Water molecules in the active site of an enzyme occupy a complex, heterogeneous environment, and the thermodynamic properties these water molecules are highly dependent on their location in the active site. As a consequence, it is thought that an enzyme inhibitor can gain affinity by extending into a region occupied by unfavorable water, or lose affinity by displacing water from a region where it was relatively stable. Recent advances in the characterization of binding-site water, based on Inhomogenous Solvation Theory (IST), applied to molecular simulations with explicit water molecules, have focused largely on simplified representations of water as occupying well-defined hydration sites. Our grid-based treatment of IST, GIST, which is now available as part of AmberTools v14, offers a more complete picture of the complex distributions of water properties. Here we present results of the first application of GIST to protein-ligand modeling, for the case of Coagulation Factor Xa, which shows that ligand scoring functions based on GIST perform at least as well as scoring functions based on a hydration-site approach (HSA), when applied to exactly the same simulation data. We will also discuss common misconceptions regarding the contributions of IST entropies and enthalpies and discuss strategies for implementing IST in a drug design and discovery setting.  

Characterizing and exploiting the hydration of protein surfaces for applications in drug design and discovery

248th National Meeting (2014)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.