Published in

Elsevier, Journal of Molecular Biology, 14(426), p. 2632-2652

DOI: 10.1016/j.jmb.2014.04.017



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Proteins Feel More Than They See: Fine-Tuning of Binding Affinity by Properties of the Non-Interacting Surface

This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

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Protein-protein complexes orchestrate most cellular processes such as transcription, signal transduction and apoptosis. The factors governing their affinity remain however elusive, especially when it comes to describing dissociation rates (koff). Here we demonstrate that, next to direct contributions from the interface, also the non-interacting surface plays an important role in binding affinity, especially polar and charged residues. Their percentage on the non-interacting surface is conserved over orthologous complexes indicating an evolutionary selection pressure. Their effect on binding affinity can be explained by long-range electrostatics contributions and surface-solvent interactions that are known to determine the local frustration of the protein complex surface. Including these in a simple model significantly improves the affinity prediction of protein complexes from structural models. The impact of mutations outside the interacting surface on binding affinity is supported by experimental alanine scanning mutagenesis data. These results enable the development of more sophisticated and integrated biophysical models of binding affinity and open new directions in experimental control and modulation of biomolecular interactions.