title: Molecular mechanics simulations on covalent complexes between polycyclic carcinogens and B-DNA.
abstract: We present molecular mechanics simulations on models of covalent complexes between the diol-epoxides of the carcinogens benzo[a]pyrene, benzo[e]pyrene and benzo[c]phenanthrene and a DNA pentamer d(GCGCG).d(CGCGC). In all the models, the carcinogen diol-epoxides lie in the minor groove with alkylation to the exocyclic amino group of the guanine. The theoretical calculations on the benzo[a]pyrene adducts to the pentamer are qualitatively consistent with the experimentally observed relative reactivities between various isomers. The adduct with the (+)trans isomer, which is the most carcinogenic of the benzo[a]pyrene stereoisomers, is calculated to be the energetically most favored. The relative energetic preferences in the adducts of benzo[e]pyrene diol-epoxides to the pentanucleotide parallel those of benzo[a]pyrene. However, there is no obvious explanation for the lack of biological activity in the diol-epoxides of the former carcinogen from the theoretical calculations. In the case of adducts with the diol-epoxides of benzo[c]phenanthrene, the energetically most favored structures are isomers with significant biological activity. The distortions in the double helix are more significant in the complexes with the diol-epoxides of this carcinogen compared to those in the complexes with the diol-epoxides of the other two carcinogens.
authors.affiliation: Department of Pharmaceutical Chemistry, University of California, San Francisco 94143.
authors.forename: S N
authors.initials: SN
authors.lastname: Rao
authors.forename: T
authors.initials: T
authors.lastname: Lybrand
authors.forename: D
authors.initials: D
authors.lastname: Michaud
authors.forename: D M
authors.initials: DM
authors.lastname: Jerina
authors.forename: P A
authors.initials: PA
authors.lastname: Kollman
mesh_terms: D001564:Benzo(a)pyrene; D001580:Benzopyrenes; D055598:Chemical Phenomena; D002621:Chemistry; D004247:DNA; D004249:DNA Damage; D004852:Epoxy Compounds; D006860:Hydrogen Bonding; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D009690:Nucleic Acid Conformation; D010616:Phenanthrenes; D013329:Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: D001580:Benzopyrenes; D004852:Epoxy Compounds; D010616:Phenanthrenes; D001564:Benzo(a)pyrene; C026487:benzo(e)pyrene; D004247:DNA; C002615:benzo(c)phenanthrene