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Binding specificity of SH2 domains: Insight from free energy simulations

Cellular signal transduction pathways are controlled by specific protein–protein interactions mediated by the binding of short peptides to small modular interaction domains. To gain insights into the specificity of these interactions, the association of phosphotyrosine‐containing peptides to Src Homology 2 (SH2) domains is characterized using computations. Molecular dynamics simulations based on high‐resolution crystal structures complemented by homology models are used to calculate the absolute binding free energies for 25 SH2‐peptides pairs. The calculations are carried out using a potential of mean force free energy simulations method with restraining potentials that was developed previously (Woo and Roux, Proc Natl Acad Sci USA 2005;102:6825–6830). The method is utilized in conjunction with an implicit solvent representation to reduce the computational cost to characterize the association of five SH2 domains and five peptides. Specificity is ascertained by directly comparing the affinities of a given SH2 domain binding for any of the different peptides. For three of the five SH2 domains, the computational results rank the native peptides, as the most preferred binding motif. For the remaining two SH2 domains, high affinity binding motifs other than the native peptides are identified. This study illustrates how free energy computations can complement experiments in trying to elucidate complex protein–protein interactions networks. Proteins 2009. © 2008 Wiley‐Liss, Inc.