From restrained stage 4, we decouple the trapped water, i.e., turn off its van der Waals (vdw) and Coulomb interactions simultaneously, in an NES simulation (edge E). Once the trapped water is decoupled, we remove the restraints in edges F through H in a reverse order to how they were applied. Finally, we transfer and re-couple the non-interacting trapped water to bulk solvent in edges I and J, respectively. Edge A represents the ABFE of the trapped water, i.e., the free energy to bring a water from the solvent to the trapped water's binding site in the complex, and is calculated by taking the negative of the summation of the free energies of all the other edges in the ABFE thermodynamic cycle.