Conformational analysis of the major DNA adduct derived from the food mutagen 2-amino-3-methylimidazo [4,5-f] quinoline

The heterocyclic amine 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) is one of a number of carcinogens found in barbecued meat and fish. It is mutageni c in bacterial and mammalian assays and induces tumors in mammals. IQ is bi ochemically activated to a derivative which reacts with DNA to form a major covalent adduct at carbon 8 of guanine. This adduct may deform the DNA and consequently cause a mutation, which may be responsible for initiating IQ' s carcinogenicity. Atomic resolution structures of the IQ-damaged DNA are n ot yet available experimentally. We have carried out an extensive molecular mechanics energy minimization search to locate feasible structures for the major IQ-DNA adduct in the representative sequence d(5'-G1-G2-C3-G4-C5-C6- A7-3'). d(5'-T8-G9-G10-C11-G12-C13-C14-3') with IQ modification at G4; this contains the GGCGCC mutational hotspot sequence known as NarI. The molecul ar mechanics program AMBER 5.0 with the force field of Cornell et al. [(199 5) J. Am. Chem. Sec. 117, 5179-5197] was employed, including explicit Na+ c ounterions and an implicit treatment for solvation. However, key parameters , the partial charges, bond lengths, bond angles, and dihedral parameters o f the modified residue, are not available in the AMBER database. We careful ly parametrized the force field, created 800 starting conformations which u niformly sampled at 18 degrees intervals each of the three flexible torsion angles that govern the IQ-DNA orientation, and minimized their energy. A c onformational mix of structural types, including major groove, minor groove , and base-displaced intercalated carcinogen positions, was generated. This mixture may be related to the diversity of mutational outcomes induced by IQ.