On the other hand, increasing the ensemble size to 20 reduces RMSE to 1.73 ± 0.36 kcal/mol despite higher uncertainities on its predictions as compared to the alternative approach. Larger ensemble size improves accuracy for 6 out of 7 ligand pairs under consideration here. The only exception is the one where the standard protocol predicts ∆∆G very close to the corresponding experimental value of -4.72 kcal/mol, whereas the large ensemble prediction falls outside the ±2 kcal/mol region. On ignoring this exceptional case, RMSEs for ensemble sizes 5 and 20 are 2.06 ± 0.46 kcal/mol and 1.56 ± 0.42 kcal/mol, respectively.