Structural characterization of N-acetyl-2-aminofluorene and its guanine and deoxyguanosine adducts via a molecular mechanics, semi-empirical, and density functional theory cascade method

Hepatic activation of N-acetyl-2-aminofluorene (AAF) produces major (C8) and minor (N2) guanine adducts to DNA. The N2 adduct may be important in mutagenesis due to its persistence in vivo but its structure has not been determined experimentally. The present study seeks to elucidate both adduct structures via quantum-mechanical study of small complexes of AAF bonded to guanine (G) or deoxyguanosine(dG). A computational cascade of MMFF94 conformer searches followed by AM1 and subsequent density-functional theory BP/DN, BP/DN*, and BP/DN** geometry optimizations was used to predict the low energy conformer distributions. C8 adducts reveal a preference for one of two orientations, with G or dG oriented either ∼180° or ∼45° with respect to the fluorenyl rings. N2 adducts similarly exhibit two general conformer classes, one of which is characterized by H-bonding between the acetyl O and N2 of guanine. The dG-N2 adduct differs somewhat from G-N2 due to attractive AAF-ribose interactions.*; *This dissertation is multimedia (contains text and other applications not available in printed format). The CD requires the following system application: Microsoft Office.