Convergent Protocols for Computing Protein–Ligand Interaction Energies Using Fragment-Based Quantum Chemistry

Fragment-based quantum chemistry
methods offer a means
to sidestep
the steep nonlinear scaling of electronic structure calculations so
that large molecular systems can be investigated using high-level
methods. Here, we use fragmentation to compute protein–ligand
interaction energies in systems with several thousand atoms, using
a new software platform for managing fragment-based calculations that
implements a screened many-body expansion. Convergence tests using
a minimal-basis semiempirical method (HF-3c) indicate that two-body
calculations, with single-residue fragments and simple hydrogen caps,
are sufficient to reproduce interaction energies obtained using conventional
supramolecular electronic structure calculations, to within 1 kcal/mol
at about 1% of the computational cost. We also demonstrate that the
HF-3c results are illustrative of trends obtained with density functional
theory in basis sets up to augmented quadruple-ζ quality. Strategic
deployment of fragmentation facilitates the use of converged biomolecular
model systems alongside high-quality electronic structure methods
and basis sets, bringing ab initio quantum chemistry
to systems of hitherto unimaginable size. This will be useful for
generation of high-quality training data for machine learning applications.