Quantum-chemical models of enzymatic active sites require hundreds of atoms to obtain converged reaction energies, severely limiting the levels of theory that can be used.   We use fragment-based methods to compute converged thermochemical properties for several large active site models, avoiding the steep nonlinear scaling associated with conventional quantum chemistry by running smaller byte-sized fragment calculations in parallel, and we have developed a protocol for such calculations as applied to enzymatic reactions.  In the presence of charged amino acid residues, the conventional low-order many-body expansion fails to converge under vacuum boundary conditions, although it converges at three-body terms when low-dielectric (ε = 4) boundary conditions are used instead.  This suggests that benchmark studies of the many-body expansion that aim to reproduce gas-phase supersystem results for proteins are fundamentally misguided.  For calculations with continuum boundary conditions, sub-kcal/mol accuracy is obtained using our fragmentation protocol, at lower (in total CPU time) as compared to brute-force supersystem calculations.

Fragmented proteins don’t live in a vacuum

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