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

Abstract

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 T(WC), reverse Watson-Crick A T(rWC), Hoogsteen A T(H) and reverse Hoogsteen A T(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-ccpVDZ//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* T(rwWC) / A* T(wWC) tautomeric transitions (~43.5 kcal mol-1) are lower than for the A T(H) / A T(rH) $ A*N7 T(rwH) / A*N7 T(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) Hbonds 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 T(H)$A*N7 T(rwH) / TSA- T+ A T(rH)$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* T (rwWC), A*N7 T(rwH) and A*N7 T(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).