Molecular Recognition of DNA Minor Groove Binding Drugs

Abstract

The molecular structure of several complexes between three minor groove binding drugs (netropsin, distamycin and Hoechst 33258) and several related DNA dodecamers has been solved and refined by single crystal X-ray diffraction analysis. In these complexes, the drug molecules bind to the central AT segment (4–6 base pairs long) in the narrow minor groove of the dodecamer B-DNA double helix. The stabilizing forces between the drugs and DNAs are provided by a combination of ionic, van der Waals and hydrogen bonding interactions. Bifurcated hydrogen bonds are found between the drugs and DNA dodecamers with AnTn sequence in which the AT base pairs have large propeller twists. In contrast, no bifurcated hydrogen bond is found in the drug-d(CGCGATATCGCG) complex due to the unique dispositions of the hydrogen bond acceptors (N3 of adenine and O2 of thymine) of the AT base pairs on the floor of the DNA minor groove. In the latter case, two of the four AT base pairs in the ATAT stretch have low propeller twist angles, even though the DNA has a narrow minor groove. In the netropsind(CGCGATATCGCG) structure, the drug is found to occupy in two orientations equally well, suggesting a disordered model. This is consistent with the results from solution studies (chemical footprinting and NMR) of the dynamic binding interactions between minor groove binding drugs and DNA. A simplified model is presented for the complete binding process of the drug to DNA based on these structural results.