where E L represents the intramolecular energy of the ligand, E R the potential energy of the receptor, including water molecules, and E RL the interaction energy between ligand and receptor. Similar to a hybrid QM/MM simulation set-up, we treat the various energetic components using different levels of theory. The protein environment is described using the OPLS-AA/M force field, and water molecules using the TIP4P model. Receptorligand interactions are described using standard OPLS/CM1A Coulombic and Lennard-Jones interactions. The intramolecular potental energy of the ligand is written in the general form: