Conformational determinants of structures in stereoisomeric cis-opened anti-benzo[a]pyrene diol epoxide adducts to adenine in DNA

As part of a comprehensive effort to understand the origins of the variety of structural motifs adopted by (+)- and (-)-cis- and trans-anti-[BP]-N-2-d G and -N-6-dA adducts, with the goal of contributing to the elucidation of the structure-function relationship, we present results of our comprehensiv e computational investigation of the C10R (+)-cis- and C10S (-)-cis-anti[BP ]-N-6-dA adducts on the nucleoside level. We have surveyed the potential en ergy surface of these two adducts by varying systematically, at 5 degrees i ntervals in combination, the three key torsion angle determinants of confor mational flexibility (chi, alpha', and beta') in each adduct, creating 373 248 structures, and evaluating each of their energies. This has permitted u s to map the entire potential energy surface of each adduct and to delineat e the low-energy regions. The energy maps possess a symmetric relationship in the (+)/(-) adduct pair. This symmetry in the maps stems from the mirror image configuration of the benzylic rings in the two adducts, which produc es opposite orientations of the BP residues in the C10R and C10S adducts on the nucleoside level. These opposite orientations result from primary ster ic hindrance between the base and the BP moiety which ensues when a (+) ste reoisomer is rotated to the conformation favored by the (-) stereoisomer, a nd vice versa. Moreover, this steric hindrance manifested on the nucleoside level governs the structure on the duplex DNA level, accounting for observ ed opposite orientations in high-resolution NMR studies of C10R/C10S adduct pairs.