Allosterically Regulated Phosphatase Activity from Peptide-PNA Conjugates Folded Through Hybridization

The importance of spatial organization in short peptide catalysts is well recognized. We synthesized and screened a library of peptides flanked by peptide nucleic acids (PNAs) such that the peptide would be constrained in a hairpin loop upon hybridization. A screen for phosphatase activity led to the discovery of a catalyst with >25‐fold rate acceleration over the linear peptide. We demonstrated that the hybridization‐enforced folding of the peptide is necessary for activity, and designed a catalyst that is allosterically controlled using a complementary PNA sequence. A library of peptides that are constrained in a hairpin loop by flanking peptide nucleic acids upon hybridization were synthesized. A screen for phosphatase activity led to the discovery of a catalyst with a more than 25‐fold rate acceleration over the linear peptide. The hybridization‐enforced folding of the peptide is decisive for the activity.