**Acknowledgements**

We prove for the first time that 2AP\* as a base of the incoming nucleotide may produce also another transversion, when 2AP\* mutagenic tautomer pairs with G base and formed G·2AP\*(w) mispair converts according to the route of the sequential tautomeric and conformational transformations—G·2AP\*(w) → G\*·2AP(w) → G·2AP(WC) → G·2APsyn (**Figure 8d**,

**Table 4.** Energetic and kinetic characteristics of the biologically important tautomeri*z*ations and conformational transitions of the structures containing canonical DNA bases and 2AP in the main or rare tautomeric forms leading to replication and incorporation errors*—*transitions and transversions (MP2/aug-cc-pVDZ//B3LYP/6-311++G(d,p) level of

**ν<sup>i</sup> ∆G ∆E ∆∆GTS ∆∆ETS ∆∆G ∆∆E τ99.9% τ**

**a)** 2AP·T(WC)↔2AP·T\*(w) [79, 88] 134.2 8.62 8.33 18.66 17.53 10.04 9.21 2.53·10−5 3.7 × 10−6 A·T(WC)↔A·T\*(w) [51, 53, 68] 99.7 13.08 14.84 20.28 20.41 7.20 5.57 2.09·10−7 3.0 × 10−8 **b)** C·2AP(w)↔C\*·2AP(WC) [79, 89] 146.9 1.85 1.42 21.95 20.30 20.11 18.88 5.87·102 8.9 × 10<sup>1</sup> C·A(w)↔C\*·A(WC) [57, 70] 588.5 −6.07 −7.20 19.51 17.61 25.58 24.81 1.74·102 7.1 × 105 **с)** A·2AP(w)↔A\*·2AP(WC) [89, 90] 117.0 13.71 13.57 29.85 31.00 16.14 17.43 0.76 0.1 A\*·2AP(WC)↔A\*·2APsyn [89] 18.0 −0.83 −0.59 6.54 8.55 7.37 9.14 5.59·10−8 4.1 × 10−8 A·A(w)↔A·A\*(WC) [72] 152.4 3.63 1.09 25.86 22.56 22.24 21.47 2.22·104 3.2 × 103 A·A\*(WC)↔A\*·A(WC) [65] 497.5 0.00 0.00 6.39 9.71 6.39 9.71 2.28·10−8 6.4 × 10−9 A\*·A(WC)↔A\*·Asyn(TF) [61, 77] 15.8 0.56 1.23 8.09 8.09 7.53 6.85 2.66·10−7 5.3 × 10−8 **d)** G·2AP\*(w)↔G\*·2AP(w) [91, 92] 1099.7 −10.70 −9.96 −0.11 2.31 10.59 12.26 4.39·10−13 4.5 × 10−6 G\*·2AP(w)↔G·2AP(WC) [90, 91] 130.1 1.33 1.07 18.04 16.58 16.70 15.51 1.77 0.3 G·2AP(WC)↔G·2APsyn [91] 17.7 0.60 1.51 8.23 10.31 7.63 8.80 3.22·10−7 6.4 × 10−8 G·A\*(w)↔G·A(WC) [73] 126.8 −6.93 −6.73 16.98 16.32 23.92 23.05 3.14 5.5 × 104 G·A(WC)↔G·Asyn [56, 62, 77] 20.7 0.76 0.58 8.39 8.89 7.64 8.31 3.47·10−7 6.4 × 10−8

tautomerically conformational transformations is mutagenic, generating appropriate transversions, when pyrimidine bases (in this case C) are replaced by the analogue of the purine base— 2AP. This also causes low-probable transitions and transversions, since in the next rounds of the DNA replication, 2AP pairs not only with T, but also with the C and A DNA bases [91].

Our theoretical data are in good agreement with existing experimental results [80, 81, 83, 84]

By analyzing profiles of the physico-chemical characteristics for the tautomerization reactions *via* the DPT and PT involving 2AP, which are integral parts of the biologically important tautomerically conformational transformations, we have established that 2AP·Т(WC)↔2AP·Т\*(w) [79], 2AP·C\*(WC)↔2AP·C(w) [79], G\*·2AP(w)↔G·2AP(WC) [90] and А·2АР(w)↔А\*·2АР(WC) [90] tautomerization pathways proceed through the stepwise concerted mechanism *via* the sequential intrapair PT between the bases followed by the shifting of the 2AP relatively the T/C\*/G\*/A bases, accordingly, while the T·2AP\*(w)↔T\*·2AP(w) and G·2AP\*(w)↔G\*· 2AP(w) [92] DPT tautomerization reactions proceed through the asynchronous concerted

points that this route of the

**Table 4**) [91]. Estimated ratio of probabilities РG·2АР\*/РG·А\* = 1.90·10<sup>7</sup>

and also allow a unified physico-chemical interpretation of them.

mechanism.

**Tautomerization/**

**Conformational transition**

46 Mitochondrial DNA - New Insights

Note: see **Tables 1** and **2**.

theory, ε = 1).

The authors gratefully appreciate technical support and computational facilities of joint computer cluster of SSI "Institute for Single Crystals" of the National Academy of Sciences of Ukraine (NASU) and Institute for Scintillation Materials of the NASU incorporated into Ukrainian National Grid. This work was partially supported by the Grant of the NASU for young scientists, Grant of the President of Ukraine to support the research of young scientists [project number F70] from the State Fund for Fundamental Research of Ukraine of the Ministry of the Education and Science of Ukraine and by the Scholarship of Verkhovna Rada (Parliament) of Ukraine for the talented young scientists in 2017 year given to DrSci Ol'ha O. Brovarets'. O. O. B. expresses sincere gratitude to organizing committee for financial support of the participation in the "EMBO/FEBS Lecture Course Spetsai Summer School 2017 for Proteins and Organized Complexity" (September 24–October 1, 2017, Spetses, Greece), to Lawyers Association "AVER Lex "(Kyiv, Ukraine) for the sponsorship of presenting the plenary lecture as invited speaker at the "EMN Meeting on Computation and Theory" (November 6–10, 2017, Dubai, United Arab Emirates), to Max Planck Institute of Molecular Plant Physiology (MPI-MP) (hosted by Prof. Yariv Brotman) for the kind invitation and financial support of the invited talk (November 29, 2017, Potsdam, Germany), to organizing committee headed by Prof. Karl Kuchler (Medical University Vienna, Austria) for the kind invitation and financial support (ABC fellow) of the participation in the seventh FEBS Special Meeting "ATP-Binding Cassette (ABC) Proteins: from Multidrug Resistance to Genetic Disease" (March 6–12, 2018, Innsbruck, Austria) and to Chemistry Biological Interface Division of the Royal Society of Chemistry (RSC, UK) for the RSC Travel Grant for the participation at the "3rd Green and Sustainable Chemistry Conference" (May 13-16, 2018, Hotel Intercontinental, Berlin, Germany). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

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