Building proficient enzymes with foldamer prostheses

Foldamers are non-natural oligomers that adopt stable conformations reminiscent of those found in proteins. To evaluate the potential of foldameric subunits for catalysis, semisynthetic enzymes containing foldamer fragments constructed from α- and β-amino acid residues were designed and characterized. Systematic variation of the α→β substitution pattern and types of β-residue afforded highly proficient hybrid catalysts, thus demonstrating the feasibility of expanding the enzyme-engineering toolkit with non-natural backbones. More than a pegleg: Foldamers (red) containing β-amino acids (green) are shown to be useful as prostheses for creating chimeric enzymes. The activity of the resulting hybrids depends on the number, type, and location of the non-natural building blocks, but rivals that of the natural enzyme in the best cases. The unique properties of foldamers could lead to novel activities not accessible with natural enzymes.