Molecular Dynamics Studies of the RNA-Dependent RNA Polymerase of the Hepatitis C Virus

Abstract

The Hepatitis C Virus (HCV) affects approximately 200 million people throughout the world. About 25% of individuals with HCV will eventually contract chronic liver ailments, such as cirrhosis or liver cancer. Currently, there is no cure for this disease and there are few effective treatments. The HCV RNA-dependent RNA polymerase (RdRp) is an enzyme that is presently a target protein for drug discovery because of its importance for viral replication. It is believed that a conformational change is necessary for RdRp to initiate the replication process. There is evidence that this conformational change is facilitated by the presence of magnesium ions and crystallographic data indicates the location of two magnesium-binding sites in the palm domain of the enzyme. We employ molecular simulations and Principal Component Analysis to demonstrate, at a molecular level of detail, that the presence of magnesium ions alters the internal motion of RdRp. Particularly large fluctuations observed in the thumb domain of the enzyme may play a role in mediating the conformational change necessary for RdRp activity. By observing the structural coupling that occurs as a result of enzyme dynamics, we hope to understand the link between the dynamic properties of RdRp and its functional attributes. In addition to providing insight into RdRp function, this study illuminates fundamental questions regarding the role that external effectors may play in altering internal enzyme dynamics.