article Open Access (hybrid) EN 2014-04-25

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

Panagiotis L. Kastritis, João Rodrigues, Gert E. Folkers, Rolf Boelens, Alexandre M. J. J. Bonvin

Journal of Molecular Biology, Vol. 426, Issue 14, pp. 2632–2652 (2014)

Utrecht University

DOI: 10.1016/j.jmb.2014.04.017 PMID: 24768922

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Abstract

Protein-protein complexes orchestrate most cellular processes such as transcription, signal transduction and apoptosis. The factors governing their affinity remain elusive however, especially when it comes to describing dissociation rates (koff). Here we demonstrate that, next to direct contributions from the interface, the non-interacting surface (NIS) also plays an important role in binding affinity, especially polar and charged residues. Their percentage on the NIS is conserved over orthologous complexes indicating an evolutionary selection pressure. Their effect on binding affinity can be explained by long-range electrostatic 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.

Topics

Protein Structure and Dynamics 1.00 RNA and protein synthesis mechanisms 1.00 Enzyme Structure and Function 1.00

Field: Biochemistry, Genetics and Molecular Biology · Subfield: Molecular Biology

Keywords

Biophysics,Surface (topology),Chemistry,Plasma protein binding,Crystallography,Biochemistry,Computational biology,Biology,Mathematics

MeSH Terms

Models, MolecularModels, MolecularModels, MolecularProtein BindingProtein BindingProtein BindingProtein ConformationProtein Conformation

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