title: Molecular dynamics simulations provide a structural basis for the experimentally observed nucleotide preferences for DNA interstrand cross-links induced by aziridinylbenzoquinones.
abstract: Two-electron reduction of the structurally related aziridinylbenzoquinones DZQ and MeDZQ to their hydroquinone forms, DZHQ and MeDZHQ, respectively, generates species which interact and cross-link DNA at distinct nucleotide sequences. Within single target site duplex oligonucleotides, DZHQ was found to cross-link DNA at 5'-GC-3' and 5'-GNNC-3' sequences, whereas MeDZHQ was found to cross-link predominantly at 5'-GNC-3' within a 5'-GTCA-3' sequence. In a multitarget site duplex oligonucleotide, which contains either the target sequence 5'-TGCAC-3' or 5'-TGCTC-3', DZHQ was found to cross-link at both a 5'-GC-3' (a 1,2 cross-link) and a 5'-GNNC-3' (a 1,4 cross-link) site with approximately equal efficiency. Molecular dynamics simulations were able to accurately reproduce the experimental results and provide a structural basis for the alkylation preferences. Calculations were performed to determine the mobility of the hydroquinone species following guanine N7 (G) alkylation at 5'-TGCAC-3' and 5'-TGTCA-3' sequences. Conformations consistent with the formation of both 1,2 and 1,4 cross-links were observed when DZHQ was placed within a 5-TGCAC-3' sequence. The 1,2 cross-link orientation was more stable and thermodynamically favored. For MeDZHQ at the same site the ligand was unable to form stable 1,2 or 1,4 cross-linking conformations, primarily due to clashes with thymine methyl groups. In contrast, the MeDZHQ monoadduct with a 5'-TGTCA-3' sequence adopted a very stable conformation consistent with formation of a 1,3 cross-link.
authors.affiliation: School of Pharmacy, University of Southern California, Los Angeles 90033.
authors.forename: I S
authors.initials: IS
authors.lastname: Haworth
authors.forename: C S
authors.initials: CS
authors.lastname: Lee
authors.forename: M
authors.initials: M
authors.lastname: Yuki
authors.forename: N W
authors.initials: NW
authors.lastname: Gibson
mesh_terms: D000478:Alkylation; D000818:Animals; D001388:Aziridines / Q000737:chemistry*; D001483:Base Sequence; D016227:Benzoquinones / Q000737:chemistry*; D003198:Computer Simulation; D003432:Cross-Linking Reagents / Q000737:chemistry*; D004249:DNA Damage; D008058:Dihydrolipoamide Dehydrogenase / Q000378:metabolism; D006873:Hydroquinones / Q000737:chemistry*; D008099:Liver / Q000201:enzymology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation; D009838:Oligodeoxyribonucleotides / Q000737:chemistry*; D051381:Rats
chemical_list: D001388:Aziridines; D016227:Benzoquinones; D003432:Cross-Linking Reagents; D006873:Hydroquinones; D009838:Oligodeoxyribonucleotides; C084722:3,6-dimethyl-2,5-diaziridinylhydroquinone; C073715:2,5-dimethyl-3,6-diaziridinyl-1,4-benzoquinone; C084721:2,5-diaziridinylhydroquinone; D008058:Dihydrolipoamide Dehydrogenase