Understanding Water's Structure and Thermodynamics using GIST (Grid Inhomogeneous Solvation Theory)
Mike Gilson Lab
Skaggs School of Pharmacy and Pharmaceutical Sciences
UC San Diego
Water solvating protein surfaces occupies a complex, heterogeneous environment considerably
different than that in the bulk and therefore has significantly different thermodynamic profile on
the surface than in the bulk. The binding of a ligand or drug molecule to a protein involves
the expulsion of these surface waters into bulk and the thermodynamic differences
of these waters often have a dominant contribution to the free energy of the binding process.
Due to the importance of water expulsion for predicting
protein-ligand affinity, a number of explicit and implicit methods have been
developed to help describe and quantify the contribution of water to the binding process.
One successful approach, Inhomogeneous fluid Solvation Theory (IST), utilizes a
statistical analysis of molecular distribution functions obtained from Molecular Dynamics
simulations to estimate the thermodynamic properties of
water on biomolecular surfaces and in the bulk. However,
previous implementations of IST have focused on relatively large hydration sites where water
positions are clustered into high density spheres that inadequately describe the complex
topology of water thermodynamic properties in protein active sites. Here, we outline an
implementation of IST which maps out solvation thermodynamic properties on a
fine-meshed grid and show an early application of a scoring function which
utilizes IST maps to predict the differences in the binding affinities of between
congeneric pairs of ligands.