Can DNA-binding proteins of replisome tautomerize nucleotide bases? Ab initio model study

Abstract

Ab initio quantum-chemical study of specific point contacts of replisome proteins with DNA modeled by acetic acid with canonical and mutagenic tautomers of DNA bases methylated at the glycosidic nitrogen atoms was performed in vacuo and continuum with a low dielectric constant (ϵ ∼ 4) corresponding to a hydrophobic interface of protein–nucleic acid interaction. All tautomerized complexes were found to be dynamically unstable, because the electronic energies of their back-reaction barriers do not exceed zero-point vibrational energies associated with the vibrational modes whose harmonic vibrational frequencies become imaginary in the transition states of the tautomerization reaction. Additionally, based on the physicochemical arguments, it was demonstrated that the effects of biomolecular environment cannot ensure dynamic stabilization. This result allows suggesting that hypothetically generated by DNA-binding proteins of replisome rare tautomers will have no impact on the total spontaneous mutation due to the low reverse barrier allowing a quick return to the canonical form.

Keywords:

• mutagenic tautomers of DNA bases
• point mutations
• proton transfer
• dynamical instability
• replisome proteins
• ab initio study

Acknowledgment

This work was partly supported by the State Fund for Fundamental Research of Ukraine in the framework of the Ukrainian–Russian (2012–2013) and Ukrainian–Slovenian (2012–2013) bilateral research projects. Authors thank Bogolyubov Institute for Theoretical Physics of the National Academy of Sciences of Ukraine and Ukrainian–American Laboratory of Computational Chemistry (President – Prof. Dr. J. Leszczynski) for providing calculation resources and software allocation.