Ligand Binding Free Energies with Adaptive Water Networks: Two-Dimensional Grand Canonical Alchemical Perturbations

Abstract

receptor. For both systems, GCAP is shown to perform well at reproducing experimental binding affinities. Calculating the relative binding affinities with a naı̈ve, conventional attempt to solvate the active site illustrates how poor results can be if proper consideration of water molecules in occluded pockets is neglected. GCAP results are shown to be consistent with time-consuming double decoupling simulations. In addition, by obtaining the free energy surface for ligand perturbations, as a function of both the free energy coupling parameter and water chemical potential, it is possible to directly deconvolute the binding energetics in terms of protein-ligand direct interactions and protein binding site hydration.