The local properties of water in a protein binding pocket play an important role in determing ligand-protein binding affinities. Using a high-affinity host molecule as a model system, we show the practicality of the new Grid Inhomogeneous Solvation Theory (GIST) approach to water structure and thermodynamics. We observe a toroidal region of high water density at the cavity's center, with unfavorable translational and orientational entropies relative to bulk water. These waters' mean interaction energies prove inadequate to balance the entropic cost, making the displacement of waters in this region by a guest molecule a highly favorable process.The use of a three-dimensional grid to analyze solvation in GIST method enables a clean analysis of water thermodynamics, not only for each grid point but also for any region of interest within the binding site. We anticipate that GIST will have applications in study of biomolecular solvation and computer-aided drug design.

Water structure and thermodynamics via grid inhomogeneous solvation theory

243rd National Meeting (2012)

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