Another interesting fact is that RESP charges are more sensitive to chemical changes in ligand structures as compared to AM1-BCC charges. This is evident from the fact that, using the same charge tolerance criteria of 0.1e (difference between atomic charges on individual MCS atoms as well as the overall charge of MCS for the two ligands), the size of the alchemical region is larger for the RESP case as compared to AM1-BCC. The average number of disappearing atoms increases from 10.42 to 15.25 on using RESP charges for the 60 ligand pairs studied here. Similarly, the average number of appearing atoms also increases from 11.02 to 15.85 for all 60 ligand pairs. This trend is also visible for both subsets of 30 lig-amount of computation without compromising with their accuracy compared to RESP based models and that it is much faster to compute charges using the AM1-BCC model, it should be preferred for free energy calculations.