8: Thermodynamics Of alpha-Helix Formation 212
I. First 50 Years of Study of the Thermodynamics of the Helix-Coil Transition 212
II. The Quest for Enthalpy of the Helix-Coil Transition 218
III. Temperature Dependence of Enthalpy of the Helix-Coil Transition 226
IV. Thermodynamic Helix Propensity Scale: Importance of Peptide Backbone Hydration 228
V. Other Instances When Peptide Backbone Hydration is Important for Stability 229
VI. Future Directions 231
References 233
Chapter 9: The Importance of Cooperative Interactions and a Solid-State Paradigm to Proteins: What Peptide Chemists Can Learn from Molecular Crystals 240
I. Introduction 241
II. Similarities and Differences Between Proteins/Peptides and Molecular Crystals 242
A. Similarities 242
B. Differences 243
III. The Importance of H-Bond Cooperativity in Molecular Crystals 244
A. Enthalpy Is Relatively More Important in the Solid Than in the Liquid 244
B. H-Bonds Are More Stable in the Solid Than in the Liquid State 245
IV. Structural Consequences of H-Bond Cooperativity in Molecular Crystals 247
A. Acetic Acid 248
B. 1,3-Cyclohexanedione 248
C. Urea 250
D. Formamide 251
E. CH...O H-Bonding Interactions and Parabenzoquinone 251
V. How Does the Use of the Crystal Paradigm Affect Protein/Peptide Study? 253
A. Low-Barrier H-Bonds 253
VI. Are H-Bonds Electrostatic? 255
A. Water-Water H-Bonding Cannot be Described Adequately Purely by Electrostatic Interactions 255
B. Comparison of H-Bonds with the Behavior of Molecules in an Electric Field 256
VII. How Strong are Peptide H-Bonds? 256
A. Amide Dimers 257
B. Formamide Chains 257
C. alpha-Helices 260
D. Protonated alpha-Helices 263
E. beta-Sheets 263
F. Collagen-like Triple Helices 265
VIII. Comparison with Experimental Data from Studies in Solution 268
A. alpha-Helices 268
IX. The Importance of a Suitable Reference State(s) 270
A. Differences between Reference States for Experimental and Theoretical Studies 270
B. Multiple Reference States 270
C. Component Amino Acids 270
D. Extended beta-Strand 271
E. Choosing More Than One Reference State 272
X. How Protein Chemists Can Deal with Problems Posed by Dual Paradigms 273
A. Theoretical and Modeling Studies 273
B. Experimental Studies 274
XI. Water, the Hydrophobic Effect and Entropy 276
A. Water 276
B. The Hydrophobic Effect and Entropy 277
C. Another Origin of Entropy Control of Protein Folding 278
XII. Concluding Remarks 280
References 280
Author Index 288
Subject Index 304