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Conversation 15
June 19-23 2007

Mechanisms of Mutagenic Action of 5BrU: Quantum Mechanical Study

To elucidate the mechanism of mutagenic action of 5BrU we investigated structure and electronic properties of mismatched nucleic acid base pairs containing the lactim and deprotonated forms of 5BrU in the gas phase by MP2/6-31G(d,p) method. Table I contains results of these calculations. The energy minimum structures of G-5BrU* and G*-5BrU base pairs assume nonplanar geometry. The calculations indicate that G-5BrU* and G*-5BrU structures are energetically less favorable than G-T* (G-U*) and G*-T (G*-U), respectively. Consequently, the tautomeric conversion cannot explain the mutagenic mechanism of action of 5-BrU. Furthermore, the calculations show that deprotonation in the N3 position and pairing with G base is energetically more favorable for 5BrU in comparison to T or U (see Table I). However the ionized base pairs have very large propeller twist (PT) and buckle (B) angles because of the unfavorable arrangement of oxygen atoms that create the energetic and geometric hindrances during their incorporation into DNA. The planar structures that are free from such hindrances are less stable for about 1.9 kcal/mol in comparison with their nonplanar counterparts. The calculations of complex formation energies for the nonplanar and planar ionized base pairs also show somewhat greater stabilization of the nonplanar structures by 0.58, 3.09, and 0.60 kcal/mol for the G-T-, G-U-, and G-5BrU- base pairs, respectively. Thus the mechanism of mutagenic action of 5BrU assuming the formation of ionized G-5BrU- base pair contradicts to these results. Alternative probable mutagenic mechanism supposes the formation of the G-5BrU wobble base pair. The calculations show that the formation of such base pair is more preferable than that of A-5BrU. It has been suggested that 5BrU, incorporated into DNA, forms stronger base stacking interactions than T and, therefore, may increase the occurrence of the corresponding mismatches. This mechanism needs further investigations.

Noriyuki Kurita1,*
Victor I. Danilov2
Victor M. Anisimov3
Dmytro Hovorun2
Taisuke Nakatsu1
Kenishi Dedachi1

1Department of Knowledge-based Information Engineering
Toyohashi University of Technology
Toyohashi 441-8580, Japan
2Institute of Molecular Biology and Genetics
National Academy of Sciences of Ukraine
150 Zabolotny Street
Kyiv-143, 03143, Ukraine
Email: vid@ipnet.kiev.ua
3Department of Pharmaceutical Sciences
School of Pharmacy
University of Maryland
20 Penn Street
Baltimore, MD 21201, USA
Email: victor@outerbanks.umaryland.edu

*Phone & Fax: 81-532-44-6875