The conformational and biological properties of the N-(2'-deoxyguanosin-8-yl)-2-aminofluorene (dG-C8-AF) and N-(2'-deoxyguanosin-8-yl)-2-acetylaminofluorene (dG-C8-AAF) adducts, derived from the prototype aromatic amine/amide carcinogens 2-aminofluorene and 2-acetylaminofluorene, are significantly different, although they differ by only a single acetyl group. NER efficiencies of these lesions placed at G1, G2 or G3 in the NarI mutational hot spot duplex sequence (5'�CTCG1G2CG3CCATC�3') were obtained in human HeLa cell extracts. Molecular dynamics simulations showed that the base-displaced intercalated conformation of each adduct displays extensive distorting/destabilizing hallmarks of NER susceptibility. Much weaker van der Waals stacking interactions between the fluorenyl residues and adjacent bases are responsible for the greater repair susceptibility of dG-C8-AAF. Differences in stacking patterns are responsible for sequence context effects on NER efficiencies, producing greater distortions in the better-repaired sequences. The key role played by the acetyl group in producing NER efficiency differences highlights that small structural differences can strongly impact NER susceptibilities. Supported by National Institutes of Health grant CA-099194 (to N.E.G.), and CA-75449 and CA-28038 (to S.B.).

Molecular dynamics simulations elucidate factors explaining different nucleotide excision repair efficiencies of 2-acetylaminofluorene- and 2-aminofluorene-(C8)guanine lesions in the three <i>Nar</i>I sequence contexts

244th National Meeting (2012)

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Molecular dynamics simulations elucidate factors explaining different nucleotide excision repair efficiencies of 2-acetylaminofluorene- and 2-aminofluorene-(C8)guanine lesions in the three NarI sequence contexts