Hepatitis C virus (HCV) affects about 170 million people worldwide and is an important public health concern. This project will 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 and the mechanism of action of these inhibitors is not well understood. To date there have not been systematic studies to understand the molecular origin of inhibition. We 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.