Solution conformation of the (+)-trans-anti-[BP]dG adduct opposite a deletion site in a DNA duplex: intercalation of the covalently attached benzo[a]pyrene into the helix with base displacement of the modified deoxyguanosine into the major groove

M. Cosman, R. Fiala, B. E. Hingerty, S. Amin, N. E. Geacintov, S. Broyde, D. J. Patel

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This paper reports on the solution structure of the (+)-trans-anti-[BP]dG adduct positioned opposite a deletion site in a DNA oligomer duplex which defines the alignment of this covalent benzo[a]pyrene-N2-deoxyguanosine stereosiomer relative to the deletion site. The combined NMR-molecular mechanics computation studies were undertaken on the (+)-trans-anti-[BP]dG adduct embedded in the d(C5-[BP]G6-C7).d(G16-G17) sequence context in a duplex containing 11 residues on the modified strand and 10 on the partner, with no base opposite the modification. The exchangeable and nonexchangeable protons of the benzo[a]pyrenyl moiety and the nucleic acid were assigned following analysis of two-dimensional NMR data sets in H2O and D2O solution. The solution conformation of the (+)-trans-anti-[BP]dG.del 11-mer duplex has been determined by incorporating intramolecular and intermolecular proton-proton distances defined by lower and upper bounds deduced from NOESY spectra as restraints in molecular mechanics computations in torsion angle space. The benzo[a]pyrene ring of [BP]dG6 is intercalated between intact Watson-Crick dC5.dG17 and dC7.dG16 base pairs with the deoxyguanosine base of [BP]dG6 displaced into the major groove. The intercalation site is wedge shaped, being narrower toward the dG16-dG17 step on the deletion-containing strand. The deoxyguanosine base of [BP]dG6 which is positioned in the major groove is inclined relative to the helix axis and stacks over the 5'-flanking dC5 residue in the solution structure. The intercalative-base displacement structure of the (+)-trans-anti-[BP]dG.del 11-mer duplex exhibits several unusually shifted proton resonances which can be readily accounted for by the ring current contribution of the deoxyguanosyl and pyrenyl rings of the [BP]dG6 adduct. This solution structure of the (+)-trans-anti-[BP]dG.del 11-mer duplex where the pyrene ring intercalates into the helix with displacement of the modified deoxyguanosine into the major groove strikingly contrasts with our previous study on the (+)-trans-anti-[BP]dG.dC 11-mer duplex [Cosman, M., et al. (1992) Proc. Natl. Acad. Sci. U.S.A. 89, 1914-1918] where the benzo[a]pyrene ring is positioned in the minor groove without disruption of the Watson-Crick pairing at the [BP]dG.dC modification site. Thus, generation of the deletion site following removal of the dC opposite the (+)-trans-anti-[BP]dG results in a displacement of the entire [BP]dG residue toward the major groove and intercalation of the benzo[a]pyrene ring into the helix.
Original languageUndefined
Pages (from-to)11507-17
Issue number38
StatePublished - 1994


  • Base Sequence Benzo(a)pyrene/*chemistry Carcinogens, Environmental/*chemistry DNA Adducts/*chemistry Deoxyguanosine/*analogs & derivatives Intercalating Agents/*chemistry Isomerism Magnetic Resonance Spectroscopy Models, Molecular Molecular Sequence Data Nucleic Acid Conformation Nucleic Acid Denaturation Protons Sequence Deletion Solutions

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