Is the DPT tautomerization of the long A·G Watson–Crick DNA base mispair a source of the adenine and guanine mutagenic tautomers? A QM and QTAIM response to the biologically important question

Abstract

Herein, we first address the question posed in the title by establishing the tautomerization trajectory via the double proton transfer of the adenine·guanine (A·G) DNA base mispair formed by the canonical tautomers of the A and G bases into the A*·G* DNA base mispair, involving mutagenic tautomers, with the use of the quantum-mechanical calculations and quantum theory of atoms in molecules (QTAIM). It was detected that the A·G ↔ A*·G* tautomerization proceeds through the asynchronous concerted mechanism. It was revealed that the A·G base mispair is stabilized by the N6H···O6 (5.68) and N1H···N1 (6.51) hydrogen bonds (H-bonds) and the N2H···HC2 dihydrogen bond (DH-bond) (0.68 kcal·mol(-1) ), whereas the A*·G* base mispair-by the O6H···N6 (10.88), N1H···N1 (7.01) and C2H···N2 H-bonds (0.42 kcal·mol(-1) ). The N2H···HC2 DH-bond smoothly and without bifurcation transforms into the C2H···N2 H-bond at the IRC = -10.07 Bohr in the course of the A·G ↔ A*·G* tautomerization. Using the sweeps of the energies of the intermolecular H-bonds, it was observed that the N6H···O6 H-bond is anticooperative to the two others-N1H···N1 and N2H···HC2 in the A·G base mispair, while the latters are significantly cooperative, mutually strengthening each other. In opposite, all three O6H···N6, N1H···N1, and C2H···N2 H-bonds are cooperative in the A*·G* base mispair. All in all, we established the dynamical instability of the А*·G* base mispair with a short lifetime (4.83·10(-14) s), enabling it not to be deemed feasible source of the A* and G* mutagenic tautomers of the DNA bases. The small lifetime of the А*·G* base mispair is predetermined by the negative value of the Gibbs free energy for the A*·G* → A·G transition. Moreover, all of the six low-frequency intermolecular vibrations cannot develop during this lifetime that additionally confirms the aforementioned results. Thus, the A*·G* base mispair cannot be considered as a source of the mutagenic tautomers of the DNA bases, as the A·G base mispair dissociates during DNA replication exceptionally into the A and G monomers in the canonical tautomeric form.

Nucleotides and nucleoside signaling in the regulation of the epithelium to mesenchymal transition (EMT)

“…Purinergic Signalling (2017) 13: [1][2][3][4][5][6][7][8][9][10][11][12]by activating the ERK1/2 and PI3K/AKT pathways [64]. It was demonstrated that P2X7 receptor activation enhances invasiveness through a mechanism involving Ca 2+ -activated SK3 K + -channel activity in the mammary carcinoma cell line MDA-MB-435 s [65].…”

“…Purine molecules, such as adenine and guanine, are components of the genetic material (DNA and RNA) of all living beings. Purine and pyrimidine tautomeric equilibria in nucleic acids was postulated to be significant in events such as DNA replication and repair as well as in the occurrence of point mutations [8].As nucleosides and nucleotides, purines play other highly strategic roles, acting as energy intermediates, allosteric regulators of key metabolic activities, redox molecules, and chemical messengers for signal transduction events. The two most important purines serving as extracellular ligands for paracrine and autocrine signaling are ATP and its dephosphorylated form, adenosine (ADO).…”

“…Purine molecules, such as adenine and guanine, are components of the genetic material (DNA and RNA) of all living beings. Purine and pyrimidine tautomeric equilibria in nucleic acids was postulated to be significant in events such as DNA replication and repair as well as in the occurrence of point mutations [8].…”

Unexpected A·T(WC)↔A·T(rWC)/A·T(rH) and A·T(H)↔A·T(rH)/A·T(rWC) conformational transitions between the classical A·T DNA base pairs: A QM/QTAIM comprehensive study

“…Bader's quantum theory of Atoms in Molecules (QTAIM), using program package AIMAll, was applied to analyze the electron density distribution. The presence of the bond critical point (BCP), namely the so‐called (3,−1) BCP, and a bond path between hydrogen donor and acceptor, as well as the positive value of the Laplacian at this BCP (Δ ρ > 0), were considered as criteria for the H‐bond formation . Wave functions were obtained at the level of theory used for geometry optimization.…”

The A·T(rWC)/A·T(H)/A·T(rH) ↔ A·T*(rwWC)/A·T*(wH)/A·T*(rwH) mutagenic tautomerizationviasequential proton transfer: a QM/QTAIM study

“…It was established for sure that generally accepted mechanism of the double proton transfer (DPT) along intermolecular H-bonds in the Watson-Crick (WC) (so-called Löwdin's mechanism), [24][25][26][27][28][29] wobble (w) base pairs, 30,31 biologically important A$G, 32 A$C*, 33 G*$T, 34 C$T, 35 G$G * syn , 36 A*$A syn , 37 A*$G * syn , 38 H$C, 39,40 H$H 39,40 and H$A 39,42 base mispairs and also in the protein-DNA complexes 26,43,44 can't be considered as the source of the mutagenic tautomers formations due to the dynamical instability of the terminal complexes containing mutagenic tautomers of the DNA bases. [26][27][28][29][31][32][33][34][35][36][37][38][39][40][41][42]44 For the rst time, we have proposed a novel theoretical approach to the elucidation of the microstructural mechanisms of the incorporation and replication errors arising at the DNA replication due to the intrinsic ability of the purine$pyrimidine (A$T, G$C, G$T and A$C), purine$purine (A$A and G$G) and pyrimidine$pyrimidine (C$C and T$T) DNA base mispairs to perform WC 4 w tautomeric transitions via the sequential proton transfer (PT). [45]…”