Prototropic tautomerism and basic molecular principles of hypoxanthine mutagenicity: an exhaustive quantum-chemical analysis.

The molecular structures, relative stability order, and dipole moments of a complete family of 21 planar hypoxanthine (Hyp) prototropic molecular-zwitterionic tautomers including ylidic forms were computationally investigated at the MP2/6-311++G(2df,pd)//B3LYP/6-311++G(d,p) level of theory in vacuum and in three different surrounding environments: continuum with a low dielectric constant (ϵ = 4) corresponding to a hydrophobic interface of protein-nucleic acid interactions, dimethylsulfoxide (DMSO), and water. The keto-N1HN7H tautomer was established to be the global minimum in vacuum and in continuum with ϵ = 4, while Hyp molecule exists as a mixture of the keto-N1HN9H and keto-N1HN7H tautomers in approximately equal amounts in DMSO and in water at T = 298.15 K. We found out that neither intramolecular tautomerization by single proton transfer in the Hyp base, nor intermolecular tautomerization by double proton transfer in the most energetically favorable Hyp·Hyp homodimer (symmetry C(2h)), stabilized by two equivalent N1H…O6 H-bonds, induces the formation of the enol tautomer (marked with an asterisk) of Hyp with cis-oriented O6H hydroxyl group relative to neighboring N1C6 bond. We first discovered a new scenario of the keto-enol tautomerization of Hyp · Hyp homodimer (C(2h)) via zwitterionic near-orthogonal transition state (TS), stabilized by N1⁺H…N1⁻ and O6⁺H…N1⁻ H-bonds, to heterodimer Hyp∗ · Hyp (C(s)), stabilized by O6H…O6 and N1H…N1 H-bonds. We first showed that Hyp∗ · Thy mispair (C(s)), stabilized by O6H…O4, N3H…N1, and C2H…O2 H-bonds, mimicking Watson-Crick base pairing, converts to the wobble Hyp · Thy base pair (C(s)), stabilized by N3H…O6 and N1H…O2 H-bonds, via high- and low-energy TSs and intermediate Hyp · Thy∗, stabilized by O4H…O6, N1H…N3, and C2H…O2 H-bonds. The most energetically favorable TS is the zwitterionic pair Hyp⁺ · Thy⁻ (C(s)), stabilized by O6⁺H…O4⁻, O6⁺H…N3⁻, N1⁺H…N3⁻, and N1⁺H…O2⁻ H-bonds. The authors expressed and substantiated the hypothesis, that the keto tautomer of Hyp is a mutagenic compound, while enol tautomer Hyp∗ does not possess mutagenic properties. The lifetime of the nonmutagenic tautomer Hyp∗ exceeds by many orders the time needed to complete a round of DNA replication in the cell. For the first time purine-purine planar H-bonded mispairs containing Hyp in the anti-orientation with respect to the sugar moiety--Hyp · Ade(syn), Hyp · Gua∗(syn), and Hyp · Gua(syn), that closely resembles the geometry of the Watson-Crick base pairs, have been suggested as the source of transversions. An influence of the surrounding environment (ϵ = 4) on the stability of studied complexes and corresponding TSs was estimated by means of the conductor-like polarizable continuum model. Electron-topological, structural, vibrational, and energetic characterictics of all conventional and nonconventional H-bonds in the investigated structures are presented. Presented data are key to understanding elementary molecular mechanisms of mutagenic action of Hyp as a product of the adenine deamination in DNA.