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Short peptides self-assemble to produce catalytic amyloids.

ABSTRACT: Enzymes fold into unique three-dimensional structures, which underlie their remarkable catalytic properties. The requirement to adopt a stable, folded conformation is likely to contribute to their relatively large size (>10,000 Da). However, much shorter peptides can achieve well-defined conformations through the formation of amyloid fibrils. To test whether short amyloid-forming peptides might in fact be capable of enzyme-like catalysis, we designed a series of seven-residue peptides that act as Zn(2+)-dependent esterases. Zn(2+) helps stabilize the fibril formation, while also acting as a cofactor to catalyse acyl ester hydrolysis. These results indicate that prion-like fibrils are able to not only catalyse their own formation, but they can also catalyse chemical reactions. Thus, they might have served as intermediates in the evolution of modern-day enzymes. These results also have implications for the design of self-assembling nanostructured catalysts including ones containing a variety of biological and non-biological metal ions.

SUBMITTER: Rufo CM

PROVIDER: S-EPMC3996680 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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Short peptides self-assemble to produce catalytic amyloids.

Rufo Caroline M CM Moroz Yurii S YS Moroz Olesia V OV Stöhr Jan J Smith Tyler A TA Hu Xiaozhen X DeGrado William F WF Korendovych Ivan V IV

Nature chemistry 20140316 4

Enzymes fold into unique three-dimensional structures, which underlie their remarkable catalytic properties. The requirement to adopt a stable, folded conformation is likely to contribute to their relatively large size (>10,000 Da). However, much shorter peptides can achieve well-defined conformations through the formation of amyloid fibrils. To test whether short amyloid-forming peptides might in fact be capable of enzyme-like catalysis, we designed a series of seven-residue peptides that act a ...[more]

PMID: 24651196

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Project description:The graphite-water interface provides a unique environment for polypeptides that generally favors ordered structures more than in solution. Therefore, systems consisting of designed peptides and graphitic carbon might serve as a convenient medium for controlled self-assembly of functional materials. Here, we computationally designed cyclic peptides that spontaneously fold into a β-sheet-like conformation at the graphite-water interface and self-assemble, and we subsequently observed evidence of such assembly by atomic force microscopy. Using a novel protocol, we screened nearly 2000 sequences, optimizing for formation of a unique folded conformation while discouraging unfolded or misfolded conformations. A head-to-tail cyclic peptide with the sequence GTGSGTGGPGGGCGTGTGSGPG showed the greatest apparent propensity to fold spontaneously, and this optimized sequence was selected for larger scale molecular dynamics simulations, rigorous free-energy calculations, and experimental validation. In simulations ranging from hundreds of nanoseconds to a few microseconds, we observed spontaneous folding of this peptide at the graphite-water interface under many different conditions, including multiple temperatures (295 and 370 K), with different initial orientations relative to the graphite surface, and using different molecular dynamics force fields (CHARMM and Amber). The thermodynamic stability of the folded conformation on graphite over a range of temperatures was verified by replica-exchange simulations and free-energy calculations. On the other hand, in free solution, the folded conformation was found to be unstable, unfolding in tens of picoseconds. Intermolecular hydrogen bonds promoted self-assembly of the folded peptides into linear arrangements where the peptide backbone exhibited a tendency to align along one of the six zigzag directions of the graphite basal plane. For the optimized peptide, atomic force microscopy revealed growth of single-molecule-thick linear patterns of 6-fold symmetry, consistent with the simulations, while no such patterns were observed for a control peptide with the same amino acid composition but a scrambled sequence.

Project description:Self-assembling peptides programed by sequence design to form predefined nanostructures are useful for a variety of biomedical applications. However, assemblies of classic ionic self-complementary peptides are unstable in neutral pH, while charged peptide hydrogels have low mechanical strength. Here, we report on the rational design of a self-assembling peptide system with optimized charge distribution and density for bioscaffold development. Our designer peptides employs a sequence pattern that undergoes salt triggered self-assembly into ?-sheet rich cationic nanofibers in the full pH range (pH 0-14). Our peptides form nanofibrils in physiological condition at a minimum concentration that is significantly lower than has been reported for self-assembly of comparable peptides. The robust fiber-forming ability of our peptides results in the rapid formation of hydrogels in physiological conditions with strong mechanical strength. Moreover, fiber structure is maintained even upon dense conjugation with a model bioactive cargo OVA257-264 peptide. Nanofibers carrying OVA257-264 significantly enhanced CD8+ T cell activation in vitro. Subcutaneous immunization of our peptide fiber vaccine also elicited robust CD8+ T cell activation and proliferation in vivo. Our self-assembling peptides are expected to provide a versatile platform to construct diverse biomaterials.This work is an attempt of rational design of materials from molecular level for targeted properties and an exploration in molecular self-assembly. Current widely studied self-assembling peptides do not have stable nanofiber structures and form weak hydrogels under physiological conditions. To address this issue, we develop charged self-assembling peptides with a novel sequence pattern for strong fiber-forming ability under physiological conditions. Our designer peptides can undergo salt-triggered self-assembly into nanofibers that are ultrastable in extreme pH (0-14) and dilute solutions, and into hydrogels with strong mechanical strength. Upon conjugation with a model bioactive cargo, our self-assembled peptides exhibit great potential as bioscaffolds for multiple applications.

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Short peptides self-assemble to produce catalytic amyloids.

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Short peptides self-assemble to produce catalytic amyloids.

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