Key microstructural mechanisms of the 2-aminopurine mutagenicity: Results of extensive quantum-chemical research.

As of today, a great amount of experimental and theoretical phenomenological data have been collected in the literature according the mutagenic action of the classical mutagen - 2-aminopurine (2AP). However, so far they have not received proper explanation and substantiation. In this Opinion Piece, we provide an overview of recent progress in computational design and modeling of the physico-chemical mechanisms of the mutagenic action of 2AP. Results of quantum-chemical studies, aimed at the elucidation of the key microstructural mechanisms of the mutagenicity of 2AP, have been summarized here. In this context, for the first time it was outlined the most important surveys: Why 2AP is incorporated into DNA in trace concentrations? Whether classical mechanisms presented in the literature according the formation of the rare tautomers of canonical DNA bases work also for base analogue - 2AP? In what way 2AP induces replication and incorporation errors? Whether the amino-imino tautomerisation of 2AP is related to its mutagenicity, that is whether the 2AP* rare tautomer is mutagenic? It is emphasized that the applied approach has a proper theoretical substantiation, since it is based on our microstructural theory of the spontaneous point mutagenesis in DNA, and at the same time it accumulates scenarios of the origin of the induced point errors - transitions and transversions, which the classical Watson-Crick tautomeric hypothesis permits. Moreover, using author's methodology, the profiles of the main physico-chemical characteristics for the tautomerisation reactions involving 2AP, which are integral parts of the biologically important tautomerically-conformational transformations, have been presented. Obtained results open new perspectives for prediction and design of the mutagenic derivatives of the nucleotide bases of any structure and origin before their synthesis and also for planning of new experiments and interpretation of the existing data. Abbreviations 2AP 2-Aminopurine A adenine C cytosine DPT double proton transfer G guanine IRC intrinsic reaction coordinate KP key point T thymine w wobble WC Watson-Crick vdW van der Waals H-bond hydrogen bond Communicated by Ramaswamy H. Sarma.