We calculated the free energy of edge M in an equilibrium free energy calculation, and the free energy of edge L in a second equilibrium free energy calculation. For calculating the free energies of decoupling the trapped water in edge E and of transforming the ligands in edge K, we ran two separate NES free energy calculations. We have described the calculation of the free energies of the edges H, I and J in the Supporting Document Section S1.2. We calculated the complex leg of the RBFE calculation between the two ligands by taking the summation of the free energies of edges M, E, K, L, H, I and J (Figure ). For calculating the solvent leg of the RBFE calculation for the ligand transformation (Figure ), we used an NES free energy calculation between equilibrium distributions of the two ligands in the solvent. For details of the equilibrium and the NES free energy calculations, for the complex and the solvent legs of the RBFE calculation, please refer to Sections 2.6.3 and 2.6.4, respectively.