Fragment-Based Calculations of Enzymatic Thermochemistry Require Dielectric Boundary Conditions

Electronic structure calculations on enzymes require
hundreds of
atoms to obtain converged results, but fragment-based approximations
offer a cost-effective solution. We present calculations on enzyme
models containing 500–600 atoms using the many-body expansion,
comparing to benchmarks in which the entire enzyme–substrate
complex is described at the same level of density functional theory.
When the amino acid fragments contain ionic side chains, the many-body
expansion oscillates under vacuum boundary conditions but rapid convergence
is restored using low-dielectric boundary conditions. This implies
that full-system calculations in the gas phase are inappropriate benchmarks
for assessing errors in fragment-based approximations. A three-body
protocol retains sub-kilocalorie per mole fidelity with respect to
a supersystem calculation, as does a two-body calculation combined
with a full-system correction at a low-cost level of theory. These
protocols pave the way for application of high-level quantum chemistry
to large systems via rigorous, ab initio treatment
of many-body polarization.