Novel Tautomerisation Mechanisms of the Biologically Important Conformers of the Reverse Löwdin, Hoogsteen, and Reverse Hoogsteen G*·C* DNA Base Pairs via Proton Transfer: A Quantum-Mechanical Survey

Abstract

For the first time, in this study with the use of QM/QTAIM methods we have exhaustively investigated the tautomerization of the biologically-important conformers of the G*·C* DNA base pair—reverse Löwdin G*·C*(rWC), Hoogsteen G*′·C*(H), and reverse Hoogsteen G*′·C*(rH) DNA base pairs—via the single (SPT) or double (DPT) proton transfer along the neighboring intermolecular H-bonds. These tautomeric reactions finally lead to the formation of the novel G·CO2*(rWC), GN2*·C(rWC), G*′N2·C(rWC), GN7*·C(H), and G*′N7·C(rH) DNA base mispairs. Gibbs free energies of activation for these reactions are within the range 3.64–31.65 kcal·mol−1 in vacuum under normal conditions. All TSs are planar structures (Cs symmetry) with a single exception—the essentially non-planar transition state TSG*·C*(rWC)↔G+·C−(rWC) (C1 symmetry). Analysis of the kinetic parameters of the considered tautomerization reactions indicates that in reality only the reverse Hoogsteen G*′·C*(rH) base pair undergoes tautomerization. However, the population of its tautomerised state G*′N7·C(rH) amounts to an insignificant value−2.3·10−17. So, the G*·C*(rWC), G*′·C*(H), and G*′·C*(rH) base pairs possess a permanent tautomeric status, which does not depend on proton mobility along the neighboring H-bonds. The investigated tautomerization processes were analyzed in details by applying the author's unique methodology—sweeps of the main physical and chemical parameters along the intrinsic reaction coordinate (IRC). In general, the obtained data demonstrate the tautomeric mobility and diversity of the G*·C* DNA base pair.

A Quantum-Mechanical Looking Behind the Scene of the Classic G·C Nucleobase Pairs Tautomerization

“…Before providing the discussion of the investigated material, let us firstly give attention to the novel mechanisms of the G * ·C * (rWC) tautomerization, which complement the results of the previous work (Brovarets' et al, 2019a ).…”

“…The atomic numbering scheme used for the nucleobases is conventional (Saenger, 1984 ). In this study mutagenic or rare tautomeric forms of the bases (Brovarets' and Hovorun, 2009 , 2014a , 2015a , b , c , d , e , f ; Brovarets' and Hovorun, 2018 ; Brovarets' et al, 2018a , b , c , d , e , f ; Brovarets' et al, 2019a , b ) are denoted by the asterisk.…”

“…However, up until recently it was considered that only a few unusual tautomers existed for the G·C Watson-Crick nucleobase pair (Pous et al, 2008 ; Alvey et al, 2014 ; Brovarets' and Hovorun, 2014a ; Nikolova et al, 2014 ; Poltev et al, 2016 ; Szabat and Kierzek, 2017 ; Brovarets' et al, 2019a , b ; Srivastava, 2019 ). In particular, tautomerization via the double proton transfer (DPT) has been carefully investigated in the reverse Löwdin G * ·C * (rWC), Hoogsteen (H) G * ′·C * (H), and reverse Hoogsteen G * ′·C * (rH) base pairs (Brovarets' et al, 2019b ), leading to the novel structures: G· (rWC), C(rWC), G *′ N2 ·C(rWC), C(H), and G *′ N7 ·C(rH).…”

“…Thus, it was suggested that the mechanism of the mutagenic tautomerization of the DNA base pairs, in particular classic Watson-Crick pairs, are accompanied by the mutual shifting (wobblization) of the bases one relative to the other into the minor or major DNA grooves at the intrapair sequential proton transfer (Brovarets' and Hovorun, 2015a ; Brovarets' et al, 2019a ). This valuable finding enables researchers to figure out, how the incorrect DNA base pairs, which architecture is different from the Watson-Crick configuration, can acquire the enzymatically-competent conformation, that guarantees their successful chemical incorporation into the composition of the main carrier of the genetic information—DNA—by the high-fidelity DNA-polymerase.…”

“…At the same time, investigations into the mechanisms of the mutagenic tautomerization of the pairs of nucleotide bases seemed to be quite a complicated issue, which may not be evident at a first glance. Thus, recent investigations into the tautomerization mechanisms of the biologically-important G·C nucleobase pairs, in which monomers are in the rare, in particular mutagenic, tautomeric form, continue to challenge researchers by its mystery (Brovarets' et al, 2019a , b ).…”