Hepatitis C virus (HCV) is a global health concern for which there is no vaccine available. The HCV polymerase is responsible for the critical function of replicating the RNA genome of the virus. Transitions between at least two conformations (open and closed) are necessary to allow the enzyme to replicate RNA. In this study, molecular dynamic simulations were initiated from multiple crystal structures to understand the free energy landscape (FEL) explored by the enzyme as it interconverts between these conformations. Our studies reveal the location of distinct states within the FEL as well as the molecular interactions associated with these states. Specific hydrogen bonds appear to play a key role in modulating conformational transitions. This knowledge is essential to elucidate the role of these conformations in replication and may also be valuable in understanding the basis by which this enzyme is inhibited by small molecules. (c) 2016 Wiley Periodicals, Inc.