Conformation of d(CpG) modified by the carcinogen 4-aminobiphenyl: a combined experimental and theoretical analysis

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 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.