Constructing a suitable QM region requires more than including residues by their distance from the active site, as such a purely distance-based approach does not guarantee to take into account all important residues on the one hand and to exclude residues which only have a small effect on the quantity of interest on the other hand. For this reason, several different schemes have been proposed which aim at obtaining a mediumsized, atom-economical QM region that provides reliable QM/MM reaction energies.