Conformational analysis of genotoxic benzo[a]pyrene- 7,8-dione-duplex DNA adducts using a molecular dynamics method

Benzo[a]pyrene-7,8-quinone (BPQ), a metabolite of the wide spread carcinogen benzo[a]pyrene, has been known to form adducts with DNA bases, namely guanine and adenine. The adducts include stereoisomers of the eight BPQ-G(1,2) and products of the formation of the cyclic five-member ring between BPQ and the G base. The stereochemical characteristics, structural properties, and thermodynamic aspects of the formation of the BPQ-G modified duplexes were investigated in this work using molecular modeling and a molecular dynamics (MD) simulation technique. Three conformations for the BPQ- oligonucleotides adduct showed the most favorable free energy (DeltaG). The molecular plane of the BPQ is nearly perpendicular to the DNA base plane for all three stable adducts. In two adducts, BPQ is located in the minor groove with either anti or syn conformations around the glycosidic bond. One of adducts in which BPQ locates into the major groove with the anti conformation around the glycosidic bond was also energetically possible. The resulting detailed structures of the three conceivable BPQ-oligonucleotide adducts are elucidated in this work.