Principles governing conformations in stereoisomeric adducts of bay regionbenzo[a]pyrene diol epoxides to adenine in DNA: Steric and hydrophobic effects are dominant

The stereochemical properties of ligands that form covalent adducts with DN A have profound effects on their biochemical functions. Differing absolute configurations of substituents about chiral carbon atoms can lead to striki ngly different conformations when such stereoisomeric compounds bind to DNA . The environmental chemical carcinogen, benzo[a]pyrene (BP), provides a re markable example of such stereochemical effects. Metabolic activation of be nzo[a]pyrene leads to a pair of enantiomers, (+)-(7R,8S,9S,10R)-7,8-dihydro xy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene and its (-)-(7S,8R,9R,10S) mirror-image, known as (+)- and (-)-anti-BPDE. Both (+)- and (-)-anti-BPDE react with the amino group of adenine in DNA via trans epoxide opening, yie lding a pair of stereochemically distinct trans-anti-benzo[a]pyrenyl adduct s, whose possible role in chemical carcinogenesis is of great interest. Hig h-resolution NMR solution studies (Schurter et al. Biochemistry 1995, 34, 1 364-75; Yeh et al. Biochemistry 1995, 34, 13570-81; Zegar et al. Biochemist ry 1996, 35, 6212-24; Schwartz et al., Biochemistry 1997, 36, 11069-76) hav e revealed that in the 10S (+)- and 10R (-)-transanti adducts, the BP is cl assically intercalated, residing on the 3'-side of the modified adenine in the (+)trans-anti adduct and on the 5'-side in the (-) stereoisomer. To elu cidate the stereochemical principles underlying these conformational prefer ences, an extensive survey of the potential energy surface of each modified nucleoside was carried out, in which the energy of 373,248 structures for each adduct was computed using AMBER 5.0. Our results reveal near mirror im age symmetries in the four pairs of low-energy structural domains of 10S ()- and 10R (-)-trans-anti-[BP]-N-6-dA adducts, which is rooted in the exact enantiomeric relationship of the BPDE precursors, and accounts for the opp osite orientations observed in solution. Steric hindrance prevents an R iso mer from assuming the orientation favored by the S isomer, and vice versa. The NMR solution structures of 10S (+)- and 10R (-)-trans-anti-[BP]-N-6-dA adducts in DNA adopt conformations which are in the low-energy domains comp uted for the nucleoside adducts. In addition, we find that the preference f or classical intercalation over a major groove position for the pyrenyl rin g system in the [BP]-N-6-dA adducts stems from the advantage of burying the hydrophobic pyrenyl moiety within the helix rather than having it exposed in the large major groove.