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(w(WC))], reverse Watson-Crick [A·T(w(rWC))], Hoogsteen [A·T(w(H))] and reverse Hoogsteen [A·T(w(rH))] – act as intermediates of the intrapair mutagenic tautomerization of the T nucleobase owing to the novel tautomerisation pathways: A·T(w(WC))↔A·T(*)(w(⊥)(WC)); A·T(w(rWC))↔A· [Formula: see text] (w(⊥)(rWC)); A·T(w(H))↔A·T(*)(w(⊥)(H)); A·T(w(rH))↔A· [Formula: see text] (w(⊥)(rH)). All of them occur via the transition states as tight ion pairs (A(+), protonated by the N6H(2) 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 N6H(2) amino group of A and then subsequently from the protonated N6(+)H(3) amino group of A to the O4/O2 oxygen atom of T, leading to the products – A·T(*)(w(⊥)(WC)), A· [Formula: see text] (w(⊥)(rWC)), A·T(*)(w(⊥)(H)), and A· [Formula: see text] (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.