These results may have important implications for the application of fragment-based quantum chemistry to study enzymatic reactions, especially for metalloenzymes where different oxidation states of a transition metal might be expected to exhibit varying degrees of SIE. Use of larger fragments may help to mitigate wild oscillations in MBE(n) that are documented here, as demonstrated previously for proteins (including ionic residues) using low-dielectric boundary conditions. That strategy is less straightforward in aqueous systems, where the simplest choice is single-H 2 O fragments, although methods with overlapping fragments have been used for calculations on various molecular clusters. Screening and culling the subsystem interactions can also mitigate oscillations in MBE(n), while simultaneously reducing cost. In that regard, there seems to exist a "Goldilocks point" at which enough solvating water molecules have been included to describe the solute's environment with reasonable accuracy, yet not so many that delocalization error overwhelms the result. Whether this balance can be codified in an unambiguous way remains an important issue for future study.