First of all, we compare the contact frequency distribution of the aggregated (biased) sampling using the splitting protocol (9 µs) with those from all the individual unbiased sampling from the 10 long simulations (10 µs each). Figure (top) displays such comparisons for ADRP-tofacitinib complex (refer to Figure in the Supporting Information for all other systems). It is evident that each 10 microsecond replica samples a mere subset of possible binding sites explored across the 9 microseconds of the splitting protocol. The only exception to this general observation are the contacts of the ligand with residues 140-160 that are exclusively observed in long simulations. We will discuss this exception below. The significant difference in sampling between the splitting protocol and each individual long replica is quantified with two-sample KS statistics. For ADRP system, KS statistics varies between 0.25 and 0.36 with an average of 0.31 and the average of all corresponding p-values is 1.37 × 10 -5 . Table shows mean and range of KS statistics values for other systems. They fall in a similar range going as high as 0.6 and as low as 0.13 in some cases.