HIV protease is a key AIDS target, yet it is susceptible to frequent mutations that lead to drug resistance. In multiple structural studies, the movement of flaps has been implicated in controlling access to the active site. Furthermore, crystal structures always show a specific change between two types of closed structures upon ligand binding. The bound form shows minimal structural diversity across mutations, however, traditional structure based drug design ignores the fact that binding affinity is affected by the energy of the unbound state. We seek to understand the possible thermodynamic role of conformation change in drug resistance by modeling differences between bound and unbound structures in both drug susceptible sequences and in mutations that lead to clinical drug resistance such as V82F and I84V. We can thus determine if further refining closed state binding is an effective strategy for new drug development or if targeting a different conformation could generate an effective class of HIV protease inhibitors.