Quotations .................................................... vii
List of Abbreviations .......................................... ix
Preface ........................................................ xi
Acknowledgements .............................................. xxv
1 Introduction, the Main Problem and the Main Tools ............ 1
1.1 The General Problem ..................................... 5
1.2 Forces and Driving Forces ............................... 9
1.3 Definition of the Solvation Process and the
Corresponding Thermodynamic Quantities ................. 31
1.4 The Conditional Solvation Process ...................... 40
1.5 Some Numerical Values of Solvation Thermodynamics ...... 42
1.5.1 Solvation of hydrophilic molecules or groups .... 42
1.5.2 Solvation of hydrophobic molecules or groups .... 54
1.6 Hydrophobicity Scales .................................. 56
1.7 Some Numerical Values of the Pairwise Hydrophobic and
Hydrophilic Interactions ............................... 60
1.7.1 Pairwise hydrophobic (НøО) interaction .......... 62
1.7.2 Pairwise hydrophilic (Нø1) interaction .......... 67
1.7.3 Potential of average force for pairs of side
chains of amino acids ........................... 74
1.8 Dissection of the Solvation Gibbs Energy of
a Globular Protein ..................................... 74
1.9 Dissection of the Solvation Gibbs Energy of a
Denatured Protein ...................................... 87
1.10 The Relationship between the Standard Gibbs Energy of
a Reaction and Solvation Gibbs Energies ................ 89
1.11 The Various Solvent-Induced Contributions to
the Driving Force for Protein Folding .................. 95
1.11.1 The solvation of the hard part .................. 96
1.11.2 The solvation of the soft part .................. 97
1.11.3 The contribution of the functional groups
(FGs) exposed to the solvent .................... 98
1.12 Concluding Remarks and Some Suggestions for the
Future ................................................. 99
2 Solvation and Solubility of Globular Proteins .............. 101
2.1 Definition of Solubility and its Relationship
to the Solvation Gibbs Energy ......................... 103
2.2 Solvation Gibbs Energy of a Model Globular Protein .... 107
2.3 Estimation of the Solvation Gibbs Energy of Real
Proteins .............................................. 117
2.4 The Relation between Solubility and Solvation Gibbs
Energy for Moderately Soluble Proteins ................ 121
2.5 A Possible Explanation for an Apparently Paradoxical
Experimental Finding .................................. 123
2.6 The Effect of the Addition of a Solute on the
Solvation Gibbs Energy ................................ 125
2.7 Concluding Remarks and Suggestions for Future
Research .............................................. 130
3 Protein Folding ............................................ 133
3.1 The Chemical Equilibrium .............................. 136
3.2 Definition of the Folded and Unfolded Forms ........... 142
3.3 Formal Dissection of the Solvent-Induced Effect on
Protein Folding into "Small" Ingredients .............. 149
3.4 Methods of Studying and Estimating the Various
Contributions to SG ................................... 155
3.5 Summary of the Factors Involved in the Stability of
the Native Protein .................................... 170
3.6 The Problem of the Preferential Protein Folding
Pathways of Proteins .................................. 174
3.7 Energy Landscapes, Gibbs Energy Landscapes and
Forces in Protein Folding ............................. 178
3.8 What Kind of Forces are Exerted on the Protein in
the Process of Protein Folding? ....................... 191
3.9 The Forces in Action .................................. 199
3.10 Is there a "Folding Code"? ............................ 210
3.11 Concluding Remarks and Suggestions for Future
Research .............................................. 213
4 Association and Self-Assembly of Biomolecules .............. 215
4.1 Thermodynamics and Statistical Thermodynamics of the
Association Process ................................... 217
4.2 The Factors Involved in the Association of two
Biomolecules .......................................... 222
4.3 Association of two Hypothetical Globular Proteins ..... 228
4.3.1 The "driving force" for dimerization ........... 229
4.3.2 Virtual dimers, probabilistic considerations ... 235
4.3.3 Some numerical estimates of various
contributions to the total PMF ................. 239
4.4 НøО or Нø1 Interaction: Which is More Important in
the Association Process? .............................. 251
4.4.1 Association of P and L in an ideal gas phase ... 254
4.4.2 Association in an organic liquid ............... 254
4.4.3 Association in aqueous solutions ............... 255
4.4.4 Enhancement of the НøО Mode by Strengthening
the НøI Effects ................................ 258
4.5 Association by the Complete Absorption of a Small
Solute into a Big Solute .............................. 262
4.5.1 Absorption without conformational changes
in P ........................................... 263
4.5.2 Absorption with conformational changes in P .... 264
4.6 Specificity of the Binding Mode; Molecular
Recognition ........................................... 266
4.6.1 The lock-and-key model for molecular
recognition .................................... 267
4.6.2 Molecular recognition through the solvent ...... 270
4.7 Self-Assembly of Macromolecules ....................... 276
4.8 Strong Solvent-Induced Forces between Macromolecules .. 279
4.8.1 Solvent-induced force by means of one-water
bridges ........................................ 280
4.8.2 Solvent-Induced Force by Means of Two-Water
Bridges ........................................ 284
4.8.3 Stronger forces between Нø1 surfaces ........... 290
4.9 Concluding Remarks and Suggestions for Future
Research .............................................. 291
Appendix A. The General Statistical Mechanical Expression
for the Chemical Potential and the Pseudo-Chemical
Potential .................................................. 293
Appendix B. The Pseudo-Chemical Potential and the
Solvation Helmholtz Energy of a Molecule Having Internal
Rotational Degrees of Freedom .............................. 306
Appendix C. The Potential of Mean Force (PMF) and the
Solvent-Induced Force ...................................... 311
Appendix D Conditional Solvation and Conditional
Correlation ................................................ 317
Appendix E Non-Additivity of the Potential of Mean Force
and of the Solvation Gibbs Energy .......................... 326
Appendix F The Statistical Mechanical Definition of
Independence of Solvation and of Conditional Solvation ..... 340
Appendix G Approximate Estimates of the Нø1 Interaction
between Two, Three and Four Нø1 Groups at a Distance of
4.5 Å ...................................................... 345
Appendix H Evaluating The Inadequacy of Kauzmann's
Model for the Role of the НøО Effect in Protein Folding .... 352
Appendix I The Cracks in the Hydrogen Bond Inventory
Argument ................................................... 355
Appendix J Can "Statistical Potential," Derived from
Protein Structures, be Interpreted as a Potential of
Mean Force? ................................................ 365
Appendix K Work of Creating a Cavity and the Probability
of Finding a Cavity in a Solvent ........................... 369
Appendix L Нø1 Interactions and Solubility of Isomeric
Compounds .................................................. 380
Appendix M Further Inflating the Already Inflated Value
of the НøО Effect .......................................... 386
Appendix N The Anfinsen Dogma and the "Thermodynamic
Hypothesis" Applied to the Process of Protein Folding ...... 393
Appendix O Entropy-Enthalpy Compensation; from an Exact
Theorem to an Approximate Manifestation .................... 405
Appendix P Probability of Finding a Specific Configuration
of a Protein and the Work Required to Obtain that
Configuration .............................................. 417
Appendix Q The Many Faces of Reversibility and
Irreversibility ............................................ 420
Appendix R Cooperativity in Protein Folding? ................. 427
Appendix S Local Densities of Water Molecules near Нø1
Groups ..................................................... 430
Appendix T What Drives the "Driving Force?" .................. 437
References ................................................. 443
Index ......................................................... 451
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