Our restraining scheme resulted in excellent phase space overlap across stages 1 through 4 in our trapped water ABFE calculations, details of which are discussed in the Results Section 3.1.1, which prompted us to further optimize our RBFE thermodynamic cycle. Specifically, we combined the edges B, C and D into a single edge, i.e., edge M (Figure ). Furthermore, we omitted the 7 intermediate λ states, which we introduced in the ABFE thermodynamic cycle to calculate the free energy of removing the restraints on the binding site. We also combined the edges F' and G' into a single edge L, because, after the (green) ligand is transformed into the bigger (purple) ligand, the binding site cavity created by the decoupling of the trapped water is filled by the bigger ligand and the solvent water or the protein residues cannot occupy the cavity. This way, combining the removal of the solvent repulsion and binding site restraints is an optimal choice.