Analysis of protein-protein interactions and the effects of amino acid mutations on their energetics. The importance of water molecules in the binding epitope

Journal of Molecular Biology
D G Covell, A Wallqvist

Abstract

A modeling analysis has been conducted to assess the determinants of binding strength and specificity for three crystal complexes; the anti-hen egg white lysozyme antibody D1.3 complexed with hen egg white lysozyme (HEL), the D1.3 antibody complexed with the anti-lysozyme antibody E5.2, and barnase complexed with barstar. The strengths of individual binding components within these interfaces are evaluated using a model of binding free energy that is based on pairwise surface preferences. In all cases the energetics of binding are dominated by a relatively small number of interfacial residues that define the binding epitope. A precise geometric arrangement of these residues was not found; they were either localized to one region, or distributed throughout the binding interface. Surprisingly, interfacial crystal water molecules were calculated to contribute around 25% of the total calculated binding strength. Theoretical alanine mutations were completed by atomic deletions of the wild-type complexes. Strong correlations were observed between the calculated changes in binding free energy (deltadeltaG(calculated)) and the experimental values (deltadeltaG(observed)) for all but three of the 30 single residue mutations in the D1.3-HE...Continue Reading

Citations

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