The DNA complexes of 2,5-diaziridinylbenzoquinone and 3,6-dimethyl-2,5-diaziridinylbenzoquinone. A molecular mechanics study.
Computer modeling has been used to study the non-covalent interaction of the quinone and hydroquinone forms of 2,5-diaziridinyl-1,4-benzoquinone (DZQ and DZHQ, respectively) and its 3,6-dimethyl derivative (MeDZQ, MeDZHQ) with DNA. Calculations were performed using DNA duplexes containing 5'-TGCA and 5'-TGTC binding sites. The results allow a rationalization of the sequence selectivity of DNA alkylation exhibited by these ligands. For DZHQ a preference for binding to the TGCA site, over the TGTC site, was predicted for a range of diverse ligand/DNA orientations. The ligand preferentially adopts a position orthogonal to the base pair planes. The complex is stabilized by guanine N7 to ligand OH hydrogen bonds at the GC step. The stability of the TGTC complexes of DZHQ is reduced by a clash between the thymine methyl of the GTC sequence and the ligand. In MeDZHQ/TGCA complexes, a similar clash causes the aromatic ring plane to rotate about 45 degrees from the base pair planes. The most stable orientation of the MeDZHQ/TGTC complex has the ligand symmetrically disposed about the T-A base pair in the center of the GTC site, with hydrogen bonds formed between both ligand hydroxyl groups and guanine N7 atoms on opposite strands. For all four complexes, a secondary energy minimum was located for an orientation in which the face of the aromatic ring interacts with a thymine methyl group. DZQ complexation is favored at the TGCA site, whereas for MeDZQ the lowest energy complexes were obtained for binding at the TGTC site. The major determinant of the strength of the non-covalent interaction for all the quinone complexes was the angle between the plane of the aromatic ring and the base pair plane. The binding interaction of the quinone forms with an adenine tract was also studied. In this case, the ligand location follows a contour defined by the thymine methyl groups. Both quinones bound less effectively to this sequence than to either the TGCA or TGTC sites.
Yuki
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Department of Pharmaceutical Sciences, University of Southern California, Los Angeles 90033.
Haworth
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D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism*; D001388:Aziridines / Q000737:chemistry* / Q000378:metabolism*; D001483:Base Sequence; D016227:Benzoquinones / Q000737:chemistry* / Q000378:metabolism*; D001665:Binding Sites; D003198:Computer Simulation; D004247:DNA / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data
D000970:Antineoplastic Agents; D001388:Aziridines; D016227:Benzoquinones; C073715:2,5-dimethyl-3,6-diaziridinyl-1,4-benzoquinone; C009970:ethylenimine quinone; D004247:DNA