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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Chem. | doi: 10.3389/fchem.2018.00532

Unexpected routes of the mutagenic tautomerization of the T nucleobase in the classical А∙Т DNA base pairs: A QM/QTAIM comprehensive view

  • 1Institute of Molecular Biology and Genetics (NAN Ukraine), Ukraine
  • 2Bogomolets National Medical University, Ukraine

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 А∙Т DNA base pairs – Watson-Crick (A∙T(wWC)), reverse Watson-Crick (A∙T(wrWC)), Hoogsteen (A∙T(wH)) and reverse Hoogsteen (A∙T(wH)) – 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*O2(w⊥rWC); A∙T(wH)↔A∙T*(w⊥H); A∙T(wrH)↔A∙T*O2(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 (А)N6+H∙∙∙O4-/O2-(Т) and (А)N6+H∙∙∙N3-(Т) H-bonds. Established tautomerizations proceed through a two-step mechanism of the two-step protons moving in the antiparallel directions along the intermolecular H-bonds. Initially, single 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 О4/О2 oxygen atom of Т, leading to the products – A∙T*(w⊥WC), A∙T*O2(w⊥rWC), A∙T*(w⊥H) and A∙T*(w⊥rH), which are substantially non-planar, conformationally-labile complexes. These mispairs are stabilized by the participation of the (А)N6H/N6H´∙∙∙N3(Т) and (Т)O2H/O4H∙∙∙N6(А) 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.

Keywords: transition state, Tight ion pair, Classical А·Т DNA base pairs, Watson-Crick, reverse Watson-Crick, Hoogsteen, reverse Hoogsteen, Wobble structure, Quantum-mechanical calculation, Double proton transfer, Mutagenic tautomerisation

Received: 15 Jul 2018; Accepted: 12 Oct 2018.

Edited by:

Xi Zhang, Shenzhen University, China

Reviewed by:

Mauricio A. Palafox, Complutense University of Madrid, Spain
Yong Wang, Ningbo University, China  

Copyright: © 2018 Brovarets', Hovorun, Tsiupa and Dinets. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Ol'ha Brovarets', Institute of Molecular Biology and Genetics (NAN Ukraine), Kiev, Ukraine,