The inter- and intramolecular interactions that determine the experimentally observed binding mode of the ligand(2Z)-2-(benzoylamino)-3-[4-(2-bromophenoxy)phenyl]-2-propenoate in complex with hepatitis C virus NS5B polymerase have been studied using QM/MM calculations. DFT-based QM/MM optimizations were performed on a number of ligand conformers in the protein-ligand complex. Using these initial poses, our aim is 2-fold. First, we identify the minimum energy pose. Second, we dissect the energetic contributions to this pose using QM/MM methods. The study reveals the critical importance of internal energy for the proper energy ranking of the docked poses. Using this protocol, we successfully identified three poses that have low RMSD with respect to the crystallographic structure from among the top 20 initially docked poses. We show that the most important energetic component contributing to binding for this particular protein-ligand system is the conformational (i.e., QM internal) energy.