For instance, there are 3 ligand pairs for which σ T IES reduces by more than 0.5 kcal/mol on applying REST2. However, 2 of them have higher unsigned errors for REST2 predictions than those for normal MD based predictions. This suggests that replica simulations have closer distributions of conformations due to mixing of states caused by exchange of conformations in REST2. However, the biased weights are equally present in all replicas and hence lower the accuracy.