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.

Automated summary

Electronic structure calculations on enzymes with hundreds of atoms can be costly, but fragment-based approximations provide a cost-effective solution. The many-body expansion method allows calculations on enzyme models with 500-600 atoms and compares well with benchmarks. Different boundary conditions can affect the convergence of the calculations, highlighting the need for appropriate assessments of errors in fragment-based approximations. Protocols involving three-body or two-body calculations combined with a full-system correction offer accurate results at a lower computational cost, making high-level quantum chemistry applicable to large systems.