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

Biochemistry. 1986 Apr 22;25(8):2198-205. doi: 10.1021/bi00356a052.

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 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.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Aminobiphenyl Compounds*
  • Carcinogens*
  • Chemical Phenomena
  • Chemistry
  • Circular Dichroism
  • Deoxycytosine Nucleotides*
  • Deoxyguanosine / analogs & derivatives*
  • Magnetic Resonance Spectroscopy
  • Models, Molecular
  • Nucleic Acid Conformation
  • Spectrophotometry

Substances

  • Aminobiphenyl Compounds
  • Carcinogens
  • Deoxycytosine Nucleotides
  • deoxycytidylyl-(3'-5')-deoxyguanosine
  • 4-biphenylamine
  • Deoxyguanosine