Incorporation of thermodynamics of water into scoring functions for accurate protein-ligand docking

Abstract

Water plays a significant role in binding process between a protein and a ligand. However, water molecules are often underappreciated or even ignored in protein-ligand docking. Usually, free energies of active-site water molecules are substantially different from those of waters in the bulk region. The binding of a ligand to a protein causes displacement of these waters from an active site to bulk, and this displacement process contributes to the free energy change of protein-ligand binding significantly. For instance, water molecules in a hydrophobic region of protein which cannot make appropriate hydrogen bonds are energetically unfavorable, and the displacement of such water molecules into bulk region earns a substantial contribution in binding free energy. The free energy of active-site water molecules can be calculated by grid inhomogeneous solvation theory (GIST), using molecular dynamics trajectory (MD) of a target protein and water. In this work, we combined GIST-based desolvation energy with the scoring function of AutoDock4 and discussed the accuracies of scoring and binding pose prediction.