Controlling binding orientation in hairpin polyamide DNA complexes

The effects of N-terminal acetylation and C-terminal tail structure on the orientation of binding of imidazole/pyrrole polyamide DNA ligands has been investigated. We find that N-terminal acetylation leads to an intramolecula r steric clash for hairpin ligands bound in the minor groove, promoting a r otation of the spatially close C-terminal pyrrole ring. This in turn leads to loss of contacts between the tail and the groove, removing the preferenc e for 5'-to-3' orientational binding typical of this class of ligand. Simil arly, introduction of a glycine linker into the tail leads to a direct ster ic clash with the groove, again promoting rotation of the attached ligand r ing. The effects of acetylation and a glycine in the tail are additive. The implications for the design of sequence-specific ligands are discussed.