While the non-equilibrium switches are typically very short compared to the equilibrium simulations, the total computational effort can still be significant due to the number of switches that need to be run (usually around 50-100) and the fact that they require an equilibrium simulation of the end states to generate the starting configurations. However, the separate switches are embarrassingly parallel and require only a short wall clock time, which allows efficient use of large distributed computational resources. 2.2. The thermodynamic cycle to calculate the ABFE of a trapped water. In the first part of this study, we present a thermodynamic cycle for calculating the ABFE of a trapped water in a protein-ligand complex (Figure ). Throughout this paper, we refer to this thermodynamic cycle as the "ABFE thermodynamic cycle". The ABFE thermodynamic cycle presented here is an optimization of the thermodynamic cycle presented in the previous work of Ge et al. In the ABFE thermodynamic cycle, we restrain the interacting trapped water to its binding site (edge B), add a solvent repulsion term at the target position of the trapped water in the protein's binding site to restrain the solvent from occupying the trapped water's binding site (edge C), and restrain the binding site to avoid changes in its conformation (edge D). We apply these three restraints sequentially across stages 1 through 4 of our thermodynamic cycle.