Scavenging neurotoxic aldehydes using lysine carbon dots.

Reactive aldehydes generated in cells and tissues are associated with adverse physiological effects. Dihydroxyphenylacetaldehyde (DOPAL), the biogenic aldehyde enzymatically produced from dopamine, is cytotoxic, generates reactive oxygen species, and triggers aggregation of proteins such as α-synuclein implicated in Parkinson's disease. Here, we demonstrate that carbon dots (C-dots) prepared from lysine as the carbonaceous precursor bind DOPAL molecules through interactions between the aldehyde units and amine residues on the C-dot surface. A set of biophysical and in vitro experiments attests to attenuation of the adverse biological activity of DOPAL. In particular, we show that the lysine-C-dots inhibit DOPAL-induced α-synuclein oligomerization and cytotoxicity. This work underlines the potential of lysine-C-dots as an effective therapeutic vehicle for aldehyde scavenging.

Tyrosine carbon dots inhibit fibrillation and toxicity of the human islet amyloid polypeptide.

Misfolding and aggregation of the human islet amyloid polypeptide (hIAPP) are believed to play key roles in the pathophysiology of type-II diabetes. Here, we demonstrate that carbon dots (C-dots) prepared from the amino acid tyrosine inhibit fibrillation of hIAPP, reduce hIAPP-induced cell toxicity and block membrane disruption by the peptide. The pronounced inhibitory effect is traced to the display of ubiquitous aromatic residues upon the C-dots' surface, mimicking the anti-fibril and anti-toxic activity of natural polyphenolic compounds. Notably, spectroscopy and thermodynamics analysis demonstrated different hIAPP interactions and fibril inhibition effects induced by tyrosine-C-dots displaying phenolic residues and C-dots prepared from phenylalanine which exhibited phenyl units on their surface, underscoring the significance of hydrogen bonding mediated by the phenolic hydroxide moieties for the fibril modulation activity. The presented experiments attest to the potential of tyrosine-C-dots as a therapeutic vehicle for protein misfolding diseases, interfering in both π-π interactions as well as hydrogen bonding involving aromatic residues of amyloidogenic peptides.

Study of Molecular Mechanisms of α-Synuclein Assembly: Insight into a Cross-ß Structure in the N-Termini of New α-Synuclein Fibrils.

Parkinson's disease is characterized by the self-assembly of α-synuclein (AS), in which its aggregates accumulate in the substantia nigra. The molecular mechanisms of the self-assembly of AS are challenging because AS is a relatively large intrinsically disordered protein, consisting of 140 residues. It is known that the N-termini of AS contribute to the toxicity of the proteins; therefore, it is important to investigate the self-assembly structure of the N-termini on AS as well. There have been extensive efforts to investigate the structural fibrils of AS(1-140), which have shown that the N-termini are disordered and do not participate in the fibrillary structure. This study illustrates for the first time that the N-termini of AS play a crucial role in the self-assembly of AS. This study reveals a new structure of AS(1-140) fibrils, in which the N-termini are essential parts of the cross-ß structure of the fibrillary structure. This study suggests that there are polymorphic states of the self-assembled AS(1-140). While the polymorphic states of the N-termini do not participate in the fibrillary structure and fluctuate, our predicted new fibrillary structure of the N-termini not only participates in the fibrillary structure but also stabilizes the fibrillary structure.

A minimal length rigid helical peptide motif allows rational design of modular surfactants.

Extensive work has been invested in the design of bio-inspired peptide emulsifiers. Yet, none of the formulated surfactants were based on the utilization of the robust conformation and self-assembly tendencies presented by the hydrophobins, which exhibited highest surface activity among all known proteins. Here we show that a minimalist design scheme could be employed to fabricate rigid helical peptides to mimic the rigid conformation and the helical amphipathic organization. These designer building blocks, containing natural non-coded α-aminoisobutyric acid (Aib), form superhelical assemblies as confirmed by crystallography and microscopy. The peptide sequence is amenable to structural modularity and provides the highest stable emulsions reported so far for peptide and protein emulsifiers. Moreover, we establish the ability of short peptides to perform the dual functions of emulsifiers and thickeners, a feature that typically requires synergistic effects of surfactants and polysaccharides. This work provides a different paradigm for the molecular engineering of bioemulsifiers.