CAREER: Computational Characterization of Protein Hydration and Interactions

University Of Pennsylvania, Philadelphia PA

Investigators

Abstract

PI: Patel, Amish J. Proposal Number: 1652646 Institution: University of Pennsylvania Title: CAREER: Computational Characterization of Protein Hydration and Interactions Because all of biology happens in water, every biomolecular binding process involves protein-water interactions being disrupted, and replaced by direct interactions between the binding partners. Protein-water interactions thus play a crucial role in protein hydration, its stability, as well as its interactions with ligands and other proteins. However, characterizing protein-water interactions is challenging, because they depend not only on the chemistry, but also on the precise topography and the chemical pattern presented by the protein surface. As a result, a fundamental understanding of how water structure is perturbed at protein interfaces, and how this perturbation in turn affects protein interactions, is lacking. The goal of this proposal is to characterize and understand the interactions between protein surfaces and their hydration waters, and to introduce students ranging from elementary to graduate school, especially those from disadvantaged backgrounds, to aspects of protein hydration and interactions through the use of innovative teaching methods and materials. The results from this project will be broadly disseminated to the research community and the general public. To enable a comprehensive characterization of protein-water interactions, the PI will employ novel simulation techniques to apply an unfavorable biasing potential to water molecules in the entire protein hydration shell. As the strength of the potential is increased, protein-water interactions are systematically disrupted, and the response of the hydration shell waters to the applied potential contains a wealth of information that can be analyzed to: (1) identify regions of the protein that have the weakest interactions with water, and investigate whether they can serve as predictors of protein interaction interfaces, (2) estimate free energies for hydrating diverse ligand-shaped cavities in the protein hydration shell, which inform protein-ligand interactions, and (3) identify super-hydrophilic patches on the protein that allow them to have strong interactions with water, and interrogate whether such interactions are able to stabilize the protein upon dehydration. The proposed research promises to break new ground by providing molecular level understanding and uncovering its impact on protein interactions and assembly. As novel protein structures continue to be solved at an incredible rate, modulating protein interactions promises to be an exciting frontier in the search for novel therapeutics.