Project Title: 16. Molecular and Cellular Radiobiology Storage and Transfer of the Genetic Message Technical Progress in FY 1973: (Cont'd.) RX-03-02-(d) However, this work with ethidium bromide did not follow the change in layer-line spacing with increasing bound drug; the value was based on molecular model-building, Although two other papers have described x-ray diffraction studies of the intercalation of planar molecules with DNA, a key contribution from the studies reported here on the interaction of daunomycin with DNA was the location of the first zero in the equatorial Fourier transform, described for the first time in such interactions. This gave hard evidence on the molecular geometry of the complex, The value derived in these studies for the untwisting of the DNA helix per molecule drug bound is most important in studies on circular DNA and will become increasingly important in studies on the structure of the chromosome and how the chromosome functions, ™ ‘ All previous evidence suggesting that daunomycin intercalates into DNA was based on solution studies whose interpretation rests on analogies with similar studies on ethidium bromide and the acridines. For these molecules earlier x-ray work was taken as major evidence for intercalation; but, in fact, it was not nearly so unambiguous as the x-ray data reported in these studies on daunomycin and DNA, In sum this is a contribution to the stereochemistry of intercalation, widely assumed to be a key mechanism in the action of many basic drugs and a possibly important way in which polynuclear hydrocarbons, largely emitted by the burning of coal, interact with the informational macromolecules to induce such late effects as oncogenesis. : The single crystal analysis of the 1:2 complex of actinomycin with deoxyguanosine by Sobell and collaborators provides strong evidence for an intercalation model for the interaction of actinomycin with the DNA double helix. An earlier model proposed by Hamilton, Fuller, and Reich was based on specific hydrogen bonding between groups on the actinomycin with those on the guanosine residues in the DNA, Ome difficulty with the intercalation model is that the basis for the high specificity of the DNA-actinomycin interaction is not clear, It may be, therefore, that the external binding model represents a transient recognition state which is a preliminary to strong binding of the actinomycin through intercalation, In fact, for many molecules which bind to DNA, there appears to be an equilibrium between a strong intercalation binding site and a weak external binding site, Work here on daunomycin binding showed that the degree of intercalation varied with the relative humidity of the environment in which the rs of the DNA daunomycin complex were maintained. The degree of int beca faction increased with the increasing relative humidity presumably increase in the amount of water in the fiber environment tended a~the to increase the hydrophobic contribution to the intercalation interaction, Experiments to date with DNA-actinomycin fibers have not yet given clear evidence for intercalation. However, these studies are being extended by maintaining fibers of the complex at very high humidity in an effort to favor the intercalation type of binding. (See Continuation Sheet) pi vazis RX-254