Protein Folding and Drug Design

Indice......Page 8
Preface......Page 14
Gruppo fotografico dei partecipanti al Corso......Page 18
1. Introduction......Page 20
2. Experimental physical-chemical determination of structure......Page 21
3. Experimental physical-chemical determination of oxidative folding pathways of RNase A......Page 23
4. Experimental physical-chemical determination of folding pathways of disulfide-intact RNase A......Page 28
6. Theoretical determination of structure with a United-Residue (UNRES) Model......Page 30
8. Conclusions......Page 34
Appendix - Hydrophobic interactions......Page 37
Introduction......Page 46
2. Random sequences......Page 47
3. The statistical energy landscape......Page 48
4. The energy landscape of long evolved proteins......Page 52
5. Local vs. global descriptions of the folding landscape......Page 59
How organisms adapt to the environment: Sequence determinants of the habitat temperature and its physical rationale......Page 66
1. Introduction......Page 67
2.1. Sequence determinants of thermal adaptation of soluble proteins......Page 69
2.2. Statistical tests and controls......Page 70
2.3. Membrane proteins and specific folds......Page 73
2.4. IVYWREL is not a consequence of nucleotide composition bias......Page 75
2.6. Purine loading bias is mainly due to IVYWREL......Page 76
2.7. Nearest-neighbor correlation in DNA sequences......Page 79
3. Physical principles of protein design and the origin of IVYWREL......Page 81
3.1. Discussion......Page 91
4.1. Methods......Page 96
1. Introduction......Page 104
2. The lattice model......Page 107
2.2. Role of the different amino acids in the folding process......Page 108
2.3. Extension of the inverse folding strategy......Page 111
2.4. How many mutations can a designed protein tollerate?......Page 112
3. Hierarchical folding of a model protein......Page 122
4. Solving the protein folding problem in the case of a notional protein (three-step-strategy (3SS))......Page 123
5. Lattice model design of resistance proof, folding-inhibitor peptides......Page 125
6. Drug resistance......Page 129
7. Design and folding of dimeric proteins......Page 130
8. Conclusions......Page 131
1. Introduction......Page 134
2.1. Monte Carlo simulations: the energy model......Page 139
2.3. Binding free energy calculations......Page 141
3. Results and discussion......Page 142
Spin glasses, tubes and proteins......Page 154
1. Introduction......Page 164
2. Laser tweezers......Page 166
3. Synthesis of molecular constructs for use in mechanical manipulation studies......Page 169
4. Mechanical manipulation of single RNase H molecules by laser tweezers......Page 170
5. Conclusion......Page 178
1. History of the hierarchical view of folding......Page 180
2. The folding of the SH3 domain: A computational model......Page 184
3. Equilibrium thermodynamics......Page 186
4. Folding kinetics......Page 187
5. The uneven distribution of energy......Page 190
6. Inhibition of the folding of SH3......Page 191
7. Conclusions......Page 193
1. Introduction......Page 196
2. Methods......Page 199
3.1. Solvation......Page 200
3.2. Association......Page 203
4. Conclusions......Page 209
Structural basis of dielectric permittivity of proteins: Insights from quantum mechanics......Page 212
1. Introduction......Page 213
2. Results......Page 214
3. Materials and methods......Page 219
4. Conclusions......Page 222
1. Introduction......Page 226
2. Calculation of electrostatic potentials in biomolecular systems......Page 227
3. Examples of the use of electrostatic potentials in biomolecular systems......Page 228
4. Comparison of protein electrostatic potentials: Protein Interaction Property Similarity Analysis (PIPSA)......Page 229
5. Electrostatic potentials in the ubiquitin and ubiquitin like systems......Page 230
6. High-throughput modelling of protein electrostatic potentials......Page 235
7. Conclusions......Page 236
1. Introduction......Page 240
2.2. A hierarchical model of biomolecular recognition......Page 244
2.3. Monte Carlo binding simulations: simulated tempering dynamics......Page 245
3. Results and discussion......Page 246
4. Conclusions......Page 254
Blocking the protein folding machinery. Rational design of inhibitors of the molecular chaperone Hsp90 as new anticancer agents......Page 258
1.1. Peptide molecular-dynamics simulations......Page 259
1.2. Docking procedure......Page 261
1.3. Pharmacophore generation......Page 262
2.2. Simulations of Shepherdin-RV mutants......Page 264
2.3. Shepherdin[79-83]......Page 265
2.4. Characterization of Hsp90/shepherdin binding interface......Page 266
2.5. Pharmacophoric hypotheses and small molecule identification......Page 267
3. Discussion......Page 268
1. Energy landscapes and molecular recognition......Page 272
2. Binding hot spots and convergent solutions at protein-protein interfaces......Page 275
3. Targeting P53-MDM2 interfaces with molecular modulators......Page 276
4.1. Structural analysis......Page 279
5.1. Conformational landscape of MDM2 and specific binding with small molecular mimics......Page 280
5.2. The energy landscape analysis of a hot spot at the consensus binding site of the constant fragment (Fc) of human immunoglobulin G......Page 283
Tetrameric voltage-gated ion channels investigated by molecular dynamics and bioinformatics......Page 292
1. Introduction......Page 293
3. Results......Page 295
4. Concluding remarks......Page 299
1. Introduction......Page 302
1.1. The Michaelis-Menten framework......Page 303
1.2. Spectrophotometic assay......Page 304
1.3. Circular Dichroism......Page 305
3. Discussion......Page 306
4. Conclusions......Page 310
1. Introduction......Page 312
2. Experimental strategy......Page 313
3. Results......Page 314
4. Conclusions......Page 316
Elenco dei partecipanti......Page 320