Figure shows the probability of the two states we obtained using different number of windows in umbrella sampling simulations. We had to use 152 windows to achieve convergence. Additional windows directly increases the computational cost. Umbrella sampling was ∼35 times more expensive than MD/NCMC simulations for ligand 1. While we invested considerable effort initially in developing simpler protocols with fewer windows which would perform adequately, we were ultimately unsuccessfulprobably in part because steric barriers associated with rotating the group between binding modes often induce ligand and/or protein mo-tions as the bond is rotated.