Extended symmetry-adapted perturbation theory (XSAPT) uses a self-consistent charge embedding to capture many-body polarization, in conjunction with a pairwise-additive SAPT calculation of intermolecular interaction energies. The original implementation of XSAPT is based on charges that are fit to reproduce molecular electrostatic potentials, but this becomes a computational bottleneck in large systems. Charge embedding based on modified Hirshfeld atomic charges is reported here, which dramatically reduces the computational cost without compromising accuracy. Exemplary calculations are presented for supramolecular complexes such as C60@C60H28, a DNA intercalation complex, and a 323-atom model of a drug molecule bound to an enzyme active site. The proposed charge embedding should be useful in other fragment-based quantum chemistry methods as well.

We introduce an implementation of the truncated many-body expansion, MBE(n), in which the n-body corrections are screened using the effective fragment potential force field, and only those that exceed a specified energy threshold are computed at a quantum-mechanical level of theory. This energy-screened MBE(n) approach is tested at the n = 3 level for a sequence of water clusters, (H 2 O) N=6−34 . A threshold of 0.25 kJ/mol eliminates more than 80% of the subsystem electronic structure calculations and is even more efficacious in that respect than is distance-based screening. Even so, the energyscreened MBE(3) method is faithful to a full-system quantum chemistry calculation to within 1−2 kJ/mol/monomer, even in good quality basis sets such as aug-cc-pVTZ. These errors can be reduced by means of a two-layer approach that involves a Hartree−Fock calculation for the entire cluster. Such a correction proves to be necessary in order to obtain accurate relative energies for conformational isomers of (H 2 O) 20 , but the cost of a full-system Hartree−Fock calculation remains smaller than the cost of three-body subsystem calculations at correlated levels of theory. At the level of second-order Møller− Plesset perturbation theory (MP2), a screened MBE(3) calculation plus a full-system Hartree−Fock calculation is less expensive than a full-system MP2 calculation starting at N = 12 water molecules. This is true even if all MBE(3) subsystem calculations are performed on a single 40-core compute node, i.e., without significant parallelization. Energy-screened MBE(n) thus provides a fragment-based method that is accurate, stable in large basis sets, and low in cost, even when the latter is measured in aggregate computer time.