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Journal of Physical Chemistry A, Vol.114, No.4, 2038-2044, 2010
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
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 center dot center dot center dot(+)-BaP DE-2 complex, which has a gas-phase interaction energy of -20.9 kcal mol(-1), the exocyclic NH2 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 center dot center dot center dot(+)-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 center dot center dot center dot(+)-BaP DE-2 complex, bound by 27.3 kcal mol(-1), the exocyclic NH2 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 center dot center dot center dot(+)-BaP DE-2 complex, is attributed to the electrostatic destabilization of the benzylic cation intermediate thought to precede cis addition.