Unexpected Routes of the Mutagenic Tautomerization of the T Nucleobase in the Classical A·T DNA Base Pairs: A QM/QTAIM Comprehensive View.

In this paper using quantum-mechanical (QM) calculations in combination with Bader's quantum theory of "Atoms in Molecules" (QTAIM) in the continuum with ε = 1, we have theoretically demonstrated for the first time that revealed recently highly-energetic conformers of the classical A·T DNA base pairs - Watson-Crick [A·T(wWC)], reverse Watson-Crick [A·T(wrWC)], Hoogsteen [A·T(wH)] and reverse Hoogsteen [A·T(wrH)] - act as intermediates of the intrapair mutagenic tautomerization of the T nucleobase owing to the novel tautomerisation pathways: A·T(wWC)↔A·T*(w⊥ WC); A·T(wrWC)↔A· T O 2 * (w⊥ rWC); A·T(wH)↔A·T*(w⊥ H); A·T(wrH)↔A· T O 2 * (w⊥ rH). All of them occur via the transition states as tight ion pairs (A+, protonated by the N6H2 amino group)·(T-, deprotonated by the N3H group) with quasi-orthogonal geometry, which are stabilized by the participation of the strong (A)N6+H···O4-/O2-(T) and (A)N6+H···N3-(T) H-bonds. Established tautomerizations proceed through a two-step mechanism of the protons moving in the opposite directions along the intermolecular H-bonds. Initially, proton moves from the N3H imino group of T to the N6H2 amino group of A and then subsequently from the protonated N6+H3 amino group of A to the O4/O2 oxygen atom of T, leading to the products - A·T*(w⊥ WC), A· T O 2 * (w⊥ rWC), A·T*(w⊥ H), and A· T O 2 * (w⊥ rH), which are substantially non-planar, conformationally-labile complexes. These mispairs are stabilized by the participation of the (A)N6H/N6H'···N3(T) and (T)O2H/O4H···N6(A) H-bonds, for which the pyramidalized amino group of A is their donor and acceptor. The Gibbs free energy of activation of these mutagenic tautomerizations lies in the range of 27.8-29.8 kcal·mol-1 at T = 298.15 K in the continuum with ε = 1.

Non-dissociative structural transitions of the Watson-Crick and reverse Watson-Crick А·Ð¢ DNA base pairs into the Hoogsteen and reverse Hoogsteen forms.

In this study it was theoretically shown that discovered by us recently (Brovarets' et al., Frontiers in Chemistry, 2018, 6:8; doi: 10.3389/fchem.2018.00008) high-energetical, significantly non-planar (symmetry C1), short-lived wobbled conformers of the classical Watson-Crick А·Ð¢(WC), reverse Watson-Crick А·Ð¢(rWC), Hoogsteen А·Ð¢(Н) and reverse Hoogsteen А·Ð¢(rН) DNA base pairs are the intermediates of their pairwise А∙Т(WC)/А∙Т(rWC) ↔ А∙Т(H)/А∙Т(rH) conformational transformations. These transitions do not require for their realization the energy-consumable anisotropic rotation of the amino group of A around the exocyclic C6-N6 bond. They are controlled by the non-planar transition states with quasi-orthogonal geometry (symmetry C1) joined by the single intermolecular (Т)N3H···N6(А) H-bond (~4 kcal∙mol-1). The Gibbs free energies of activation for these non-dissociative, dipole-active conformational transitions consist 7.33 and 7.81 kcal∙mol-1, accordingly. Quantum-mechanical (QM) calculations in combination with Bader's quantum theory of "Atoms in Molecules" (QTAIM) have been performed at the MP2/aug-cc-pVDZ//B3LYP/6-311++G(d,p) level of QM theory in the continuum with ε = 4 under normal conditions.

Novel pathway for mutagenic tautomerization of classical А∙Т DNA base pairs via sequential proton transfer through quasi-orthogonal transition states: A QM/QTAIM investigation.

In this paper we have theoretically predicted a novel pathway for the mutagenic tautomerization of the classical A∙T DNA base pairs in the free state, the Watson-Crick A·Ð¢(WC), reverse Watson-Crick A·Ð¢(rWC), Hoogsteen A·Ð¢(H) and reverse Hoogsteen A·Ð¢(rH) pairs, via sequential proton transfer accompanied by a significant change in the mutual orientation of the bases. Quantum-mechanical (QM) calculations were performed at the MP2/aug-cc-pVDZ//B3LYP/6-311++G(d,p) level in vacuum phase, along with Bader's quantum theory of Atoms in Molecules (QTAIM). These processes involve transition states (TSs) with quasi-orthogonal structures (symmetry C1), which are highly polar, tight ion pairs (A-, N6H2-deprotonated)∙(T+, O4/O2-protonated). Gibbs free energies of activation for the A∙T(WC) / A∙T(rWC) ↔ A*∙Т(rwWC) / A*∙Т(wWC) tautomeric transitions (~43.5 kcal∙mol-1) are lower than for the A∙T(H) / A∙T(rH) ↔ A*N7∙Т(rwH) / A*N7∙Т(wH) tautomerisations (~53.0 kcal∙mol-1) (rare tautomers are marked by an asterisk; w-wobble configured tautomerisation products). The (T)N3+H⋯N1-(A), (T)O4+H⋯N1-(A) / (T)N3+H⋯N1-(A) and (T)O2+H⋯N1-(A) H-bonds are found in the transition states TSA-·T+A·T(WC)↔A*·T(rwWC) / TSA-·T+A·T(rWC)↔A*·T(wWC). However, in the transition state TSA-·T+A·Ð¢(H)↔A*N7·T(rwH) / TSA-·T+A·Ð¢(rH)↔A*N7·T(wH), the (T)N3+H⋯N7-(A), (T)O4+H⋯N7-(A) / (T)N3+H⋯N7-(A) and (T)O2+H⋯N7-(A) H-bonds are supplemented by the attractive (T)O4+/O2+⋯N6-(A) van der Waals contacts. It was demonstrated that the products of the tautomerization of the classical A∙T DNA base pairs-A*∙Т(rwWC), A*N7∙Т(rwH) and A*N7∙Т(wH) (symmetry Cs)-further transform via double proton transfer into the energetically favorable wobble A∙T*(rwWC), A∙T*(rwH) and A∙T*O2(wH) base mispairs (symmetry Cs).

Surprising Conformers of the Biologically Important A·T DNA Base Pairs: QM/QTAIM Proofs.

For the first time novel high-energy conformers-A·T(wWC) (5.36), A·T(wrWC) (5.97), A·T(wH) (5.78), and A·T(wrH) (ΔG = 5.82 kcal·mol-1) (See Graphical Abstract) were revealed for each of the four biologically important A·T DNA base pairs - Watson-Crick A·T(WC), reverse Watson-Crick A·T(rWC), Hoogsteen A·T(H) and reverse Hoogsteen A·T(rH) at the MP2/aug-cc-pVDZ//B3LYP/6-311++G(d,p) level of quantum-mechanical theory in the continuum with ε = 4 under normal conditions. Each of these conformers possesses substantially non-planar wobble (w) structure and is stabilized by the participation of the two anti-parallel N6H/N6H'…O4/O2 and N3H…N6 H-bonds, involving the pyramidalized amino group of the A DNA base as an acceptor and a donor of the H-bonding. The transition states - TSA·T(WC)↔A·T(wWC), TSA·T(rWC)↔A·T(wrWC), TSA·T(H)↔A·T(wH), and TSA·T(rH)↔A·T(wrH), controlling the dipole-active transformations of the conformers from the main plane-symmetric state into the high-energy, significantly non-planar state and vice versa, were localized. They also possess wobble structures similarly to the high-energy conformers and are stabilized by the participation of the N6H/N6H'…O4/O2 and N3H…N6 H-bonds. Discovered conformers of the A·T DNA base pairs are dynamically stable short-lived structures [lifetime τ = (1.4-3.9) ps]. Their possible biological significance and future perspectives have been briefly discussed.

The A·T(rWC)/A·T(H)/A·T(rH) ↔ A·T*(rwWC)/A·T*(wH)/A·T*(rwH) mutagenic tautomerization via sequential proton transfer: a QM/QTAIM study.

In this study for the first time we have revealed by QM and QTAIM calculations at the MP2/aug-cc-pVDZ//B3LYP/6-311++G(d,p) level of QM theory the novel routes of the mutagenic tautomerization of three biologically important A·T DNA base pairs - reverse Watson-Crick A·T(rWC), Hoogsteen A·T(H) and reverse Hoogsteen A·T(rH) - followed by their rebuilding into the wobble (w) A·T*(rwWC), A·T*(wH) and A·T*(rwH) base mispairs by the participation of the mutagenic tautomers of the DNA bases (denoted by asterisk) and vice versa, thus complementing the physico-chemical property of the canonical A·T(WC) Watson-Crick DNA base pair reported earlier (Brovarets' et al., RSC Adv., 2015, 5, 99594-99605). These non-dissociative tautomeric transformations in the classical A·T(rWC), A·T(H) and A·T(rH) DNA base pairs proceed similarly to the canonical A·T(WC) DNA base pair via the intrapair sequential proton transfer with shifting towards major or minor grooves of DNA followed by further double proton transfer along the intermolecular H-bonds and are controlled by the plane symmetric and highly stable transition states - tight ion pairs formed by the A+ nucleobase, protonated by the N1/N7 nitrogen atoms, and T- nucleobase, deprotonated by the N3H imino group. Comparison of the estimated populations of the tautomerised states (10-21 to 10-14) with similar characteristics for the canonical A·T(WC) DNA base pair (10-8 to 10-7) leads authors to the conclusion, that only a base pair with WC architecture can be a building block of the DNA macromolecule as a genetic material, which is able for the evolutionary self-development. Among all four classical DNA base pairs, only A·T(WC) DNA base pair can ensure the proper rate of the spontaneous point errors of replication in DNA.