Hence, when, e.g., the electric charges on the alchemical ligand are turned off, as commonly done in a FEP calculations where electrostatic and Lennard-Jones interaction are sequentially switched off, the probability ratio of the two main poses in the BRD4(I)-ODR complex is likely to change significantly, with a direct effect on the free energy change. This fact is reported in Figure of SI where we computed, at constant invested simulation time of 288 ns, the COM-COM distance distribution and corresponding PMF using HREM with and without acceptance ratio balancing and MD with replicates on the BRD4(I)-ODR system at a typical λ point in FEP protocols, i.e.