Molecular dynamics simulations provide a structural basis for the experimentally observed nucleotide preferences for...

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.