Consistency in structural energetics of protein folding and peptide recognition

✍ Scribed by Chao Zhang; James L. Cornette; Charles Delisi

• Publisher: Cold Spring Harbor Laboratory Press
• Year: 1997
• Tongue: English
• Weight: 886 KB
• Volume: 6
• Category: Article
• ISSN: 0961-8368
• DOI: 10.1002/pro.5560060512

✦ Synopsis

Abstract

We report a new free energy decomposition that includes structure‐derived atomic contact energies for the desolvation component, and show that it applies equally well to the analysis of single‐domain protein folding and to the binding of flexible peptides to proteins. Specifically, we selected the 17 single‐domain proteins for which the three‐dimensional structures and thermodynamic unfolding free energies are available. By calculating all terms except the backbone conformational entropy change and comparing the result to the experimentally measured free energy, we estimated that the mean entropy gain by the backbone chain upon unfolding (Δ__S~bb~__) is 5.3 cal/K per mole of residue, and that the average backbone entropy for glycine is 6.7 cal/K. Both numbers are in close agreement with recent estimates made by entirely different methods, suggesting a promising degree of consistency between data obtained from disparate sources. In addition, a quantitative analysis of the folding free energy indicates that the unfavorable backbone entropy for each of the proteins is balanced predominantly by favorable backbone interactions. Finally, because the binding of flexible peptides to receptors is physically similar to folding, the free energy function should, in principle, be equally applicable to flexible docking. By combining atomic contact energies, electrostatics, and sequence‐dependent backbone entropy, we calculated a priori the free energy changes associated with the binding of four different peptides to HLA‐A2.1 MHC molecule and found agreement with experiment to within 10% without parameter adjustment.