Binding of a hairpin polyamide in the minor groove of DNA: Sequence-specific enthalpic discrimination (polyamide-DNA binding affinityyisothermal calorimetryy2:1 pyrrole-imidazole DNA binding motifypolyamide-base hydrogen bondsyimidazole-guanine interaction)

Hairpin polyamides are synthetic ligands for sequence-specific recognition in the minor groove of doublehelical DNA. A thermodynamic characterization of the DNAbinding properties exhibited by a six-ring hairpin polyamide, ImPyPy-g-PyPyPy-b-Dp (where Im 5 imidazole, Py 5 pyrrole, g 5 g-aminobutyric acid, b 5 b-alanine, and Dp 5 dimethylaminopropylamide), reveals an '1-2 kcalymol 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 enthalpy and entropy data at 20°C reveal this sequence specificity to be entirely enthalpic in origin. Correlations between the thermodynamic driving forces underlying the sequence specificity exhibited by ImPyPy-g-PyPyPy-b-Dp and the structural properties of the heterodimeric complex of PyPyPy and ImPyPy bound to the minor groove of DNA provide insight into the molecular forces that govern the affinity and specificity of pyrrole-imidazole