Atomistic nature of the DPT tautomerisation of the biologically important C·C* DNA base mispair containing amino and imino tautomers of cytosine: a QM and QTAIM approach

Abstract

A theoretical study of tautomerisation of the biologically important cytosine·cytosine* (C·C*) DNA mismatch with a propeller-like structure (|C4N3N3C4| = 32.4°; C₁ symmetry) and cis-oriented N1H glycosidic bonds, formed by the amino and imino tautomers of the C nucleobase, via the asynchronous concerted double proton transfer (DPT) along two H-bonds through the transition state (TS_{C·C*↔C*·C}) (|C4N3N3C4| = 48.5°; C₁ symmetry) into the C*·C mispair was carried out for the first time. It was established that the C·C*/C*·C DNA base mispair is associated by the antiparallel N4H⋯N4 (6.66 kcal mol⁻¹), N3H⋯N3 (6.47 kcal mol⁻¹) H-bonds and the O2⋯O2 van der Waals (vdW) contact (0.33 kcal mol⁻¹), while the zwitterionic TS_{C·C*↔C*·C} is stabilized by the parallel N4⁺H⋯N4⁻ (13.55 kcal mol⁻¹), N3⁺H⋯N3⁻ (13.20 kcal mol⁻¹) H-bonds and the O2⁺⋯O2⁻ vdW contact (0.60 kcal mol⁻¹). It was shown that the C·C* ↔ C*·C tautomerisation via the DPT is assisted by the O2⋯O2 vdW contact, that in contrast to the two others N4H⋯N4 and N3H⋯N3 H-bonds exists along the entire intrinsic reaction coordinate (IRC) range. The positive values of the Grunenberg's compliance constants (30.919 and 21.384 Å mdyn⁻¹ for C·C*/C*·C and TS_{C·C*↔C*·C}, respectively) indicate that the O2⋯O2 vdW contact is a stabilizing closed-shell interaction. It was found that the middle N3H⋯N3 H-bond is anti-cooperative with the upper N4H⋯N4 H-bond and cooperative with the lower O2⋯O2 vdW contact. The 9 key points, which can be considered as electron-topological “fingerprints” of the asynchronous concerted C·C* ↔ C*·C tautomerisation process via the DPT were revealed along the IRC and examined in detail. It was shown that the C·C*/C*·C base mispair is a thermodynamically and dynamically stable structure. Its lifetime is equal to 1.53 × 10⁻⁷ s at the MP2/cc-pVQZ//B3LYP/6-311++G(d,p) level of theory in vacuum. All 6 low-frequency intermolecular vibrations are able to develop during this time span.