Understanding Water's Structure and Thermodynamics using GIST (Grid Inhomogeneous Solvation Theory)

Crystal Nguyen
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.