For the DIV dataset as shown in Figure the improvements are yet more marked. The biggest improvement is seen in the 1traj results. Furthermore, the MUE for these rankings does not increase with adding more water near peak performance 3.38/3.54 for 0 and 3.08/3.08 for 5 water molecules (2OSS/4BJX). In line with the results of Aldeghi et al. the peak performance has r s > 0.9; however, unlike in the previous work here we see this at 2 water molecules included with a decline after 5 (as opposed to a peak at 20 and consistent performance thereafter). A number of factors could impact this including our use of ensembles of 4 ns trajectories (compared to single 16 ns runs) and Gaussian/RESP charges (as opposed to AM1-BCC). Overall though, it is important to retain at least four of the conserved water molecules in the binding site for the ESMACS calculations in order to obtain consistently good rankings across datasets. Moreover, the impact of adding water molecules differs between runs initiated with different starting structures, as shown in Table .