Molecular Simulation and Biophysical Modeling

My core interests are to understand the fundamental physical principles that govern the interplay between protein structure, function and dynamics. My objective is to study biological questions that have a tangible, positive impact on societal problems. Primary tools in this undertaking are theoretical and molecular simulation methods. I embrace a multidisciplinary approach to research and value collaborations with experimental groups.

Allosteric Inhibition of Hepatitis C Viral Polymerase

Hepatitis C virus (HCV) affects about 170 million people worldwide and is an important public health concern. I intend to identify novel therapeutic strategies to counter HCV infection by examining, at the molecular level, the physical properties that govern inhibition of the viral RNA-dependent RNA polymerase (RdRp) which replicates the HCV genome. Several classes of allosteric inhibitors bind to the enzyme away from the site of nucleotide addition to a nascent RNA strand. The mechanism of action of these inhibitors is not well understood, and to date there have not been systematic studies to understand the molecular origin of inhibition. I will employ molecular simulation methods to obtain a detailed physical description of the structural and dynamic properties of RdRp in order to determine the source of allosteric inhibition. My goals are to: 

 i) identify the molecular origin of allosteric inhibition

ii) locate novel allosteric binding sites on the enzyme surface

iii) identify new small molecule inhibitors that can bind to known or newly identified allosteric sites.

Engineering Enzymes for Biofuel Production

This project will design enzymes that can degrade the plant polymer cellulose more efficiently. Cellulose is composed of sugar subunits which could serve as the basis for a sustainable and renewable source of fuels. Plant tissues contain large amounts of cellulose as the primary structural component of their cell walls. Unfortunately, this material is resistant to microbial and enzymatic breakdown. Naturally occurring enzymes (cellulases) exist that are able to degrade cellulose into simpler sugars, but these tend to be too inefficient for large scale production. I intend to combine the structural information available for these enzymes with molecular simulation, phylogenetic analysis and biochemical data to identify rational design strategies to enhance cellulase efficiency. My goals are to:

i) understand how cellulases bind to cellulose

ii) understand how  cellulases facilitate the cleavage of glycosidic bonds in cellulose

iii) design cellulases that are more stable in harsh industrial environments