NES simulation in edge E. After decoupling the trapped water, we perform a ligand transformation using a second NES simulation in edge K. After the ligand is transformed, we remove all the restraints, except the position restraint on the decoupled trapped water in edge L. Thereafter, we remove the restraint on the decoupled trapped water in edge H, and the transfer and re-couple the water to bulk solvent, in edges I and J, respectively. Throughout this paper, we will refer to this shortened thermodynamic cycle for ligand transformation as the "RBFE thermodynamic cycle", unless mentioned otherwise.