In the calculations presented below, the ellipticine ligand (33 atoms) is treated as one monomer and the entire double-stranded DNA model as a second monomer (with 124 atoms and -2 charge). These two systems are interesting in part because there is a discrepancy in both cases between various benchmark interaction energies available in the literature. For the DNA intercalation complex, a recent CCSD(T)/CBS benchmark (E int = 38.0±2.2 kcal/mol 103 ) is inconsistent with an older quantum Monte Carlo (QMC) estimate (E int = -33.6 ± 0.9 kcal/mol 102 ), even after accounting for the reported uncertainties in both values. For coronene dimer, the QMC benchmark (E int = -18.1 ± 0.8 kcal/mol 104 ) and the CCSD(T)/CBS benchmark (E int = -20.93 ± 0.44 kcal/mol 103 ) remain 1.6 kcal/mol apart after accounting for the uncertainties, although the smaller uncertainty in the CCSD(T)/CBS value in this case means that the two values of E int are not so far apart as they are for the DNA intercalation complex. A few other examples where QMC calculations are inconsistent with CCSD(T)/CBS values have also been reported recently, 104,105 and it is unclear to us which values are more reliable. QMC calculations are subject to an unknown fixed-node error that is not reflected in the statistical uncertainty, while the CCSD(T)/CBS benchmarks are computed using the domain-localized pair natural orbital (DLPNO) approximation. 106-108 For noncovalent interactions, this approximation is especially sensitive to numerical thresholds, 109 although this has been taken into consideration in the benchmark calculations cited above. Accuracy of the DLPNO approximation is also sensitive to system size. For these large systems, the δE HF correction is the most time-consuming part of an XSAPT calculation and the mixed-basis approach introduced above stands to yield considerable savings. We therefore benchmark this approach for these larger systems, using a variety of small basis sets to evaluate δE HF ; see Table . With only one exception, errors in δE HF are ≤ 0.3 kcal/mol for each of the smaller basis sets that we test, as measured with respect to the value computed in the largest basis set that is practical in either case. The one slightly larger error (of 0.5 kcal/mol) occurs when def2-SVP is used to evaluate δE HF for the DNA-ellipticine complex. Given the -2 charge on the DNA backbone, this would seem to be an inappropriate choice and is included here mostly for completeness, although it is interesting that the δE HF error remains rather small even in the absence of any diffuse functions at all. Based on these tests, we recommend 6-31+G(d) for the δE HF correction, as the error is < 0.3 kcal/mol but this basis is much more efficient than any of the others that are listed in Table .