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·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 C(1)), which are highly polar, tight ion pairs (A(-), N6H(2)-deprotonated)∙(T(+), O4/O2-protonated). Gibbs free energies of activation for the A∙T(WC) / A∙T(rWC) ↔ A*∙Т(rw(WC)) / A*∙Т(w(WC)) tautomeric transitions (~43.5 kcal∙mol(-1)) are lower than for the A∙T(H) / A∙T(rH) ↔ A*(N7)∙Т(rw(H)) / A*(N7)∙Т(w(H)) 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(rw(WC)), A*(N7)∙Т(rw(H)) 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)).