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8756 J Am Chem Soc 1997 119 8756 8765 Orientation Preferences of Pyrrole Imidazole Polyamides in the Minor Groove of DNA Sarah White Eldon E Baird and Peter B Dervan Contribution from the DiVision of Chemistry and Chemical Engineering California Institute of Technology Pasadena California 91125 ReceiVed May 14 1997X Abstract In order to determine whether there is an orientation preference of pyrrole imidazole Py Im polyamide dimers with respect to the 5 3 direction of the backbone in the DNA helix equilibrium association constants Ka were determined for a series of six ring hairpin polyamides which differ with respect to substitution at the N and C termini Affinity cleaving experiments using hairpin polyamides of core sequence composition ImPyPy PyPyPy with an EDTA Fe II moiety at the C terminus reveal a single binding orientation at each formal match site 5 A T G A T 3 3 and 5 A T C A T 3 3 A positive charge at the C terminus and no substitution at the N terminus imidazole affords the maximum binding orientation preference calculated from Ka 5 TGTTA 3 Ka 5 TCTTA3 with the N terminal end of each three ring subunit located toward the 5 side of the target DNA strand Removal of the positive charge rearrangement of the positive charge to the N terminus or substitution at the N terminal imidazole decreases the orientation preference These results suggest that second generation design principles superimposed on the simple pairing rules can further optimize the sequence specificity of Py Im polyamides for double helical DNA Polyamides containing pyrrole Py and imidazole Im amino acids bind cooperatively as antiparallel dimers in the minor groove of the DNA helix 1 2 Sequence specificity depends on the side by side pairings of N methylpyrrole and N methylimidazole amino acids 1 A pairing of Im opposite Py targets a G C base pair while Py opposite Im targets a C G base pair 1 A pyrrole pyrrole combination is degenerate and targets both T A and A T base pairs 2 Py Im

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