The physicochemical essence of the purine·pyrimidine transition mismatches with Watson-Crick geometry in DNA: A·C* <i>versa</i> A*·C. A QM and QTAIM atomistic understanding

<div><p>It was established for the first time by DFT and MP2 quantum-mechanical (QM) methods either in vacuum, so in the continuum with a low dielectric constant (<i>ε</i> = 4), typical for hydrophobic interfaces of specific protein-nucleic acid interactions, that the repertoire for the tautomerisation of the biologically important adenine·cytosine* (A·C*) mismatched DNA base pair, formed by the amino tautomer of the A and the imino mutagenic tautomer of the C, into the A*·C base mispair (∆G = 2.72 kcal mol<sup>−1</sup> obtained at the MP2 level of QM theory in the continuum with <i>ε</i> = 4), formed by the imino mutagenic tautomer of the A and the amino tautomer of the C, proceeds <i>via</i> the asynchronous concerted double proton transfer along two antiparallel H-bonds through the transition state (TS<sub>A·C*↔A*·C</sub>). The limiting stage of the A·C*→A*·C tautomerisation is the final proton transfer along the intermolecular N6H···N4 H-bond. It was found that the A·C*/A*·C DNA base mispairs with Watson–Crick geometry are associated by the N6H⋯N4/N4H⋯N6, N3H⋯N1/N1H⋯N3 and C2H⋯O2 H-bonds, respectively, while the TS<sub>A·C*↔A*·C</sub> is joined by the N6–H–N4 covalent bridge and the N1H⋯N3 and C2H⋯O2 H-bonds. It was revealed that the A·C*↔A*·C tautomerisation is assisted by the true C2H⋯O2 H-bond, that in contrast to the two others conventional H-bonds exists along the entire intrinsic reaction coordinate (IRC) range herewith becoming stronger at the transition from vacuum to the continuum with <i>ε</i> = 4. To better understand the behavior of the intermolecular H-bonds and base mispairs along the IRC of the A·C*↔A*·C tautomerisation, the profiles of their electron-topological, energetical, geometrical, polar and charge characteristics are reported in this study. It was established based on the profiles of the H-bond energies that all three H-bonds are cooperative, mutually strengthening each other. The nine key points, providing a detailed physicochemical picture of the A·C*↔A*·C tautomerisation, were revealed and thoroughly examined along the IRC. It was shown that the A*·C base mispair with the population ~1 % obtained at the MP2 level of QM theory in the continuum with <i>ε</i> = 4 is thermodynamically and dynamically stable structure. Its lifetime was calculated to be 5.76·10<sup>−10</sup> s at the MP2 level of QM theory in the continuum with <i>ε</i> = 4. This lifetime, from the one side, enables all six low-frequency intermolecular vibrations to develop, but, from the other side, it is by order less than the time (several ns) required for the replication machinery to forcibly dissociate a base pair into the monomers during DNA replication. This means that the A*·C base mispair “slips away from the hands” of the replication machinery into the A·C* mismatched base pair. Consequently, the authors came to the conclusion that exactly the A·C* base mispair is an active player of the point mutational events and is effectively dissociated by the replication machinery into the A and C* monomers in contrast to the A*·C base mispair, playing the mediated role of a provider of the A·C* base mispair in DNA that is synthesised.</p></div>