Solution conformation of the (-)-cis-anti-benzo[a]-pyrenyl-dG adduct opposite dC in a DNA duplex: Intercalation of the covalently attached BP ring into the helix with base displacement of the modified deoxyguanosine into the major groove
- Memorial Sloan Kettering Cancer Center, New York, NY (United States)
- Oak Ridge National Lab., TN (United States); and others
This paper reports on the combined NMR-molecular mechanics computational studies of the solution structure of the (-)-cis-anti-[BP]dG adduct positioned opposite dC in the sequence context d(C1-C2-A3-T4-C5-[BP]G6-C7-T8-A9-C10-C11){center_dot}d(G12-G13-T14-A15-G16-C17-G18-A19-T20-G21-G22) duplex [designated (-)-cis-anti-[BP]dG{center_dot}dC 11-mer duplex]. This adduct is derived from cis addition at C{sup 10} of (-)-anti-7(S),8(R)-dihydroxy-9(R), 10(S)-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene[(-)-anti-BPDE] to the N{sup 2} position of dG6 in this duplex sequence. The exchangeable and nonexchangeable protons of the benzo[a]pyrenyl moiety and nucleic acid of the major conformation were assigned following analysis of two-dimensional NMR data sets in H{sub 2}O and D{sub 2}O solution. The solution conformation of the major conformation of the (-)-cis-anti[BP]dG{center_dot}dC 11-mer duplex has been determined by incorporating DNA-DNA and intermolecular BP-DNA proton-proton distances defined by lower and upper bounds deduced from NOESY data sets as restraints in molecular mechanics computations in torsion angle space. The results establish that the covalently attached benzo[a]pyrenyl ring intercalates between intact Watson-Crick dC5{center_dot}dG18 and dC7{center_dot}dG16 base pairs. The solution structure of the (-)-cis-anti[BP]dG{center_dot}dC 11-mer duplex is compared with those of the stereoisomeric (+)-trans-anti-[BP]dG,(-)-trans-anti-[BP]dG, and (+)-cis-anti-[BP]dG adducts positioned opposite dC in the same duplex sequence context. Studies of the biological activities of stereochemically defined BP-DNA adducts and the comparison of the solution structure of the (-)-cis-anti-[BP]dG{center_dot}dC 11-mer duplex with its stereoisomeric counterparts should lead to new insights into the relationships between defined helical distortions and mutagenic specificity and activity. 55 refs., 7 figs., 2 tabs.
- DOE Contract Number:
- FG02-90ER60931; AC05-96OR22464
- OSTI ID:
- 490280
- Journal Information:
- Biochemistry (Eaton), Journal Name: Biochemistry (Eaton) Journal Issue: 30 Vol. 35; ISSN 0006-2960; ISSN BICHAW
- Country of Publication:
- United States
- Language:
- English
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