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

High-order quantum chemistry is applied to hydro-gen-bonded natural DNA nucleobase pairs [adenine:thymine (A:T) and guanine:cytosine (G:C)] and non-natural Hachimoji nucleo-base 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, induc-tion/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)delta MP2/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.

Automated summary

High-order quantum chemistry methods were used to study the intermolecular interaction energies and their components for hydrogen-bonded DNA nucleobase pairs and non-natural Hachimoji nucleobase pairs. The most attractive component of the interaction energies was found to be the electrostatic interactions, followed closely by the sum of induction/polarization and London dispersion. Non-natural Hachimoji base pairs exhibited stronger interactions than the corresponding natural base pairs, while the natural base pairs were more stabilized in their Hoogsteen geometries. Hoogsteen geometries were less favorable for non-natural Hachimoji base pairs compared to Watson-Crick geometries.