Binding of a hairpin polyamide in the minor groove of DNA: Sequence-specific enthalpic discrimination

Abstract

Hairpin polyamides are synthetic ligands for sequence-specific recognition in the mirror groove of double-helical DNA. A thermodynamic characterization of the DNA-binding properties exhibited by a six-sing hairpin polyarmide, ImPyPy-gamma-PyPyPy-beta-Dp (where Im = imidazole, Pv = pyrrole, gamma = gamma-amimobutyric acid, beta = beta-alaniae, and Dp = dimethylaminopropylamide), reveals an approximate to 1-2 kcal/mol greater affinity for the designated match site, 5'-TGTTA-3' relative to the single base pair mismatch sites, 5'-TGGTA-3' and 5'-TATTA-3'. The enathalpy and entropy data at 20 degrees C reveal this sequence specificity to be entirely enthalpic in origin. Correlations between the thermodynamic driving forces underlying the sequence specificity exhibited by Im-PyPy-gamma-PyPyPy-beta-Dp and the structural properties of the heterodimeric complex of PyPyPy and ImPyPy bound to the minor grope of DNA provide insight into the molecular forces that govern the affinity and specificity of pyrrole-imidazole polyamides.

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