Solvation Contribution to the Free Energy of Ligand Binding is Determined by the Coupling Between Surface Hydration Structure and Side Chain Motion

Abstract

Surface hydration significantly influences binding of a ligand to a protein. Yet its contribution to the binding free energy has been difficult to quantify. We introduce a computational method to calculate the desolvation penalty upon ligand binding based on the analysis of the surface hydration structure in all-atom molecular dynamics simulation. As a test system, we use the Src homology 3 (SH3) domain and two intrinsically disordered proline-rich motifs as ligands, one from the cellular protein cAbl and the other from NS1 of the 1918 Spanish influenza a virus.