A systematic examination of the computational expense and accuracy of Symmetry-Adapted Perturbation Theory (SAPT) for the prediction of non-covalent interaction energies is provided with respect to both method [SAPT0, DFT-SAPT, SAPT2, SAPT2+, SAPT2+(3), and SAPT2+3; with and without CCD dispersion for the last three] and basis set [Dunning cc-pVDZ through aug-cc-pV5Z wherever computationally tractable, including truncations of diffuse basis functions]. To improve accuracy for hydrogen-bonded systems, we also include two corrections based on exchange-scaling (sSAPT0) and the supermolecular MP2 interaction energy (δMP2). When considering the best error performance relative to computational effort, we recommend as the gold, silver, and bronze standard of SAPT: SAPT2+(3)δMP2/aug-cc-pVTZ, SAPT2+/aug-cc-pVDZ, and sSAPT0/jun-cc-pVDZ. Their respective mean absolute errors in interaction energy across the S22, HBC6, NBC10, and HSG databases are 0.15 (62.9), 0.30 (4.4), and 0.49 kcal mol(-1) (0.03 h for adenine·thymine complex).

Recently, we introduced an effective atom-pairwise partition of the many-body symmetry-adapted perturbation theory (SAPT) interaction energy decomposition, producing a method known as atomic SAPT (A-SAPT) [Parrish, R. M.; Sherrill, C. D. J. Chem. Phys. 2014, 141, 044115]. A-SAPT provides ab initio atom-pair potentials for force field development and also automatic visualizations of the spatial contributions of noncovalent interactions, but often has difficulty producing chemically useful partitions of the electrostatic energy, due to the buildup of oscillating partial charges on adjacent functional groups. In this work, we substitute chemical functional groups in place of atoms as the relevant local quasiparticles in the partition, resulting in a functional-group-pairwise partition denoted as functional-group SAPT (F-SAPT). F-SAPT assigns integral sets of local occupied electronic orbitals and protons to chemical functional groups and linking σ bonds. Link-bond contributions can be further assigned to chemical functional groups to simplify the analysis. This approach yields a SAPT partition between pairs of functional groups with integral charge (usually neutral), preventing oscillations in the electrostatic partition. F-SAPT qualitatively matches chemical intuition and the cut-and-cap fragmentation technique but additionally yields the quantitative many-body SAPT interaction energy. The conceptual simplicity, chemical utility, and computational efficiency of F-SAPT is demonstrated in the context of phenol dimer, proflavine(+)-DNA intercalation, and a cucurbituril host-guest inclusion complex.

Symmetry-adapted perturbation theory (SAPT) is applied to pairs of hydrogen-bonded nucleobases to obtain the energetic components of base stacking (electrostatic, exchange-repulsion, induction/polarization, and London dispersion interactions) and how they vary as a function of the helical parameters Rise, Twist, and Slide. Computed average values of Rise and Twist agree well with experimental data for B-form DNA from the Nucleic Acids Database, even though the model computations omitted the backbone atoms (suggesting that the backbone in B-form DNA is compatible with having the bases adopt their ideal stacking geometries). London dispersion forces are the most important attractive component in base stacking, followed by electrostatic interactions. At values of Rise typical of those in DNA (3.36 Å), the electrostatic contribution is nearly always attractive, providing further evidence for the importance of charge-penetration effects in π-π interactions (a term neglected in classical force fields). Comparison of the computed stacking energies with those from model complexes made of the "parent" nucleobases purine and 2-pyrimidone indicates that chemical substituents in DNA and RNA account for 20-40% of the base-stacking energy. A lack of correspondence between the SAPT results and experiment for Slide in RNA base-pair steps suggests that the backbone plays a larger role in determining stacking geometries in RNA than in B-form DNA. In comparisons of base-pair steps with thymine versus uracil, the thymine methyl group tends to enhance the strength of the stacking interaction through a combination of dispersion and electrosatic interactions.

Molecular mechanics (MM) force field models have been demonstrated to have difficulty reproducing certain potential energy surfaces of π-stacked complexes. Here, we examine the performance of the AMBER and CHARMM models relative to high-quality ab initio data across systematic helical parameter scans and typical B-DNA geometries for π-stacking energies of nucleobase dimers. These force fields perform best for typical B-DNA geometries (mean absolute error < 1 kcal mol(-1)), whereas errors typically approach ∼2 kcal mol(-1) for broader potential scans, with maximum errors > 10 kcal mol(-1) relative to high-quality ab initio reference interaction energies. The adequate performance of MM models near minimum energy structures is accomplished through cancellation of errors in various energy terms, whereas large errors at short intermolecular distances are caused by large MM electrostatics errors due to a lack of explicit terms modeling charge penetration effects.

A metal-mediated interprotomer hydrogen bond has been implicated in the allosteric mechanism of DNA operator binding in several metal-sensing proteins. Using computational methods, we investigate the energetics of such zinc-mediated interactions in members of the ArsR/SmtB family of proteins (CzrA, SmtB, CadC and NmtR) and the MarR family zinc-uptake repressor AdcR, each of which feature similar interactions, but in sites that differ widely in their allosteric responsiveness. We provide novel structural insight into previously uncharacterized allosteric forms of these proteins using computational methodologies. We find this metal-mediated interaction to be significantly stronger (~8 kcal/mol) at functional allosteric metal binding sites compared to a non-responsive site (CadC) and the apo-proteins. Simulations of the apo-proteins further reveal that the high interaction energy works to overcome the considerable disorder at these hydrogen-bonding sites and functions as a “switch” to lock in a weak DNA-binding conformation once metal is bound. These findings suggest a conserved functional role of metal-mediated second-coordination shell hydrogen bonds at allosterically responsive sites in zinc-sensing transcription regulators.