Visualization of drug nucleic acid interactions at atomic resolution part 3 unifying structural concepts in understanding drug dna interactions and their broader implications in understanding protein dna interactions
Sobell, H.M.; Tsai, C.C.; Jain, S.C.; Gilbert, S.G.
Journal of Molecular Biology 114(3): 333-366
Structural information afforded by the X-ray crystallographic studies of ethidium-dinucleoside monophosphate crystalline complexes described previously has led to a detailed model for ethidium-DNA binding. Features of ethidium-DNA binding have led to unifying structural concepts in understanding a wide range of drug-DNA interactions. These concepts may have still broader implications in understanding the nature of protein-DNA interactions. The stereochemical aspects of ethidium-DNA, actinomycin-DNA and irehdiamine-DNA binding, molecules that use intercalative and kinked-type geometries in binding to DNA, are described. Superhelical DNA structures formed by kinking DNA periodically varying numbers of base-pairs apart are also described. .kappa.-Kinked B DNA, a structure formed by kinking DNA every 10 base-pairs, is a left-handed superhelical structure that may be utilized in the organization of DNA within the nucleosome in chromatin. .beta.-Kinked B DNA is a right-handed superhelical structure formed by kinking DNA every 2 base-pairs. Premelting conformational changes may occur in DNA which utilize elements of this structure. This would expose base-pairs to solvent denaturation, and could lower the activation energy necessary for strand separation during DNA denaturation. RNA polymerase and other DNA melting proteins could capitalize on this type of premelting conformational change when binding to DNA. The concept that conformational flexibility exists in DNA structure (and that drug intercalation is a phenomenon that reflects this flexibility) can, in addition, explain a wide variety of physicochemical data about DNA.