Ol'ha O. Brovarets - Novel QM/QTAIM horizons of the microstructural mechanisms of the spontaneous and induced transitions and transversions in DNA

Although DNA is replicated in the cell with a high fidelity, spontaneous point mutations still occur, in particular, base substitutions – transitions and transversions (Brookhaven Symp. Biol., 1959, 12, 63). It is suggested in the literature that their root cause is the formation of the base mispairs in the active center of the high-fidelity DNA-polymerase in its closed state, that guarantees their incorporation into the chemical structure of the synthesized DNA double helix (Cold Spring Harb. Symp. Quant. Biol., 1953, 18, 123; Nature, 1976, 263, 285). However, the physico-chemical mechanisms of their formation and their geometrical architecture have not been precisely determined to date.

Using quantum-mechanical calculations, we originally elaborated the theory of the origin of the spontaneous point mutations arising due to the intrinsic ability of the purine·pyrimidine (A·T, G·C, G·T and A·C), purine·purine (A·A, A·G and G·G) and pyrimidine·pyrimidine (С·С, С·T and Т·Т) DNA base mispairs (A – adenine, G – guanine, T – thymine, C – cytosine) to perform wobble↔Watson-Crick tautomeric transitions. They were established to occur via the sequential intrapair transfer of protons and significant shifting of the bases within nucleobase pairs according each other towards both the minor and major grooves of DNA and vice versa, that are controlled by the highly stable, highly polar and zwitterionic transition states of the type (protonated base)·(deprotonated base) (Phys. Chem. Chem. Phys., 2015, 17, 15103; Phys. Chem. Chem. Phys., 2015, 17, 21381; RSC Adv., 2015, 5, 66318; RSC Adv., 2015, 5, 99594; J. Biomol. Struct. & Dynam., 2015, 33, 2297; J. Biomol. Struct. & Dynam., 2015, 33, 2710; Struct. Chem., 2016, 27, 119).

Reported results are of crucial importance for the better understanding and clarification of the various mechanisms of the origin of the spontaneous point mutations in DNA, as well for the establishment of the principles governing the action of the mutagens, which are the derivatives of the nucleotide bases.

In particular, within this approach we have managed to significantly advance in understanding the mechanisms underlying the mutagenicity of 2-aminopurine (2AP), in particular, the origin of the 2AP induced transitions and transversions (RSC Adv., 2016, 6, 99546; RSС Adv., 2016, 110, 108255; J. Biomol. Struct. & Dynam., 2016, DOI: 10.1080/07391102.2016.1253504; New J. Chem., 2017, 41, 7232; J. Biomol. Struct. & Dynam., 2017, DOI: 10.1080/07391102.2017.1331864) arising according to the pathways: 2AP∙Т(WC)→2AP∙Т*(w) determining replication errors and С·2АР(w)→С*·2АР(WC), А·2АР(w)→А*·2АР(WC)→А*·2АРsyn, and G·2AP*(w)→G*·2AP(w)→G·2AP(WC)→G·2APsyn determining incorporation errors.