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Insights from the energetics binding at the domain-ligand of the Src SH2 domain of water interface

de Fabritiis, G. and Geroult, S. and Coveney, P.V. and Waksman, Gabriel (2008) Insights from the energetics binding at the domain-ligand of the Src SH2 domain of water interface. Proteins-Structure, Function and Bioinformatics 72 (4), p. 1290. ISSN 0887-3585.

Full text not available from this repository.
Official URL: http://dx.doi.org/10.1002/prot.22027

Abstract

SH2 domains play important roles in signal transduction by binding phosphorylated tyrosine residues on cell surface receptors. In an effort to understand the mechanism of ligand binding and more specifically the role of water, we have designed a general computational protocol based on the potential of mean force to compute the thermodynamics of water molecules at the protein-ligand interface for two SH2 domain complexes of the Src kinase, those bound to the two peptides Ac-PQpYEpYI-NH2 and Ac-PQpYIpYV-NH2 where pY indicates a phosphotyrosine. These two peptides were chosen because they have similar binding affinities but very different entropic/enthalpic thermodynamic binding signatures, indicating different interactions with solvent. We find that the isoleucine to valine mutation at position +3 (the third amino acid C-terminal to pY) in the ligand has only limited impact on the water structure. By contrast, the glutamic acid to isoleucine mutation at position +1 has a significant impact by not only abrogating a local hydrophilic binding site but, more importantly and surprisingly, inducing a favorable nonlocal entropic contribution from the water molecules around the phophorylated tyrosine at the +2 position. Our study demonstrates the validity of the method reported here for exploring the thermodynamic solvation landscape of protein-protein interactions. Proteins 2008. © 2008 Wiley-Liss, Inc.

Item Type: Article
Keyword(s) / Subject(s): SH2 domains, potential of mean force (PMF), phosphotyrosine; protein–protein interactions, salvation, thermodynamics, energetics, water
School or Research Centre: Birkbeck Schools and Research Centres > School of Science > Biological Sciences
Depositing User: Administrator
Date Deposited: 04 Aug 2010 14:09
Last Modified: 17 Apr 2013 12:17
URI: http://eprints.bbk.ac.uk/id/eprint/1161

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