ESTIMATION OF THE DNA-SEQUENCE DISCRIMINATORY ABILITY OF HAIRPIN-LINKED LEXITROPSINS

Three- and four-ring polyamides containing N-methylimidazole and N-met hylpyrrole, and their hairpin-linked derivatives, bind side-by-side in the minor groove of DNA in a sequence-specific manner, The sequences recognized by side-by-side molecules are dependent on the pairings of the polyamide rings to the bases, In this study we report a mathematic al model for estimating the free energies of binding for gamma-aminobu tyric acid-linked polyamides to 5- and 6-bp DNA sequences. The model p arameters are calibrated by a least-squares fit to 35 experimental bin ding constants. The model performs well in cross-validation experiment s and the parameters are consistent with previously proposed empirical rules of polyamide-DNA binding. We apply the model to the design of t argeted polyamides, evaluating the ability of the proposed polyamides to bind to a DNA sequence of interest while minimizing binding to the remaining DNA sequences.