ChBE Seminar Series: Amish Patel
Tuesday, December 1, 2015
11:00 a.m.-12:15 p.m.
Room 2108, Chemical and Nuclear Engineering Building
Professor Dongxia Liu
Reliance Industries Term Assistant Professor
Department of Chemical and Biomolecular Engineering
University of Pennsylvania
Characterizing Protein Hydration to Inform its Solubility, Interactions, and Assembly
The last 2 decades have seen an incredible revolution in structural biology, with over 100,000 protein structures solved at atomic resolution. Translating this wealth of static structural information into a molecular understanding of dynamic intracellular processes represents a grand challenge in molecular biology, with grave implications on our understanding of human health and disease. Progress in this area hinges on our ability to understand, predict, and manipulate the interactions of proteins with the numerous molecules that it encounters in the cellular milieu – ligands, peptide fragments, nucleic acids, membranes, and other proteins. Because every biomolecular binding process involves protein-water interactions being disrupted, and replaced by direct interactions between the binding partners, the free energetics of these protein-water interactions play a crucial role in protein solubility, as well as its interactions with ligands and other proteins. However, accurately characterizing protein-water interactions is challenging, because proteins have incredibly complex surfaces that disrupt the inherent structure of water in countless different ways, depending not only on the chemistry of the underlying protein surface, but also on the precise topography and chemical pattern of amino acids. Using a combination of statistical mechanics and novel simulation techniques, we are working towards a computational framework for accurately estimating the strength of protein-water interactions in a highly efficient manner. Our approach involves application of 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, which we exploit. In particular, we quantify the protein hydration free energy, which determines its solubility, estimate proteinligand binding free energies, and identify putative protein interaction interfaces. By facilitating an efficient and accurate characterization of protein – water interactions, which makes concrete connections to experimental observables, we hope that our approach will transform our understanding of protein interactions as well as our ability to predict them.