Abstract
A systematic study of techniques for treating non-covalent interactions within the
computationally efficient density functional theory (DFT) framework is presented
through comparison to benchmark-quality evaluations of binding strength com-
piled for molecular complexes of diverse size and nature. In particular, the effi-
cacy of functionals deliberately crafted to encompass long-range forces, a posteri-
ori DFT+dispersion corrections (DFT-D2 and DFT-D3), and exchange-hole dipole
moment (XDM) theory is assessed against a large collection (469 energy points)
of reference interaction energies at the CCSD(T) level of theory extrapolated to
the estimated complete basis set limit. The established S22 and JSCH test sets
of minimum-energy structures, as well as collections of dispersion-bound (NBC10)
and hydrogen-bonded (HBC6) dissociation curves and a pairwise decomposition of
a protein-ligand reaction site (HSG), comprise the chemical systems for this work.
From evaluations of accuracy, consistency, and efficiency for PBE-D, BP86-D, B97-D,
PBE0-D, B3LYP-D, B970-D, M05-2X, M06-2X, ωB97X-D, B2PLYP-D, XYG3, and
B3LYP-XDM methodologies, it is concluded that distinct, often contrasting, groups
of these elicit the best performance within the accessible double-ζ or robust triple-ζ
basis set regimes and among hydrogen-bonded or dispersion-dominated complexes.
For overall results, M05-2X, B97-D3, and B970-D2 yield superior values in conjunc-
tion with aug-cc-pVDZ, for a mean absolute deviation of 0.41 – 0.49 kcal/mol, and
B3LYP-D3, B97-D3, ωB97X-D, and B2PLYP-D3 dominate with aug-cc-pVTZ, af-
fording, together with XYG3/6-311+G(3df,2p), a mean absolute deviation of 0.33 –
0.38 kcal/mol.
