To determine an optimal protocol for building up a larger QM system, we compared two different approaches. In the first approach, we used the distance from the oxygen or hydrogen of the central water O cen (H cen )• • • H(O) to select the next water molecule to be added to the QM system. In the second approach, we used the distance from the waters in the first solvation shell O 1 st shell (H 1 st shell )• • • H(O) to select the next water. Fig. shows the shifts in the IE of the central water (δ) upon increasing the QM size from 5 to 6 waters (with the rest of the waters described by point charges) for two MD snapshots (the