Whether 2-aminopurine induces incorporation errors at the DNA replication? A quantum-mechanical answer on the actual biological issue

Abstract

In this paper, we consider the mutagenic properties of the 2-aminopurine (2AP), which has intrigued molecular biologists, biophysicists and physical chemists for a long time and been widely studied by both experimentalists and theorists. We have shown for the first time using QM calculations, that 2AP very effectively produces incorporation errors binding with cytosine (C) into the wobble (w) C·2AP(w) mispair, which is supported by the N4H⋯N1 and N2H⋯N3 H-bonds and is tautomerized into the Watson–Crick (WC)-like base mispair C*·2AP(WC) (asterisk denotes the mutagenic tautomer of the base), that quite easily in the process of the thermal fluctuations acquires enzymatically competent conformation. 2AP less effectively produces transversions forming the wobble mispair with A base – A·2AP(w), stabilized by the participation of the N6H⋯N1 and N2H⋯N1 H-bonds, followed by further tautomerization A·2AP(w) → A*·2AP(WC) and subsequent conformational transition A*·2AP(WC) → A*·2AP_syn thus acquiring enzymatically competent structure. In this case, incorporation errors occur only in those case, when 2AP belongs to the incoming nucleotide. Thus, answering the question posed in the title of the article, we affirm for certain that 2AP induces incorporation errors at the DNA replication. Obtained results are consistent well with numerous experimental data.

Keywords:

• 2-aminopurine
• mutagenicity
• induced point mutations
• incorporation errors
• DNA replication
• Watson–Crick↔wobble tautomeric transition

Acknowledgments

Authors gratefully appreciate technical support and computational facilities from joint computer cluster of SSI “Institute for Single Crystals” of the National Academy of Sciences of Ukraine (NASU) and Institute for Scintillation Materials of the NASU incorporated into Ukrainian National Grid. O.O.B. expresses sincere gratitude to the organizing committee of the FEBS Workshop on Chromatin Proteomics (October 3–8, 2016, Crete, Greece), mainly to Prof. John Strouboulis (Institute of Molecular Biology and Biotechnology, Foundation of Research & Technology, Heraklion, Crete, Greece), and FEBS organisation for the Youth Travel Fund (YTF) grant for visiting. The authors sincerely thank Corresponding Member of NASU, Prof. Dmytro M. Hovorun for his invaluable suggestions and comments at the fruitful manuscript discussion, Dr. Ivan S. Voiteshenko (Institute of High Technologies, Taras Shevchenko National University of Kyiv) and Dr. Fernando R. Clemente (Gaussian, Inc.) for their technical support of the work.