Anthracycline-DNA interactions studied with linear dichroism and fluorescence spectroscopy

DNA-binding geometry and dynamics of a number of anthracyclines, including adriamycin and 4-demethoxydaunorubicin, interacting with DNA have been studied by means of linear dichroism and fluorescence techniques. The anthracycline chromophore is found to be approximately parallel to the plane of the DNA bases and to have a restricted mobility, as would be expected for an intercalative binding mode, but there are variations between different directions in the chromophore as well as between the drugs. From dichroic spectra of adriamycin in an anisotropic host of poly(vinyl alcohol), absorption components corresponding to transitions with mutually orthogonal polarizations have been resolved. These can be exploited to determine the orientations of the two chromophore axes in the DNA complex relative to the DNA helix axis. In a certain binding regime the long axis of the bound anthracycline chromophores (with the exception of 4-demethoxydaunorubicin) is found to be approximately 10 degrees closer to perpendicular to the helix axis than are the DNA bases. This demonstrates that the average base tilt is at least 10 degrees. By contrast, the short axis of the aglycon moiety is found to be tilted some 20-30 degrees from perpendicular. This may be because it is probing a base direction with a more pronounced, static or dynamic, inclination than the average in DNA. The drug orientation and the DNA orientation (reflecting flexibility) are observed to vary differently and nonmonotonically with binding ratio, suggesting specific binding and varying site geometries.(ABSTRACT TRUNCATED AT 250 WORDS)