NMR studies of the post-activated neocarzinostatin chromophore-DNA complex. Conformational changes induced in drug...

The glutathione post-activated neocarzinostatin chromophore (NCSi-glu)-DNA complex was studied in detail by 2-D NMR spectroscopy. The complex is a model for understanding the sequence specific cleavage of DNA by the native neocarzinostatin chromophore (NCS chrom), a highly potent enediyne antitumor agent. NMR spectral analysis is presented for the free NCSi-glu, the free DNA duplex and the NCSi-glu-DNA complex. In addition to the previously reported structural details of the complex (Gao, X.; Stassinopoulos, A.; Rice, J. S.; Goldberg, I. H. Biochemistry 1995, 34, 40), we demonstrate that the binding of NCSi-glu in minor groove results in a patch of negatively charged surface covering the otherwise relatively neutral minor groove. The formation of the complex is largely driven by hydrophobic forces and the solvation of the polar surface of the complex. Comparison of the conformations of NCSi-glu and DNA duplex in their free and bound form reveals an induced mutual fit of DNA and NCSi-glu upon complex formation. The reduced NCS chrom represents a DNA binding motif for sequence specific recognition of DNA via intercalation and minor groove interactions.