Ligand preorganization has long been considered to be an effective way to improve binding affinity by making the binding entropy more favorable. However, recent thermodynamic measurements revealed that less favorable binding entropies may result from constraining ligands in their biologically active conformations. In this work, we investigated four charged phosphorylated peptides binding to the Grb2 SH2 domain using AMOEBA polarizable force field. The simulations reveal that in solution a large fraction of the ligands lacking the constraining element exist in compact, macrocyclic-like structures that are stabilized by interactions between the phosphate group and the amide moieties of the pY+2 residue. In contrast, the three-membered ring in the constrained ligands, which was introduced to preorganize the phosphotyrosine residue in the bound conformation, prevents the formation of such macrocyclic structures, leading instead to globally extended, less ordered conformations. This study suggests that introducing local conformational constraints in flexible molecules may have unexpected consequences. Accordingly, a detailed understanding of the conformational preferences of ligands in their unbound states is critical.

Thermodynamic effects of conformational constraints in protein-ligand interactions

244th National Meeting (2012)

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