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Proteins. 2008 Sep;72(4):1290-7. doi: 10.1002/prot.22027.

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

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1
Computational Biochemistry and Biophysics Laboratory (GRIB), Universitat Pompeu Fabra, Barcelona Biomedical Research Park (PRBB), C/Dr Aiguader 88, 08003 Barcelona, Spain. gianni.defabritiis@upf.edu

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 phosphorylated 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.

PMID:
18384045
DOI:
10.1002/prot.22027
[Indexed for MEDLINE]

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