DNA DISTORTION IN BIS-INTERCALATED COMPLEXES

The bis-intercalators Flexi-Di and ditercalinium are synthetic dimers that bis-intercalate into DNA and cause cell death in prokaryotes from futile and abortive repair of DNA. Each is composed of two 7H-pyridoc arbazole units and a linker. Flexi-Di has a flexible spermine-like lin ker while ditercalinium has a rigid bis(ethylpiperidinium) linker. Thi s report, describing the 2.5-angstrom X-ray structure of Flexi-Di comp lexed with [d((Br)CGCG)]2, appears to be the first report of a three-d imensional structure of a DNA complex with a bis-intercalator with a f lexible linker. DNA complex formation with a ditercalinium analog havi ng a flexible linker was not anticipated to yield unstacked and bent D NA as was observed in the previously reported ditercalinium.[d(CGCG)]2 complex. Surprisingly, the DNA in the Flexi-Di complex is bent to a d egree exceeding that of the ditercalinium complex. A comparison of the DNA complexes of Flexi-Di and ditercalinium has allowed us to propose a mechanism by which these bis-intercalators distort DNA. We propose that this class of bis-intercalators pulls the internal base pairs int o the major groove and pushes the external base pairs into the minor g roove. The result is a bend toward the minor groove. It appears that h ydrogen bonds between the linker and the internal guanines effectively pull the central base pairs of the complex out into the major groove. At the external regions of the complex, stacking interactions between the chromophores and terminal base pairs effectively push the termina l base pairs into the minor groove. The result of this push/pull combi nation is to bend the DNA.