Building Proficient Enzymes with Foldamer Prostheses

Abstract

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.

Effects of Single α-to-β Residue Replacements on Structure and Stability in a Small Protein: Insights from Quasiracemic Crystallization

“…19,20 Collectively, these studies of α→β replacement in distinct tertiary contexts lay a foundation for the design of α/β tertiary structures intended to perform specific functions. 17,21,22,46,16 In the future it will be interesting to examine the impact of β residue substitutions in non-helical segments within discrete tertiary structures. Loops that connect α-helices and/or β-strands should be regions of particular interest because such loops are often involved in protein-protein interactions, and β substitutions at these positions may exert larger effects on non-local contacts within crystal lattices than is observed for substitutions within α-helices.…”

Coordination complexes and biomolecules: A wise wedding for catalysis upgrade

“…artificial folded molecular architectures inspired by the structures and functions of biopolymers (glycoproteins [112,113] and peptide analogues [114]), is also of great potential [115]. Foldamers are already being used for organocatalysis [116][117][118], and can coordinate metallic ions [119], or form cavities [120]. Yet, to the best of our knowledge, no example was described for chemistrybased catalysis hosted by foldamer scaffolds, but this is likely to appear in a very close future.…”

Protein backbone engineering as a strategy to advance foldamers toward the frontier of protein-like tertiary structure

“…Application of such sequence-guided α→β residue substitution has produced mixed α/β-peptides that fold to form helix-bundle quaternary structures, act as potent mimics of protein–protein binding interactions, and replace an α-helix in the enzyme chorismate mutase. 2d,16 …”

“…9–10 The enhanced conformational flexibility of β 3 -residues resulting from three freely rotatable backbone bonds makes them compatible with a variety of secondary structures, including α-helix, β-turn, and β-sheet. 2d,15–16,21a,21b Although both β 3 -residues and Aib are well accomodated in helices, only the former maintain native side-chain functionality.…”

“…As an example, a trans -cyclopentane-based β cyc -residue promotes a particular helical conformation in β-peptides 25 and also supports α-helix-like folds in heterogeneous α/β-peptides based on natural sequences. 16b,16c …”