When dielectric boundaries are employed, MBE(3) provides converged results with sub-kcal/mol fidelity, without the need for electrostatic embedding, conjugated caps, or an ONIOM-style supersystem correction, and using single-residue fragments for most of the protein. This relatively simple three-body approach represents a reliable fall-back procedure for systems that are too large even for conventional DFT. That said, even for a 632atom enzyme-substrate model, a full-system DFT cal-culation is far less expensive when a high-performance electronic structure code is used. A practical alternative to MBE(3) is MBE(2) with distance screening, in a double-ζ basis set, plus an ONIOM-style supersystem correction at the HF/6-31G level. This composite approach is converged below 1 kcal/mol with respect to a triple-ζ benchmark and is generally less expensive than the full-system calculation. Moreover, that cost is readily distributable across hardware.