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. 2002 Oct 29;99(22):14116-21.
doi: 10.1073/pnas.202485799. Epub 2002 Oct 15.

A simple physical model for binding energy hot spots in protein-protein complexes

Affiliations

A simple physical model for binding energy hot spots in protein-protein complexes

Tanja Kortemme et al. Proc Natl Acad Sci U S A. .

Abstract

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.

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Figures

Fig 1.
Fig 1.
Predicted versus observed changes in binding free energy brought about by alanine replacement for four selected protein complexes. Lines reflect linear fit with a fixed zero intercept. (a) Protein G bound to an IgG Fc fragment (1fcc). Linear fit yields a correlation coefficient of 0.97. (b) Barnase–barstar (1brs). Residues marked in red are reported to form water-mediated hydrogen bonds in the interface, and show underpredictions in five of seven cases (red squares). If these residues are excluded, a linear fit yields a correlation coefficient of 0.96. (c) Hen egg-white lysozyme bound to the antibody D1.3 (1vfb). Residues reported to form water-mediated hydrogen bonds in the complex are indicated by red squares. A linear fit to all mutations yields a correlation coefficient of 0.82. (d) Hen egg-white lysozyme bound to the antibody HYHEL-10 (3hfm). A linear fit to all mutations excluding a residue making a water mediated hydrogen bond (red square) yields a correlation coefficient of 0.76.
Fig 2.
Fig 2.
Predicted versus observed changed in binding free energy brought about by alanine replacement for two selected protein complexes, illustrating the effect of including side-chain rearrangements in the vicinity of the mutation. Solid lines at 1 kcal/mol indicate the qualitative hot spot classification (see Materials and Methods; correctly predicted hot spots are in the upper right quadrant). (a and b) Staphylococcal enterotoxin C3 bound to the T cell receptor β chain (1jck). a and b are excluding or including side-chain conformational changes, respectively. (c and d) Human growth hormone bound to its receptor (hGHbp; 1a22); for clarity only mutations on the hGHbp are shown. Hot spots (red squares) and residues exerting indirect effects on the binding free energy (green diamonds) are marked as identified by the authors (ref. ; Pro-106 is not shown; a Pro to Ala mutation might cause a structural change in the backbone, which is not accounted for in the current method). c and d are excluding or including side-chain conformational changes, respectively.
Fig 3.
Fig 3.
Comparison of changes in binding energy for the interaction of mdm2 and a p53 fragment (1ycq) brought about by alanine scanning calculated by the simple model or by the MM-PBSA approach (25).

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