title: Noncovalent interactions of a benzo[a]pyrene diol epoxide with DNA base pairs: insight into the formation of adducts of (+)-BaP DE-2 with DNA.
abstract: Noncovalent complexes of a tumorigenic benzo[a]pyrene diol epoxide with the guanine-cytosine (GC) and adenine-thymine (AT) base pairs have been examined computationally. (+)-BaP DE-2 forms covalent adducts with DNA via nucleophilic attack on the (+)-BaP DE-2 epoxide. Computational results predict five thermodynamically accessible complexes of AT with (+)-BaP DE-2 that are compatible with intact DNA. Among these, two are expected to lead to adenine adducts. In the lowest energy AT...(+)-BaP DE-2 complex, which has a gas-phase interaction energy of -20.9 kcal mol(-1), the exocyclic NH(2) of adenine is positioned for backside epoxide attack and formation of a trans adduct. The most energetically favorable complex leading to formation of a cis ring-opened adduct lies only 0.6 kcal mol(-1) higher in energy. For GC...(+)-BaP DE-2, there are only two thermodynamically accessible complexes. The higher-lying complex, bound in the gas phase by 24.4 kcal mol(-1) relative to separated GC and (+)-BaP DE-2, would lead to a trans ring-opened N(2)-guanine adduct. In the global minimum energy GC...(+)-BaP DE-2 complex, bound by 27.3 kcal mol(-1), the exocyclic NH(2) group of cytosine is positioned for cis epoxide addition. However, adducts of (+)-BaP DE-2 with cytosine are rarely observed experimentally. The paucity of cytosine adducts, despite the predicted thermodynamic stability of this GC...(+)-BaP DE-2 complex, is attributed to the electrostatic destabilization of the benzylic cation intermediate thought to precede cis addition.
authors.affiliation: Center for Computational Quantum Chemistry, University of Georgia, Athens, Georgia 30602, USA.
authors.forename: Jacqueline C
authors.initials: JC
authors.lastname: Hargis
authors.forename: Henry F
authors.initials: HF
authors.lastname: Schaefer
authors.forename: K N
authors.initials: KN
authors.lastname: Houk
authors.forename: Steven E
authors.initials: SE
authors.lastname: Wheeler
mesh_terms: D020029:Base Pairing; D001564:Benzo(a)pyrene / Q000737:chemistry*; D004247:DNA / Q000737:chemistry*; D018736:DNA Adducts / Q000737:chemistry*; D004852:Epoxy Compounds / Q000737:chemistry*; D015394:Molecular Structure
chemical_list: D018736:DNA Adducts; D004852:Epoxy Compounds; D001564:Benzo(a)pyrene; D004247:DNA