These results once again demonstrate that consistent, sub-kcal/mol accuracy is achievable is two ways: MBE(3) alone, or MBE(2) with a supersystem correction. Distance cutoffs with R cut = 8 Å can safely be applied in either case. This consistency indicates that the supersystem correction (which is performed at the HF/6-31G level for the calculations reported in Table ) primarily accounts for three-body polarization, and that four- In summary, we find that low-dielectric boundary conditions lead to rapid convergence of the many-body expansion, which otherwise suffers from oscillatory behavior in the presence of charged fragments. Larger, chargeneutral fragments can be used as an alternative strategy to avoid these oscillations, but this will significantly increase the cost if a correlated wave function method is used for the two-body interactions. At the same time, ionic residues must be anticipated in general, and this makes dielectric boundary conditions effectively mandatory for QC calculations of enzymatic thermochemistry. These observations furthermore suggest that the use of gas-phase supersystem calculations to benchmark fragmentation approximations distorts the performance of those approximations. Where charged fragments are involved, comparison to a gas-phase benchmark may exaggerate the role of higher-order n-body terms.