Interactions of heteroaromatic compounds with nucleic acids. 1. The influence of heteroatoms and polarizability on the base specificity of intercalating ligands.

We have examined the origins of base specificity in intercalating ligands by studying the interaction with DNA of a series of proflavine and acridine orange analogs differing in the heteroatoms present in the chromophore. Base specificity was determined by differential dialysis of the dye against DNA samples of differing G-C content. We find that G-C specificity increases as the visible absorbance band of the chromophore moves to longer wavelength, implying a relation between specificity and polarizability of the chromophore. This can be rationalized by recognizing that the G-C pair is more polar than A-T, and should therefore interact more favorably with an easily polarized ring system. We find in addition that dimethylation of the chromophore amino groups increases specificity which we discuss in terms of steric and coupled steric-electronic contributions. Our results also bear on the origin of G-C specificity in binding actinomycin to DNA. Some of the compounds studied are as G-C specific as actinomycin, yet they lack hydrogen-bonding functions as plausible determinants of specificity. This observation gives new life to the hypothesis that the specificity of actinomycin is determined primarily by preferential interaction of the chromophore with a G-C pair.