Protein aggregation results in beta-sheet-like assemblies that adopt either a variety of amorphous morphologies or ordered amyloid-like structures. These differences in structure also reflect biological differences; amyloid and amorphous beta-sheet aggregates have different chaperone affinities, accumulate in different cellular locations and are degraded by different mechanisms. Further, amyloid function depends entirely on a high intrinsic degree of order. Here we experimentally explored the sequence space of amyloid hexapeptides and used the derived data to build Waltz, a web-based tool that uses a position-specific scoring matrix to determine amyloid-forming sequences. Waltz allows users to identify and better distinguish between amyloid sequences and amorphous beta-sheet aggregates and allowed us to identify amyloid-forming regions in functional amyloids.

Suitably functionalized dipeptides have been shown to be effective hydrogelators. The design of the hydrogelators and the mechanism by which hydrogelation occurs are both currently not well understood. Here, we have utilized the hydrolysis of glucono-delta-lactone to gluconic acid as a means of adjusting the pH in a naphthalene-alanylvaline solution allowing the specific targeting of the final pH. In addition, this method allows the assembly process to be characterized. We show that assembly begins as charge is removed from the C-terminus of the dipeptide. The removal of charge allows lateral assembly of the molecules leading to pi-pi stacking (shown by CD) and beta-sheet formation (as shown by IR and X-ray fiber diffraction). This leads to the formation of fibrous structures. Electron microscopy reveals that thin fibers form initially, with low persistence length. Lateral association then occurs to give bundles of fibers with higher persistence length. This results in the initially weak hydrogel becoming stronger with time. The final mechanical properties of the hydrogels are very similar irrespective of the amount of GdL added; rather, the time taken to achieving the final gel is determined by the GdL concentration. However, differences are observed between the networks under strain, implying that the kinetics of assembly do impart different final materials' properties. Overall, this study provides detailed understanding of the assembly process that leads to hydrogelation.

Controlling the order and spatial distribution of self-assembly in multicomponent supramolecular systems could underpin exciting new functional materials, but it is extremely challenging. When a solution of different components self-assembles, the molecules can either coassemble, or self-sort, where a preference for like-like intermolecular interactions results in coexisting, homomolecular assemblies. A challenge is to produce generic and controlled 'one-pot' fabrication methods to form separate ordered assemblies from 'cocktails' of two or more self-assembling species, which might have relatively similar molecular structures and chemistry. Self-sorting in supramolecular gel phases is hence rare. Here we report the first example of the pH-controlled self-sorting of gelators to form self-assembled networks in water. Uniquely, the order of assembly can be predefined. The assembly of each component is preprogrammed by the pK a of the gelator. This pH-programming method will enable higher level, complex structures to be formed that cannot be accessed by simple thermal gelation.

No abstract

BackgroundAlzheimer’s disease (AD) is characterized by the deposition of insoluble amyloid plaques in the neuropil composed of highly stable, self-assembled Amyloid-beta (Aβ) fibrils. Copper has been implicated to play a role in Alzheimer’s disease. Dimers of Aβ have been isolated from AD brain and have been shown to be neurotoxic.ResultsWe have investigated the formation of dityrosine cross-links in Aβ42 formed by covalent ortho-ortho coupling of two tyrosine residues under conditions of oxidative stress with elevated copper and shown that dityrosine can be formed in vitro in Aβ oligomers and fibrils and that these links further stabilize the fibrils. Dityrosine crosslinking was present in internalized Aβ in cell cultures treated with oligomeric Aβ42 using a specific antibody for dityrosine by immunogold labeling transmission electron microscopy. Results also revealed the prevalence of dityrosine crosslinks in amyloid plaques in brain tissue and in cerebrospinal fluid from AD patients.ConclusionsAβ dimers may be stabilized by dityrosine crosslinking. These results indicate that dityrosine cross-links may play an important role in the pathogenesis of Alzheimer’s disease and can be generated by reactive oxygen species catalyzed by Cu2+ ions. The observation of increased Aβ and dityrosine in CSF from AD patients suggests that this could be used as a potential biomarker of oxidative stress in AD.