Abstract
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(wWC)], reverse Watson-Crick [A·T(wrWC)], Hoogsteen [A·T(wH)] and reverse Hoogsteen [A·T(wrH)] – 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·(w⊥rWC); A·T(wH)↔A·T*(w⊥H); A·T(wrH)↔A·(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 (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 N6H2 amino group of A and then subsequently from the protonated N6+H3 amino group of A to the O4/O2 oxygen atom of T, leading to the products – A·T*(w⊥WC), A·(w⊥rWC), A·T*(w⊥H), and A·(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.
Highlights
Clarification at the microstructural level of the physico-chemical mechanisms underlying the formation of the mutagenic tautomers of the DNA bases via the mutagenic tautomerization of the classical Watson-Crick DNA base pairs is a matter of extreme importance for such branches of life science as molecular biophysics and molecular biology, since it enables us to understandUnexpected Routes of the T Mutagenic Tautomerization the sources of the genome instability (Watson and Crick, 1953a,b; Löwdin, 1963, 1966; Topal and Fresco, 1976)
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(wWC)], reverse Watson-Crick [A·T(wrWC)], Hoogsteen [A·T(wH)] and reverse Hoogsteen [A·T(wrH)] – 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)
Distinguished quantum chemist Per-Orlov Löwdin proposed original idea based on the electronic structure of the complementary A·T and G·C pairs of the DNA bases (Löwdin, 1963, 1966), which makes possible their conversion into the high-energy tautomerized states – A∗·T∗(L) and G∗·C∗(L) base pairs [currently known as Löwdin’s base pairs; here and below rare, in particular mutagenic (Brovarets’ and Hovorun, 2010a; Brovarets’, 2015), tautomers are marked with an asterisk] causing origin of the transitions and transversions during the DNA replication
Summary
Clarification at the microstructural level of the physico-chemical mechanisms underlying the formation of the mutagenic tautomers of the DNA bases via the mutagenic tautomerization of the classical Watson-Crick DNA base pairs is a matter of extreme importance for such branches of life science as molecular biophysics and molecular biology, since it enables us to understandUnexpected Routes of the T Mutagenic Tautomerization the sources of the genome instability (Watson and Crick, 1953a,b; Löwdin, 1963, 1966; Topal and Fresco, 1976). Distinguished quantum chemist Per-Orlov Löwdin proposed original idea based on the electronic structure of the complementary A·T and G·C pairs of the DNA bases (Löwdin, 1963, 1966), which makes possible their conversion into the high-energy tautomerized states – A∗·T∗(L) and G∗·C∗(L) base pairs [currently known as Löwdin’s base pairs; here and below rare, in particular mutagenic (Brovarets’ and Hovorun, 2010a; Brovarets’, 2015), tautomers are marked with an asterisk] causing origin of the transitions and transversions during the DNA replication Löwdin believed that these transformations should be carried out by the double proton transfer (DPT) in the opposite directions along the neighboring intermolecular hydrogen (H) bonds through the quantum tunneling. These representations played an extremely important role in the formation of new visions in quantum biology and attracted the attention of a wide range of Löwdin’s followers (Florian et al, 1994; Gorb et al, 2004; Bertran et al, 2006; Cerón-Carrasco and Jacquemin, 2013; Maximoff et al, 2017)
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