Comparison of the results of all ESMACS protocols across the full DIV + THQ dataset shows a distinct trend in which inclusion of the receptor average energy considerably improves the predictions obtained for both initial protein models. In both cases 1traj results have a Spearman rank coefficient, r s , of 0.46 [CI: 0.16-0.84 for both] which improves to 0.66 [CI: 0.50-0.94]/0.60 [CI: 0.40-0.91] (2OSS/4BJX) when both ligand and receptor flexibility are accounted for in the 2traj-ar protocol. In the DIV dataset better ranking can be obtained using receptor flexibility alone, but in order to obtain good rankings for THQ both additional contributions are required. This is the same behaviour observed in the simulation results for the THQ dataset in Wan et al. ; however the overall ranking is less good (the original study obtained an r s of 0.78 [CI: 0.53-0.92]), primarily due to the stronger predicted binding affinity for the experimentally least potent drug, THQ16, in the present study. The improvement between 1traj and 2traj-ar is illustrated in Figure , which shows that outliers are moved closer to the overall trend line (particularly apparent for the DIV ligands 3, 4 and 5 which were also outliers in Aldeghi et al. ). These three ligands have similar experimental binding energies but a difference of 15 kcal mol -1 in 1traj and 10 kcal mol -1 in 2traj-ar is seen in ∆G MMPBSA The ranking improvement is larger for the THQ ligands than the DIV dataset, with the 1traj results exhibiting little if any correlation with experiment. The main THQ outliers in the 1traj results are THQ12, THQ13 and THQ9. The first two are moved closer to the trend in the 2traj-ar results but THQ9 remains more negative than might be expected. Another feature of the 2traj-ar data here is that greater separation is seen between the results obtained from the two BRD4 structures for TH12, THQ13 and most pronouncedly THQ16. This is in contrast to nearly all other ligands where the values obtained from simulations with either model are well within the error margin, many sitting on top of one another in Figure .