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 subkilocalorie 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 manybody polarization.

Automated summary

Electronic structure calculations on enzymes are improved by fragment-based approximations and many-body expansion. When using amino acid fragments with ionic side chains, low-dielectric boundary conditions are necessary to restore rapid convergence. Traditional gas-phase calculations do not provide accurate benchmarks for assessing errors in fragment-based approximations. Three-body and two-body protocols with a full-system correction achieve high-level quantum chemistry calculations on large systems.