title: Contribution of the hydrophobic effect to protein stability: analysis based on simulations of the Ile-96----Ala mutation in barnase.
abstract: Molecular dynamics simulations have been used to compute the difference in the unfolding free energy between wild-type barnase and the mutant in which Ile-96 is replaced by alanine. The simulations yield results (-3.42 and -5.21 kcal/mol) that compare favorably with experimental values (-3.3 and -4.0 kcal/mol). The major contributions to the free energy difference arise from bonding terms involving degrees of freedom of the mutated side chain and from nonbonded interactions of that side chain with its environment in the folded protein. By comparison with simulations of an extended peptide in the absence of solvent, used as a reference state, hydration effects are shown to play a minor role in the overall free energy balance for the Ile----Ala transformation. The implications of these results for our understanding of the hydrophobic effect and its contribution to protein stability are discussed.
authors.affiliation: Unité de Conformation des Macromolécules Biologiques, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: M
authors.initials: M
authors.lastname: Prevost
authors.forename: S J
authors.initials: SJ
authors.lastname: Wodak
authors.forename: B
authors.initials: B
authors.lastname: Tidor
authors.forename: M
authors.initials: M
authors.lastname: Karplus
mesh_terms: D000409:Alanine; D000595:Amino Acid Sequence; D001407:Bacillus / Q000201:enzymology; D001426:Bacterial Proteins; D002151:Calorimetry; D003198:Computer Simulation; D004355:Drug Stability; D004795:Enzyme Stability; D007532:Isoleucine; D008958:Models, Molecular; D009154:Mutation; D011487:Protein Conformation; D012260:Ribonucleases / Q000737:chemistry* / Q000235:genetics; D013816:Thermodynamics
chemical_list: D001426:Bacterial Proteins; D007532:Isoleucine; D012260:Ribonucleases; C019760:Bacillus amyloliquefaciens ribonuclease; D000409:Alanine