To further investigate this issue, we pulled out some large transformations from our dataset to see if the same behaviour persists. To do so, we selected all transformations with the absolute difference between the number of disappearing and appearing atoms greater than 10, which amounts to 43 ligand pairs including 1 from the PDE2 set. We ignored the only transformation from the PDE2 dataset and the MUE for the remainder is 1.07 ± 0.14 kcal/mol. The MUE for the full dataset (503 ligand pairs) is 1.04 ± 0.04 kcal/mol. Thus, the accuracy for 'large' transformations is almost the same as that for the full dataset. Figure (b) displays the variation of unsigned errors for these 42 transformations with the size of transformation (defined as the absolute difference between the number of disappearing and appearing atoms). There is no correlation between the two quantities which implies that the observed errors are independent of the size of the transformation. This indicates that the issue of less accurate predictions for large transformations is specific to the PDE2 system and is not a general one for alchemical methods.