In this award funded by the Theoretical and Computational Chemistry Program of the Chemistry Division and the Molecular Biophysics Program in the Division of Molecular and Cellular Biosciences, Steven Rick will examine theoretically how water affects protein-ligand binding and protein flexibility. Work will be pursued in three areas. First, the free energy of adding a water molecule to positions bridging a ligand and a protein will be calculated using free energy perturbation, in order to examine the correlation between water thermodynamics and binding constants. Next, the influence of interior water molecules on protein flexibility will be tested, by simulations both with and without all interior water molecules. Finally, water in simple models for protein cavities will be examined, where these cavities have varying degrees of hydrophilicity. A key part of this research is the comparison of different potentials, including polarizable models. As part of the effort, Rick will develop improved algorithms for implementing simulations using polarizable potentials as well as improved replica exchange sampling methods for large systems. These developments will be made available to the scientific community through the CHARMM program. Outcomes of this project are expected to lead to better understanding of the role of interior water molecules on protein flexibility, and improved methods for protein simulations with explicit solvent.
The results of this research will lead to new knowledge of the thermodynamics and structure of bound water molecules in biological systems. Water molecules that are buried in protein interiors between a protein and a ligand can have strong influences on function of biomolecules. For example, the mutations that lead to drug resistance are thought to involve the addition of a tightly bound water molecule. Rick will continue his association with Southern University of New Orleans (SUNO), a historically black primarily undergraduate institution, to offer SUNO students opportunities to carry out research in chemistry.
