High-Order Quantum-Mechanical Analysis of Hydrogen Bonding in Hachimoji and Natural DNA Base Pairs

High-order quantum chemistry is applied
to hydrogen-bonded natural
DNA nucleobase pairs [adenine:thymine (A:T) and guanine:cytosine (G:C)]
and non-natural Hachimoji nucleobase pairs [isoguanine:1-methylcytosine
(B:S) and 2-aminoimidazo[1,2a][1,3,5]triazin-4(1H)-one:6-amino-5-nitropyridin-2-one
(P:Z)] to see how the intermolecular interaction energies and their
energetic components (electrostatics, exchange-repulsion, induction/polarization,
and London dispersion interactions) vary among the base pairs. We
examined the Hoogsteen (HG) geometries in addition to the traditional
Watson–Crick (WC) geometries. Coupled-cluster theory through
perturbative triples [CCSD(T)] extrapolated to the complete basis
set (CBS) limit and high-order symmetry-adapted perturbation theory
(SAPT) at the SAPT2+(3)(CCD)δMP2/aug-cc-pVTZ level are used
to estimate highly accurate noncovalent interaction energies. Electrostatic
interactions are the most attractive component of the interaction
energies, but the sum of induction/polarization and London dispersion
is nearly as large, for all base pairs and geometries considered.
Interestingly, the non-natural Hachimoji base pairs interact more
strongly than the corresponding natural base pairs, by −21.8
(B:S) and −0.3 (P:Z) kcal mol–1 in the WC
geometries, according to CCSD(T)/CBS. This is consistent with the
H-bond distances being generally shorter in the non-natural base pairs.
The natural base pairs are energetically more stabilized in their
Hoogsteen geometries than in their WC geometries. The Hoogsteen geometry
makes the A:T base pair slightly more stable, by −0.8 kcal
mol–1, and it greatly stabilizes the G:C+ base pair, by −15.3 kcal mol–1. The G:C+ stabilization is mainly due to the fact that C has typically
added a proton when found in Hoogsteen geometries. By contrast, Hoogsteen
geometries are substantially less favorable than WC geometries for
non-natural Hachimoji base pairs, by 17.3 (B:S) and 13.8 (P:Z) kcal
mol–1.