Solution Conformation of the (—)-trans-anti-5-Methylchrysene—dG Adduct opposite dC in a DNA Duplex: DNA Bending Associated with Wedging of the Methyl Group of 5-Methylchrysene to the 3′-Side of the Modification Site

Monique Cosman, Xu Rong, Hingerty E. Brian, Amin Shantu, G. Harvey Ronald, E. Geacintov Nicholas, Broyde Suse, Dinshaw J. Patel

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Abstract

This paper reports on NMR molecular mechanics structural studies of the (-)-trans-anti-[MC]dG adduct positioned opposite dC in the sequence context of the d(C1-C2-A3-T4-C5-[MC]G6-C7-T8-A9-C10-C11)•d(G 12-G13-T14-A15-G16-C17-G18-A19-T20-G21-G22) duplex [designated (-)-transanti-[MC]dG•C 11-mer duplex]. This adduct is derived from the trans addition at C4 of (-)-anti-1 (S),2(R)-dihydroxy-3(R),4(5)-epoxy-1,2,3,4-tetrahydro-5-methylchrysene [(-)-anti-5-MeCDE] to the N2 position of dG6 in this duplex sequence. The 5-methyl group is located adjacent to the MC(C4) binding site, with these groups juxtaposed in a sterically crowded bay region in the adduct duplex. The 5-methylchrysenyl and the nucleic acid exchangeable and nonexchangeable protons were assigned following analysis of two-dimensional NMR data sets in H2O and D2O buffer solution. The solution structure of the-ranj-anri-[MC]dG•dC 11-mer duplex has been determined by incorporating DNA-DNA and carcinogen-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 [MC]dG6•dC17 base pair and flanking dC5•dG18 and dC7•dG16 base pairs retain Watson-Crick alignments upon adduct formation. The aromatic chrysenyl ring is positioned in the minor groove of a right-handed B-DNA helix and stacks predominantly over the sugar of the dC17 residue across from it on the unmodified complementary strand. The chrysenyl ring points toward the 3'-end of the modified strand with its 5-methyl group inserting between the modified [MC]dG6•dC17 and dC7•dG16 base pairs. The adduct duplex bends by ~47° as a result of the wedged insertion of the 5-methyl group from the minor groove face of the duplex. The solution structure of the (-)-frans-anf/-[MC]dG•dC 11-mer duplex is compared with that of the corresponding-trans-anti-[BP]dG•dC 11-mer [De los Santos et al. (1992) Biochemistry 31, 5245-5252] in which the [BP]dG adduct is derived from the binding of (-)-anti-BPDE [7(S),8(R)-dihydroxy-9(R), 10(S)-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene] to the N2 position of dG in the same DNA sequence context. Although the solution structures of the (-)-trans-anti stereoisomers of 5-methylchrysenyl-dG and benzo[ti]pyrenyl-dG adducts opposite dC exhibit many features in common with each other, the [MC]-dG adduct which contains a bay region methyl group bends the DNA helix to a greater extent than in the corresponding [BP]dG adduct, which lacks a bay region methyl group. Carcinogen-induced bending effects may be important factors in the expression of the mutagenic potential of these [MC]dG lesions. Because of the stabilities of these lesions, site-directed mutagenesis studies are now feasible which should lead to new insights into the relationships between adduct structure, DNA structural distortions, and mutagenic specificity and activity.

Original languageEnglish (US)
Pages (from-to)6247-6260
Number of pages14
JournalBiochemistry
Volume34
Issue number18
DOIs
StatePublished - May 1 1995

All Science Journal Classification (ASJC) codes

  • Biochemistry

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