The nature of the transition mismatches with Watson–Crick architecture: the G*·T or G·T* DNA base mispair or both? A QM/QTAIM perspective for the biological problem

Abstract

This study provides the first accurate investigation of the tautomerization of the biologically important guanine*·thymine (G*·T) DNA base mispair with Watson–Crick geometry, involving the enol mutagenic tautomer of the G and the keto tautomer of the T, into the G·T* mispair (∆G = .99 kcal mol⁻¹, population = 15.8% obtained at the MP2 level of quantum-mechanical theory in the continuum with ε = 4), formed by the keto tautomer of the G and the enol mutagenic tautomer of the T base, using DFT and MP2 methods in vacuum and in the weakly polar medium (ε = 4), characteristic for the hydrophobic interfaces of specific protein–nucleic acid interactions. We were first able to show that the G*·T↔G·T* tautomerization occurs through the asynchronous concerted double proton transfer along two antiparallel O6H···O4 and N1···HN3 H-bonds and is assisted by the third N2H···O2 H-bond, that exists along the entire reaction pathway. The obtained results indicate that the G·T* base mispair is stable from the thermodynamic point of view complex, while it is dynamically unstable structure in vacuum and dynamically stable structure in the continuum with ε = 4 with lifetime of 6.4·10⁻¹² s, that, on the one side, makes it possible to develop all six low-frequency intermolecular vibrations, but, on the other side, it is by three orders less than the time (several ns) required for the replication machinery to forcibly dissociate a base pair into the monomers during DNA replication. One of the more significant findings to emerge from this study is that the short-lived G·T* base mispair, which electronic interaction energy between the bases (−23.76 kcal mol⁻¹) exceeds the analogical value for the G·C Watson–Crick nucleobase pair (−20.38 kcal mol⁻¹), “escapes from the hands” of the DNA replication machinery by fast transforming into the G*·T mismatch playing an indirect role of its supplier during the DNA replication. So, exactly the G*·T mismatch was established to play the crucial role in the spontaneous point mutagenesis.

Keywords:

• spontaneous point mutations
• transition mismatches
• DPT tautomerization
• mutagenic tautomer
• DNA replication
• hydrogen bond cooperativity
• B3LYP and MP2
• QTAIM

Acknowledgments

The authors express their sincere gratitude to Prof. Cherif F. Matta (Mount Saint Vincent University, Halifax, Canada) for fruitful discussion of the work, valuable suggestions, and comments.

Funding

This work was partially supported by the State Fund for Fundamental Research (SFFR) of Ukraine within the Ukrainian-Japanese project № F 52.2/001 for 2013–2014 years and by the Science and Technology Center in Ukraine (STCU) within the project № 5728 for 2012–2014 years. O.O.B. was supported by the Grant of the President of Ukraine to support scientific research of young scientists for 2014 year from the State Fund for Fundamental Research of Ukraine (project № GP/F56/074) and by the Grant of the Cabinet of Ministers of Ukraine for collectives of young researchers for carrying out applied scientific researches, scientific and technological development in the priority areas of science and technology (N^o 123). This work was performed using computational facilities of joint computer cluster of SSI “Institute for Single Crystals” of the National Academy of Sciences of Ukraine and Institute for Scintillation Materials of the National Academy of Sciences of Ukraine incorporated into Ukrainian National Grid.