Principles Governing Catalytic Activity of Self-Assembled Short Peptides

Abstract

Molecular self-assembly provides a chemical strategy for the synthesis of nanostructures by using the principles of nature, and peptides serve as the promising building blocks to construct adaptable molecular architectures. Recently, a series of heptapeptides with alternative hydrophobic and hydrophilic residues were reported to form amyloid-like structures, which are capable of catalyzing acyl ester hydrolysis with remarkable efficiency. However, information remains elusive about the atomic structures of the fibrils. What is the origin of the sequence-dependent catalytic activity? How is the ester hydrolysis catalyzed by the fibrils? In this work, the atomic structures of the aggregates were determined by using molecular modeling and further validated by solid-state NMR experiments, where the fibril with high activity adopts twisted parallel configuration within each layer, and the one with low activity is in flat antiparallel configuration. The polymorphism originates from the interactions between different regions of the building block peptides, where the delicate balance between rigidity and flexibility plays an important role. We further show that the p-nitrophenylacetate (pNPA) hydrolysis reactions catalyzed by two different fibrils follow a similar mechanism, and the difference in microenvironment at the active site between the natural enzyme and the present self-assembled fibrils should account for the discrepancy in catalytic activities. The present work provides understanding of the structure and function of self-assembled fibrils formed with short peptides at an atomic level and thus sheds new insight on designing aggregates with better functions.

Covalent Linkage and Macrocylization Preserve and Enhance Synergistic Interactions in Catalytic Amyloids

“…While its catalytic efficiency of 6.3±0.9 M −1 s −1 was lower than that of the unconstrained peptide assembly, it was nearly double the value of the corresponding β‐hairpin, oQQ, suggesting that additional stabilization provided by the macrocyclic structure can help overcome the inefficiencies of the linker. The macrocycle that forces parallel arrangements of the two strands, mQQ p , shows a value that is the same within the error of the measurement to that of mQQ a , consistent with the notion that while both antiparallel and parallel arrangements of the stands are productive, [5b] the relative positioning of the residues is critical for the activity as an antiparallel arrangement of the strands in peptide mQQ a* shows very little activity (Scheme 2, Table 2). These results are quite remarkable considering the difference in morphology between mQQ a and mQQ p , with the parallel macrocycles forming far more ordered and diffuse fibril networks upon self‐assembly (Figure 3).…”

Biocatalysts Based on Peptide and Peptide Conjugate Nanostructures

“…These structural studies revealed that the high-activity Ac-IHIHIQI-NH 2 peptide and its analogue, with Q6Y substitution which shows even higher activity, adopt a twisted parallel β-sheet structure while the lower activity peptide Ac-IHIHIRI-NH 2 forms a planar antiparallel β-sheet assembly. 155 In another study, fiber XRD was used to probe the fibril structure of the Ac-IHIHIYI-NH 2 peptide and related derivatives (in the presence and absence of Zn 2+ ), for which the Zn 2+ -dependent pNPA hydrolysis was also assayed. 105 Riek and co-workers examined the catalytic activity of a series of related designed amyloid peptides with alternating charged/uncharged residues with general sequence Ac-YV X 1 V X 2 V X 3 V-CONH 2 with X 1 , X 2 , X 3 = A, D, H or S (as well as Ac-IHIHIQI-NH 2 , for comparison), the catalytic activity for the most active example being shown in Table 1 .…”

Catalytically active peptides affected by self-assembly and residues order

“…In a previous study we also found that among these three peptides, that were tested at concentrations 50, 100 250 and 400 μM, for adsorption of the organophosphate paraoxon, ESH performed best at the fairly low concentration of 100 μM 37 . It is interesting to note that the internal dynamics of fibrils was also pointed out by others to be a pivotal factor in catalytic activity 52 .…”