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

摘要

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·Т(WC), reverse Watson-Crick A·Т(rWC), Hoogsteen A·Т(H) and reverse Hoogsteen A·Т(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 TS^A-·T+A·T(WC)↔A*·T(rwWC) / TS^A-·T+A·T(rWC)↔A*·T(wWC). However, in the transition state TS^A-·T+A·Т(H)↔A*N7·T(rwH) / TS^A-·T+A·Т(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(w_H) (symmetry C_s)–further transform via double proton transfer into the energetically favorable wobble A∙T*(rw_WC), A∙T*(rw_H) and A∙T*_O2(w_H) base mispairs (symmetry C_s).