We revised the ABFE thermodynamic cycle to calculate the RBFEs of ligand pairs, where in each ligand pair, one ligand binds to its target protein with a trapped water while the other ligand displaces it. In the RBFE thermodynamic cycle, we used the same restraints as used in the ABFE thermodynamic cycle. After applying the restraints, we decoupled the trapped water and transformed the ligand in two subsequent NES simulations, and then removed the relevant restraints.