which allows us to perform standard MM simulations using the OPLS/CM1A force field (λ = 1), GAP simulations in which the ligand energetics are determined as described above (λ = 0), or any intermediate state determined by the coupling parameter λ. The latter feature allows us to employ free energy perturbation (FEP) theory to smoothly alter the ligand intramolecular energy between the GAP and OPLS/CM1A force fields, and thus to compute the free energy difference between the two states. Figure shows the proposed free energy cycle used to correct the MM binding free energy. Conventional FEP studies compute the (absolute or relative) free energy required to extract the ligand from solution into the protein binding site (∆G M M ). The corrected binding free energy is given by: