Solution Conformation of the (-)-trans-anti-Benzo[c]phenanthrene-dA ([BPh]dA) Adduct opposite dT in a DNA Duplex: Intercalation of the Covalently Attached Benzo[c]phenanthrenyl Ring to the 3'-Side of the Adduct Site and Comparison with the (+)-trans-anti-[BPh]dA opposite dT Stereoisomer

Abstract

This paper reports on NMR-molecular mechanics structural studies of the (-)- trans-anti-benzo[c]phenanthrene-dA adduct positioned opposite dT in the sequence context of the d(C1-T2-C3-T4-C5-[BPh]A6-C7-T8-T9-C10-C11).d(G12- G13-A14-A15-G16-T17-G18-A19-G20-A21- G22) duplex (designated as the (-)-trans-anti-[BPh]dA.dT 11-mer duplex). This adduct is derived from the covalent binding of (-)-1,2-dihydroxy-3,4-epoxy-1,2,3,4-tetrahydro-benzo[c]phenanthrene [(-)-anti-BPhDE] to N6 of dA6 in this duplex sequence. The benzo[c]phenanthrenyl and nucleic acid exchangeable and nonexchangeable protons were assigned in the predominant conformation following analysis of two-dimensional NMR data sets in H2O and D2O buffer solution. The solution structure of the (-)-trans-anti-[BPh]dA.dT 11-mer duplex has been determined by incorporating intramolecular 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 show that the [BPh]dA6.dT17 base pair propeller twists and buckles slightly to permit the covalently attached benzo[c]phenanthrenyl ring to intercalate between the [BPh]dA6.dT17 and dC7.dG16 base pairs to the 3'-side of the [BPh]dA6 lesion site without disrupting the Watson-Crick hydrogen bond alignments in the modified duplex. The strain in the highly sterically hindered fjord region of the benzo[c]phenanthrenyl moiety is relieved by the propeller-like nonplanar geometry of the aromatic phenanthrenyl ring system, which stacks predominantly with the dG16 and dT17 bases on the unmodified strand. The benzylic ring adopts a distorted half-chair form, in which the H1 and H2 protons are pseudo-diequatorial and the H3 and H4 protons are pseudodiaxial. The current observation that the (-)-trans-anti-[BPh]dA positioned opposite dT intercalates to the 3'-side of the intact modified base pair contrasts with our previous demonstration that the stereoisomeric (+)-trans-anti-[BPh]dA adduct positioned opposite dT intercalates to the 5'-side of the intact modified base pair [Cosman, M., et al. (1993b) Biochemistry 32, 12488-12497]. These stereochemically induced structural differences between isomeric [BPh]dA lesions derived from the binding of chiral (+)- and (-)-anti-BPhDE enantiomers may in turn profoundly influence the interactions of the carcinogen-modified DNA with repair and replication enzymes in the cell.

Solution structure of the 2-amino-1- methyl-6-phenylimidazo[4,5- b ]pyridine C8-deoxyguanosine adduct in duplex DNA

“…The factors that influence this conformational exchange are the relative stabilities of DNA base pairing vs. those of ligand DNA-stacking interactions. However, in the case of the N6-dAbenzo[c]phenanthrenyl-DNA adducts, both types of interactions could be accommodated simultaneously without any conformational exchange (40), suggesting that the allowed topology of the ligand at the base-linkage site is also an important determinant (30).…”

Position-specific trapping of topoisomerase I–DNA cleavage complexes by intercalated benzo[ a ]- pyrene diol epoxide adducts at the 6-amino group of adenine

“…trans-R dA adducts are intercalated toward the 5Ј side of the modified base (17)(18)(19)(20)(21). Although the evidence is less compelling for trans-10S-BaP DE-2 dA adducts, such adducts are thought to intercalate toward the 3Ј side of their adducted base (22,23). Thus, four unique structural motifs with intercalated adducts (compare Figs.…”

Accommodation of a 1S-(−)-Benzo[c]phenanthrenyl-N6-dA Adduct in the Y-Family Dpo4 DNA Polymerase Active Site: Structural Insights through Molecular Dynamics Simulations

“…To create the intercalation structures, we remodeled the 3′ (proximal) template base to a 3′-intercalated 1S-(-)-B[c]Ph-dA adduct in the active site, guided by the NMR solution structure (65), and the favored α′ and β′ domains computed for the adduct (64). The torsion angles of the modified adenine and its surrounding residues were adjusted (Table S1 (64), and guided by steric feasibility.…”