Dynamics of a benzo[a]pyrene-derived guanine DNA lesion in TGT and CGC sequence contexts: Enhanced mobility in TGT explains conformational heterogeneity, more flexible bending and greater nucleotide excision repair susceptibility

TOXI 65

Yuqin Cai, yc385@nyu.edu1, Nicholas E. Geacintov, nicholas.geacintov@nyu.edu1, and Suse Broyde, broyde@nyu.edu2. (1) Department of Chemistry, New York University, 100 Washington Square East, 1001, New York, NY 10003, (2) Department of Biology, New York University, 100 Washington Square East, New York, NY 10003
We employ molecular modeling and MD simulations to delineate differences in conformational properties of the 10S (+)–trans–anti–[BP]–N2–dG adduct in CGC and TGT modified duplexes in order to define the sequence–dependent structural perturbations. These duplexes contain stereochemically identical adducts flanked by different natural Watson–Crick paired nucleobases. Our goal was to elucidate the origin of the greater excision efficiency in the TGT case, and more broadly, to delineate structural parameters that enhance NER. Our results show that the BP rings are 5′–directed along the modified strand in the B–DNA minor groove in both sequence contexts. However, the TGT modified duplex is much more dynamically flexible, with more perturbed and mobile Watson–Crick hydrogen bonds flanking the lesion, greater impaired stacking, more minor groove flexibility and more dynamic local Roll/bending. These characteristics explain the more flexible bend and greater conformational heterogeneity observed experimentally and contribute to an understanding of the greater NER susceptibility.(This research is supported by NIH Grants CA–28038 to S.B. and CA–099194 N.E.G.)
 

Poster Session and Awards
6:00 PM-10:00 PM, Tuesday, August 21, 2007 BCEC -- 204 A/B, Poster

Sci-Mix
8:00 PM-10:00 PM, Monday, August 20, 2007 BCEC -- Exhibit Hall - B2, Sci-Mix

Division of Chemical Toxicology

The 234th ACS National Meeting, Boston, MA, August 19-23, 2007