There is substantial variation in the binding sites sampled both across replicas for each system as well as across all systems studied. For instance, in the case of the ADRP-tofacitinib system, four different binding sites are sampled by 3, 4, 9 and 6 replicas respectively. Comparing this behaviour with that of the other four systems studied (all relatively bigger in size), we can clearly see that they differ in that the number of sites observed is much higher with the number of replicas visiting each site being smaller. Taking the example of the PLPro-GRL system, there are 15 different binding sites observed with each only sampled by a single replica for all but one site. Furthermore, 9 out of 12 replicas exclusively sample only a single binding site. This behaviour is in contradiction to what we see for the ADRP-tofacitinib system exhibiting the extent of variation in sampling that may be observed across different systems using an ensemble of long independent simulations. The sampling behaviours of the other three systems fall in between the two extremes discussed above. It should be noted here that, in the above analyses, a replica is considered to have sampled a given binding site only if its ligand fractional occupancy is ≥ 0.03 around that site. In other words, a replica is assumed to have sampled only those binding sites that appear in the volume occupancy maps (and have non-negligible peaks in the corresponding contact frequency distributions) displayed in Figures and. It is possible that a replica has visited other binding sites too for a very short period of time but such transient events are neglected in our analyses as such a binding process cannot be considered stable.