We performed a single MD/NCMC simulation for each protein-ligand system and NCMC parameter settings. The uncertainties were calculated based on blocking. We chose the number of blocks in such a way that the standard deviation was maximized across the blocks. For probabilities of the modes, we divided the simulation into smaller pieces of 1 ns length for MD/NCMC (10 ns for MD) and then calculated the uncertainties for each chunk of simulation. 3.4. Umbrella sampling performed by sampling different orientations of the rotatable bond. OpenMM was used to carry out the umbrella sampling simulations. We used the same MD simulation parameters described in section 3.2. The rotatable bond of the ligand was harmonically restrained to sample specified dihedral regions in each window. We tried three different parameter settings for the umbrella sampling simulations -i) 72 windows each with 200 kcal/mol/Å 2 force constant, ii) 128 windows each with 200 kcal/mol/Å 2 force constant, and iii) 152 windows with different force constants -400 or 600 or 800 kcal/mol/Å 2 . Each window was simulated for 10 ns.