for details). Force constants of 10 kcal/(mol*Å 2 ), 10 kcal/(mol*rad 2 ) and 20 kcal/(mol*rad 2 ) were used for distance, angle and dihedral angle restraints, respectively. All λ-windows were minimized and equilibrated using the protocol described above, with the addition of harmonic restraints applied to two water molecules in the binding pocket during minimization and heating, and gradually removed during equilibration. No restraints were applied during production. A total of 30 independent simulations were performed for all protocols. All uncertainties were quantified using samples of multiple replicates.