Polyamides (PA) are N-methylpyrrole (Py) and N-imidazole (Im) based small molecules that derive from the natural products distamycin and netropsin, and have strong sequence specificity for DNA recognition. In rational drug design, �-alanine (�) is generally incorporated in large PAs since it has the same recognition capability as Py, but �'s relative flexibility is thought to help maintain registry between DNA and PA H-bonding functional groups. Recently, we have observed that the � substitution frequently and significantly decreases the DNA binding affinity and specificity of PAs, which is in contrast to most published studies, in which � helps maintain strong and selective DNA binding. The role of � in DNA complex formation by PAs is thus more nuanced than anticipated. Clearly, it is essential to understand the influence of the number and position of � substitutions on PA affinity and specificity for rational design of the most effective, biologically active agents. To aid in establishing the diverse effects of � inserts, we initiated in this work a detailed study of the binding affinity, selectivity and kinetics for heterocyclic hairpin PAs and their �-containing derivatives with cognate and mutant DNA sequences. The results of both PA modification and DNA base mutation show a large position-dependent effect of the � substitution on PA-DNA binding affinity and kinetics. This study provides a better understanding of the molecular basis of specific DNA recognition by PAs, and supports efforts for future development of PA design. (Supported by NIH AI064200 to W.D.W and NIH AI083803 to J.K.B)

Modulation of DNA-polyamide interaction by <i>�</i>-alanine inserts: A study of positional effects on binding affinity and kinetics

247th National Meeting (2014)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.

Modulation of DNA-polyamide interaction by �-alanine inserts: A study of positional effects on binding affinity and kinetics