Cured of “Stickiness”, Poly-l β-Hairpin is Promoted with ll-to-dd Mutation as a Protein and a Hydrolase Mimic

The planar ribbon of the poly-l β-hairpin is modified to a local ∼90° bend by mutating a cross-strand pair of residues from ll to dd structure. The bend is furnished aromatic side chains in proximity of acid−base−nucleophile side chains, toward the possibility of catalyzed hydrolysis of an active-site-anchored substrate. Six sequences permuted in putative catalytic side chains are evaluated for activity and variability as hydrolase enzymes. Studies using CD, NMR, spectorofluorometry, ITC, and molecular dynamics establish that the sequences over the bent β-hairpin are by and large aggregation-free folds soluble to at least millimolar concentration, and thus remarkably contrasted with “stickiness” of the canonical poly-l β-hairpin. The heterochiral fold displays cooperative ordering and affinity for acetylcholine, p-nitrophenylacetate, and p-nitrophenylphosphate, presumably as the ligands in its aromatic pocket as a bent hairpin. The fold displays hydrolytic activity against p-nitrophenylacetate and manifes...