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-benzoqui none (DZQ and DZHQ, respectively) and its 3,6-dimethyl derivative (MeD ZQ, MeDZHQ) with DNA. Calculations were performed using DNA duplexes c ontaining 5'-TGCA and 5'-TGTC binding sites. The results allow a ratio nalization of the sequence selectivity of DNA alkylation exhibited by these ligands. For DZHQ a preference for binding to the TGCA site, ove r the TGTC site, was predicted for a range of diverse ligand/DNA orien tations. The ligand preferentially adopts a position orthogonal to the base pair planes. The complex is stabilized by guanine N7 to ligand O H hydrogen bonds at the GC step. The stability of the TGTC complexes o f DZHQ is reduced by a clash between the thymine methyl of the GTC seq uence 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 th e ligand symmetrically disposed about the T-A base pair in the center of the GTC site, with hydrogen bonds formed between both ligand hydrox yl groups and guanine N7 atoms on opposite strands. For all four compl exes, a secondary energy minimum was located for an orientation in whi ch 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. Th e major determinant of the strength of the non-covalent interaction fo r all the quinone complexes was the angle between the plane of the aro matic ring and the base pair plane. The binding interaction of the qui none forms with an adenine tract was also studied. In this case, the l igand 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.