A simple physical model for binding energy hot spots in protein-protein complexes.
Protein-protein recognition plays a central role in most biological processes. Although the structures of many protein-protein complexes have been solved in molecular detail, general rules describing affinity and selectivity of protein-protein interactions do not accurately account for the extremely diverse nature of the interfaces. We investigate the extent to which a simple physical model can account for the wide range of experimentally measured free energy changes brought about by alanine mutation at protein-protein interfaces. The model successfully predicts the results of alanine scanning experiments on globular proteins (743 mutations) and 19 protein-protein interfaces (233 mutations) with average unsigned errors of 0.81 kcal/mol and 1.06 kcal/mol, respectively. The results test our understanding of the dominant contributions to the free energy of protein-protein interactions, can guide experiments aimed at the design of protein interaction inhibitors, and provide a stepping-stone to important applications such as interface redesign.
Kortemme
Tanja
T
Howard Hughes Medical Institute and Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.
Baker
David
D
D000409:Alanine / Q000235:genetics; D004735:Energy Transfer; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D011506:Proteins / Q000737:chemistry*; D014867:Water / Q000737:chemistry
D011506:Proteins; D014867:Water; D000409:Alanine