Ours is the first systematically improvable fragmentation protocol to be applied to systems of this size. Our approach is robust in high-quality basis sets (up to augmented quadruple-ζ quality) and can be extended beyond the two-body level should the desired accuracy prove to be unobtainable using MBE (2). In future work, we will consider the use of counterpoise corrections that are compatible with MBE(n), and will implement energy screening to identify the most important subset of threebody terms, as we showed that these are few in number even for the problematic Zn 2+ -containing enzymes. Our scheme holds the potential to enable rigorous electronic structure theory calculations for large-scale computational biochemistry applications.