Probing the effect of conformational constraint on phosphorylated ligand binding to an SH2 domain using polarizable force field simulations.

ABSTRACT: Preorganizing a ligand in the conformation it adopts upon binding to a protein has long been considered to be an effective way to improve affinity by making the binding entropy more favorable. However, recent thermodynamic studies of a series of complexes of the Grb2 SH2 domain with peptide analogues having constrained and flexible replacements for a phosphotyrosine residue revealed that less favorable binding entropies may result from constraining ligands in their biologically active conformations. Toward probing the origin of this unexpected finding, we examined the complexes of four phosphotyrosine-derived analogues with the Grb2 SH2 domain using molecular dynamics simulations with a polarizable force field. Significantly, the computed values for the relative binding free energies, entr

SUBMITTER: Shi Y 

PROVIDER: S-EPMC3277292 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature