This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Singh, S. B. Articles by Broyde, S. Search for Related Content PubMed PubMed Citation Articles by Singh, S. B. Articles by Broyde, S.

Structures of the (+)- and (-)-trans-7,8-Dihydroxy-anti-9,10-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene Adducts to Guanine-N² in a Duplex Dodecamer¹

Departments of Chemistry [S. B. S., N. E. G.] and Biology [S. B.], New York University, New York, New York 10003; Health and Safety Research Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37831 [B. E. H.]; Department of Molecular Biology, Research Institute of Scripps Clinic, La Jolla, California 92037 [U. C. S.]; and San Diego Supercomputing Center, San Diego, California 92186-9784 [J. P. G.]

The structures of the mirror image (+)- and (-)-trans-anti-adducts of 7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene to guanine N² have been of great interest because the high biological activity of 7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene in mammalian mutagenesis and tumorigenesis has been attributed to the predominant (+)-trans-anti-adduct. We have carried out new potential energy minimization studies, involving wide-scale conformational searches on small modified DNA subunits, followed by energy-minimized build-up techniques, to generate atomic resolution views of these adducts. These energy-minimized duplex dodecamers were then subjected to 100-ps molecular dynamic simulations with solvent and salt to yield animated molecular structures. The most favored computed structure for the (+)-adduct places the pyrenyl moiety in the B-DNA minor groove, with its long axis directed toward the 5' end of the modified strand, and with a pronounced bend in the helix axis. In the (-)-adduct, there are 2 favored structures. One places the pyrenyl moiety in the minor groove, whereas the other positions it in the major groove; in both cases, the pyrenyl long axis is directed more toward the 3' end of the modified strand, and with much less helix axis bend. Structures with intercalation character computed for these adducts are less preferred. The favored computed structures agree with spectroscopic data on the (+)- and (-)-trans-anti-adducts, whereas recent experimental evidence suggests that cis-adducts assume intercalation-type structures. Perhaps the conformational distinctions elucidated for the (+)- and (-)-trans-anti-adducts play a role in their differential tumorigenic properties in mammalian systems.

¹ This research was supported by NIH Grant CA-28038. Department of Energy Grant DE-FGO2-90ER60931. National Science Foundation Grant DMB-8416009 (S. B.), NIH Grant GM-39310 (U. C. S.), Department of Energy Contract DE-AC05-84OR21400 with Martin-Marietta Energy Systems (B. E. H.), and Department of Energy Grants DE-FGO25-86ER60405 and DE-FGO2-88ER60674 (N. G.).

² To whom requests for reprints should be addressed, at Department of Biology, New York University, 1009 Main Building, Washington Square, New York, NY 10003.

Received 12/14/90. Accepted 4/17/91.

This article has been cited by other articles:

				L. Wang, B. E. Hingerty, A. R. Srinivasan, W. K. Olson, and S. Broyde Accurate Representation of B-DNA Double Helical Structure with Implicit Solvent and Counterions Biophys. J., July 1, 2002; 83(1): 382 - 406. [Abstract] [Full Text] [PDF]

				R. E. Kozack and E. L. Loechler Molecular modeling of the major adduct of (+)-anti-B[a]PDE (N2-dG) in the eight conformations and the five DNA sequences most relevant to base substitution mutagenesis Carcinogenesis, January 1, 1999; 20(1): 85 - 94. [Abstract] [Full Text] [PDF]

				W. G. McGregor, M. C.-M. Mah, R.-H. Chen, V. M. Maher, and J. J. McCormick Lack of Correlation between Degree of Interference with Transcription and Rate of Strand Specific Repair in the HPRT Gene of Diploid Human Fibroblasts J. Biol. Chem., November 10, 1995; 270(45): 27222 - 27227. [Abstract] [Full Text] [PDF]

				G. I. Gorodeski and U. Hopfer Regulation of the Paracellular Permeability of Cultured Human Cervical Epithelium by a Nucleotide Receptor Reproductive Sciences, September 1, 1995; 2(5): 716 - 720. [Abstract] [PDF]