We calculated the free energies of the edges B through D using an equilibrium free energy calculation and those of the edges F through G using a second equilibrium free energy calculation. We used an NES free energy calculation to estimate the free energy of decoupling the trapped water in edge E. The free energies of edges H, I and J depend on the restraint details and the water model, and not on the proteinligand complex. We have described their calculations in the Supporting Document Section S1.2.