Bioinspired Phosphatase-like Mimic Built from the Self-Assembly of De Novo Designed Helical Short Peptides

Abstract

Enzymes play vital roles in catalyzing biochemical reactions with high activity and selectivity, which is largely attributed to the delicately organized structure and groups at catalytic domains. Reconstruction of the enzymatic catalytic domains in artificial systems, to produce enzyme-like mimic, has become an attractive but challenging subject. Herein, inspired by the helical structure in the catalytic center of natural phosphatases, we created a phosphatase-like mimic through the self-assembly of de novo designed helical heptapeptides. The helical heptapeptides were elaborately decorated with well-studied catalytic groups and exhibited obvious phosphatase-like catalytic activity upon hierarchically self-assembling. In comparison with β-sheet-organized peptide assemblies, we emphasized the significance of helical structure in the hydrolysis of phosphoester bonds (over 1000 times higher in catalytic efficiency). The structure−activity relationship reveals that the phosphatase-like function attributed to the specific helical dipole moment for the binding of substrates as well as the supramolecular assembly for the formation of catalytic center. Moreover, we verified the feasibility of these helical species as a potential substitute for adenosine triphosphatase (ATPase) and alkaline phosphatase (ALPase) in some specific biological processes. This work not only presents an approach for the construction of artificial enzymes with simple peptide modules but also provides a model for primitive enzymes formed from helical short peptides that relied on self-assembly to achieve a folded structure.

Nanoarchitectonics of Fullerene‐Based Enzyme Mimics for Osteogenic Induction of Stem Cells

“…The undeniable performance of fullerene enzyme mimics in phosphoester hydrolysis reactions, biomineralization, and osteoinduction is unique among the other artificial catalysts such that they simultaneously recapitulate the catalytic and metabolic activity of native enzymes. Furthermore, they have significantly higher catalytic efficiencies for the hydrolysis of pNPP than one of the most promising peptide‐based phosphatase mimics in literature, [ 24 ] taking advantage of the hydrophobic tuning by the nonfunctionalized fullerene parts [ 39 ] and a greater portion of active groups that synergistically interact with each other due to clustering spherical structures rather than the linear arrangement of active groups. Structural, chemical, and surface features of fullerene molecules distinguish them from the peptide‐based and organic molecule‐based artificial catalysts, which are far more stable than peptide‐based enzyme mimics and less toxic and soluble compared to organic molecule‐based enzyme mimics.…”

“…Hydrolysis or deesterification reactions can be facilitated through this catalytic action, and it has also been shown that this combination can be used for the cleavage of phosphate esters. [10,24] The scaffold selection is another important contributor to catalytic action, and selfassembling scaffolds presenting multifunctional units are ideal for developing effective nanocatalysts.…”

Systems chemistry of peptide-assemblies for biochemical transformations

“…94 Inspired by this, there have been very few attempts in the recent past to mimic the P-O bond breaking ability of this complex enzyme via minimal self-assembling systems. [95][96][97][98][99] Guler and co-workers have designed a diimidazole containing peptide amphiphile (Lauryl-VVAGHH-Am) that self-assembled into catalytic nanofibers to show phosphatase like activity (Fig. 4a).…”

“…Very recently, enthused by the helical catalytic domain of metal free phosphatase, He and co-workers developed heptapeptide containing self-assembled nanostructures with the ability to mimic the active site of phosphatases. 96 To design a helical configuration, the 'abcdefg' rule has been followed where hydrophobic phenylalanine was placed at a and d positions. a-Aminoisobutyric acid (Aib) was placed at c, e and g positions to overcome the thermodynamic barrier to fold in a helical manner (Fig.…”

“…94 Inspired by this, there have been very few attempts in the recent past to mimic the P-O bond breaking ability of this complex enzyme via minimal self-assembling systems. 95–99…”