Conformation of d(CpG) Modified by the Carcinogen 4-Aminobiphenyl: A Combined Experimental and Theoretical Analysis

R. Shapiro, G. R. Underwood, H. Zawadzka, S. Broyde, B. E. Hingerty

Research output: Contribution to journalArticle

Abstract

The change in DNA conformation produced by the attachment of a reactive substance is likely to be a vital factor in determining the biological consequences of the reaction. We have prepared a deoxydinucleoside monophosphate containing the major adduct derived from the carcinogenic amine 4-aminobiphenyl and analyzed its conformation by theoretical and experimental methods. Reaction of d(CpG) with N-acetoxy-N-(trifluoroacetyl)-4-aminobiphenyl afforded the product modified at C-8 of guanine with 4-aminobiphenyl. After purification by reverse-phase high-performance liquid chromatography, milligram amounts of product were obtained. It was analyzed by circular dichroism, proton magnetic resonance, and minimized potential-energy calculations. A flexible molecule with a mixture of conformers is indicated. Both carcinogen-base-stacked states and base-base-stacked states, with guanine both syn and anti, contribute to the population mixture on the dimer level. The global minimum-energy conformation has syn-guanine and carcinogen-base stacking. Forms of this type are calculated to represent roughly 58% of the conformer population. Because of the twisted nature of the biphenyl moiety, carcinogen-base stacking inherently involves less overlap than that in the planar and rigid three-ringed aminofluorene analogue. This difference might relate to the diminished effectiveness of the aminobiphenyl vs. the aminofluorene adduct as a frameshift mutagen in Salmonella typhimurium 1538.

Original languageEnglish (US)
Pages (from-to)2198-2205
Number of pages8
JournalBiochemistry
Volume25
Issue number8
DOIs
StatePublished - Apr 1986

ASJC Scopus subject areas

  • Biochemistry

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