We also took notice of learnings from Deflorian et al. who noticed that extended equilibration times are critical to correctly template the protein and water since many of these compounds had to be modeled in place. In fact, for some ligands, we had to decide how to dock them since multiple equivalent solutions were possible (named up and down). To this end, we used absolute-binding FEP and simulated the most stable solutions. Hence we extended the equilibration time for these systems to 100 ns (see Supporting Information for further detail).