Non-Covalent Interactions of a Benzo[a]pyrene Diol Epoxide with DNA Base Pairs: Insight into the Formation of Adducts of (+)-BaP DE-2 with DNA

• Published in: The journal of physical chemistry. A, Molecules, spectroscopy, kinetics, environment, & general theory Vol. 114; no. 4; pp. 2038 - 2044
• Main Authors: Hargis, Jacqueline C., Schaefer, Henry F., Houk, K. N., Wheeler, Steven E.
• Format: Journal Article
• Language: English
• Published: 04.02.2010
• ISSN: 1089-5639; 1520-5215
• DOI: 10.1021/jp911376p

Non-covalent complexes of a tumorigenic benzo[ a ]pyrene diol epoxide with the guanine-cytosine and adenine-thymine base pairs have been examined computationally. (+)-B a P DE-2 forms covalent adducts with DNA via nucleophilic attack on the (+)-B a P DE-2 epoxide. Computational results predict five thermodynamically accessible complexes of AT with (+)-B a P DE-2 that are compatible with intact DNA. Among these, two are expected to lead to adenine adducts. In the lowest energy AT ... (+)-B a P 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 ... (+)-B a P 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 (+)-B a P DE-2, would lead to a trans ring opened N 2 -guanine adduct. In the global minimum energy GC ... (+)-B a P 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 (+)-B a P DE-2 with cytosine are rarely observed experimentally. The paucity of cytosine adducts, despite the predicted thermodynamic stability of this GC ... (+)-B a P DE-2 complex, is attributed to the electrostatic destabilization of the benzylic cation intermediate thought to precede cis addition.