Considering the relevance of accumulation and selfassembly of metabolites and aftermath of biological consequences, it is important to know whether they undergo coassembly and what properties the resultant hybrid higher-order structures would exhibit. This work reveals the inherent tendency of aromatic amino acids to undergo a spontaneous coassembly process under physiologically mimicked conditions, which yields neurotoxic hybrid nanofibers. Resultant hybrid nanostructures resembled the β-structured conformers stabilized by H-bonds and π−π stacking interactions, which were highly toxic to human neuroblastoma cells. The hybrid nanofibers also showed strong cross-seeding potential that triggered in vitro aggregation of diverse globular proteins and brain extract components, converting the native structures into cross-β-rich amyloid aggregates. The heterogenic nature of the hybrid nanofibers seems crucial for their higher toxicity and faster cross-seeding potential as compared to the homogeneous amino acid nanofibers. Our findings reveal the importance of aromaticity-driven optimized intermolecular arrangements for the coassembly of aromatic amino acids, and the results may provide important clues to the fundamental understanding of metabolite accumulation-related complications.

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Naturally occurring osmoprotectants are known to prevent aggregation of proteins under various stress factors including extreme pH and elevated temperature conditions. Here, we synthesized gold nanoparticles coated with selected osmolytes (proline, hydroxyproline, and glycine) and examined their effect on temperature-induced amyloid-formation of insulin hormone. These uniform, thermostable, and hemocompatible gold nanoparticles were capable of inhibiting both spontaneous and seed-induced amyloid aggregation of insulin. Both quenching and docking experiments suggest a direct interaction between the osmoprotectant-coated nanoparticles and aggregation-prone hydrophobic stretches of insulin. Circular-dichroism results confirmed the retention of insulin’s native structure in the presence of these nanoparticles. Unlike the indirect solvent-mediated effect of free osmolytes, the inhibition effect of osmolyte-coated gold nanoparticles was observed to be mediated through their direct interaction with insulin. The results signify the protection of the exposed aggregation-prone domains of insulin from temperature-induced self-assembly through osmoprotectant-coated nanoparticles, and such effect may inspire the development of osmolyte-based antiamyloid nanoformulations.

Molecular self-assembly of biologically relevant aromatic metabolites is known to generate cytotoxic nanostructures and this unique property has opened up newer concepts in the molecular mechanisms of metabolite-linked disorders. Because...

Dietary consumption of Trp via protein-based foods is essential for the maintenance of crucial metabolic processes including the synthesis of proteins and several vital metabolites such as serotonin, melatonin, Acetyl...