Aliphatic peptides show similar self-assembly to amyloid core sequences, challenging the importance of aromatic interactions in amyloidosis

Abstract

The self-assembly of abnormally folded proteins into amyloid fibrils is a hallmark of many debilitating diseases, from Alzheimer's and Parkinson diseases to prion-related disorders and diabetes type II. However, the fundamental mechanism of amyloid aggregation remains poorly understood. Core sequences of four to seven amino acids within natural amyloid proteins that form toxic fibrils have been used to study amyloidogenesis. We recently reported a class of systematically designed ultrasmall peptides that self-assemble in water into cross-β-type fibers. Here we compare the self-assembly of these peptides with natural core sequences. These include core segments from Alzheimer's amyloid-β, human amylin, and calcitonin. We analyzed the self-assembly process using circular dichroism, electron microscopy, X-ray diffraction, rheology, and molecular dynamics simulations. We found that the designed aliphatic peptides exhibited a similar self-assembly mechanism to several natural sequences, with formation of α-helical intermediates being a common feature. Interestingly, the self-assembly of a second core sequence from amyloid-β, containing the diphenylalanine motif, was distinctly different from all other examined sequences. The diphenylalanine-containing sequence formed β-sheet aggregates without going through the α-helical intermediate step, giving a unique fiberdiffraction pattern and simulation structure. Based on these results, we propose a simplified aliphatic model system to study amyloidosis. Our results provide vital insight into the nature of early intermediates formed and suggest that aromatic interactions are not as important in amyloid formation as previously postulated. This information is necessary for developing therapeutic drugs that inhibit and control amyloid formation.

Tunable Pentapeptide Self‐Assembled β‐Sheet Hydrogels

“…Comparing IDIDI (1 wt %) and D2I3 (2 wt %) hydrogels, the G′ value increased by two orders of magnitude from 2 to 200 kPa, respectively. These stiffness values are in the region of many soft tissues and compare well to previously published peptide hydrogel systems, including aromatic peptides4, 17 and peptide–amphiphile hydrogels 27, 28. The ability to tune the G′ value across a large range holds great promise for applications in tissue engineering, given that the behavior of cells has been found to be heavily influenced by the mechanical properties of their surrounding environment 29, 30…”

“…Experimental and computational approaches have yielded a selection of di‐ and tripeptide sequences,3, 4, 5, 6, 7 which have been proven to assemble into nanostructures and hydrogels under aqueous conditions, generating nanospheres,8 fibrous and plate‐like assemblies,9, 10 heterogeneous nanostructures,4, 11, 12 and micelles and nanotubes 13, 14, 15. To improve gelation characteristics, these small molecules often require either the inclusion of aromatic amino acid residues or a synthetic terminal group 1, 16, 17, 18, 19. This introduces π–π stacking and hydrophobic interactions, which promote self‐assembly and gelation 3.…”

Amyloid-based nanosensors and nanodevices

“…Structural investigations on amyloidogenic core sequences, peptides of the size of 3-7 amino acids, have revealed conformational transition of the peptides from a random-coiled soluble form via possibly a-helical intermediates into insoluble, cross b-pleated fiber aggregates. 190 These a-helical intermediates are thought to be a key event in amyloidogenesis. 106 While recent investigations have focussed on the mechanism of molecular recognition and self-assembly in amyloidogenesis in order to inhibit this process, there are so far no effective preventions or treatments for any of these diseases available.…”

Superhydrophobic Devices Molecular Detection

“…The polymeric nanostructured superhydrophobic surfaces, just described in the previous section, have been extensively used for accurate in situ detection of conformational changes of biological and inorganic compounds [29,30]. The general experimental approach is shown schematically in Fig.…”