The combined DIV + THQ 4BJX 1traj ranking shows only a consistent result, with no improvement, as the first 5 water molecules were incorporated, whereas in 2OSS the ranking improves from an r s of 0.46 [CI: 0.16-0.84] to 0.54 [CI: 0.16-0.84] after the first two water molecules are included. In 1traj-ar the 4BJX results improve from a lower baseline rapidly whilst those from 2OSS remain consistent until 5 water molecules are added, at which point the results from both structures give an r s of around 0.6. A similar pattern is seen in 2traj-ar, but with the peak performance at 2 water molecules of 0.70 [CI: 0.54-0.97]/0.67 [CI: 0.49-0.96] (2OSS/4BJX) as shown in Table . The increase in MUE which accompanies the improvement in correlation indicates that the effects are not uniform across all ligands. Marginal gains in correlation coefficient should not be over emphasized (as can be seen in Table improvements are often within error); we rather wish to draw attention to the trend that inclusion of water molecules likely to be involved in mediating stable ligand-protein interactions improves (or at least does not degrade) calculation performance. The most important observation is that the addition of explicit water molecules improves the reproducibility of the ranking when using different starting models. .62 (0.47) 0.67 (0.12) 3 4.28 (0.49) 0.68 (0.12) 5.04 (0.52) 0.67 (0.12) 4 4.57 (0.51) 0.68 (0.12) 5.35 (0.56) 0.66 (0.12) 5 4.79 (0.54) 0.68 (0.12) 5.59 (0.58) 0.66 (0.12) * MUE corrected for mean signed error in kcal mol -1 .