that with the charge on the ODR molecule set to zero, so that the ligand in the bound state interact with the environment only via the Lennard Jones potential. For this particular alchemical state, the COM-COM distance distribution has two maxima with similar intensity corresponding to two binding poses with comparable strength, at variance with the disparate intensities observed in Figure . Note that, as for the case of Figure referring to the end state of the bound system, the COM-COM distribution using replicates of MD simulations is found to recover the HREM results.