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A wide range of natural and artificial peptides and proteins possess an intrinsic propensity to self-assemble into fibrillar nanostructures that are rich in β-sheet secondary structure. These fibrils are generally organized in a similar manner at the molecular level; they are characterized by β-strands that are oriented perpendicularly to the fibril axis, and connected through a dense hydrogen-bonding network, which results in supramolecular β-sheets that often extend continuously over<span class="external-identifiers"> <a target="_blank" rel="external noopener noreferrer" href="https://doi.org/10.1038/nnano.2011.102">doi:10.1038/nnano.2011.102</a> <a target="_blank" rel="external noopener" href="https://www.ncbi.nlm.nih.gov/pubmed/21804553">pmid:21804553</a> <a target="_blank" rel="external noopener" href="https://fatcat.wiki/release/ovvvzjesxjhf3my26egqckz7wa">fatcat:ovvvzjesxjhf3my26egqckz7wa</a> </span>
more »... of molecular units 1-5 (Fig. 1) . Such fibrillar structures first received attention through their association with diseases related to protein misfolding 6 , including neurodegenerative disorders such as Alzheimer's and Parkinson's diseases 7,8 , where normally soluble proteins are deposited pathologically into obdurate aggregates known as amyloid fibrils 9-14 (see Table 1 for an overview of key terminology and concepts). Subsequently, however, functional amyloid-like materials were discovered in varying roles throughout nature 15-20 . Moreover, under conditions where the natively folded states of proteins are thermodynamically destabilized, a wide range of unrelated peptides and proteins have been observed to form artificial fibrillar materials in vitro that are characterized by a quaternary amyloid structure and this has led to the design of functional nanomaterials. Amyloid materials, which are present in cells and in the extracellular space, represent a class of nanoscale structures that have various functional and pathological roles (Table 2; Fig. 2 )    19, 21 . As such, amyloid nanostructures are increasingly viewed as a general alternative form of protein structure that is different from, but in many cases no less organized than, the native states of proteins 1,22 . Moreover, this type of structure does not depend primarily on highly evolved side-chain interactions, but rather on universal physical and chemical characteristics that are inherent in the nature of all polypeptide molecules such as the propensity for hydrogen bonding in the backbone 23 . Understanding why certain material characteristics have been conserved or refined over millions of years of evolution underlies many fundamental questions in biology, but this knowledge is also required to develop methods for using artificial proteinaceous nanostructures as practical functional materials. The question of material selection becomes particularly intriguing from a technological Amyloid or amyloid-like fibrils represent a general class of nanomaterials that can be formed from many different peptides and proteins. Although these structures have an important role in neurodegenerative disorders, amyloid materials have also been exploited for functional purposes by organisms ranging from bacteria to mammals. Here we review the functional and pathological roles of amyloid materials and discuss how they can be linked back to their nanoscale origins in the structure and nanomechanics of these materials. We focus on insights both from experiments and simulations, and discuss how comparisons between functional protein filaments and structures that are assembled abnormally can shed light on the fundamental material selection criteria that lead to evolutionary bias in multiscale material design in nature. viewpoint because many protein materials are formed from scarce amounts of building blocks (that is, small volumes of material), from a few distinct building blocks (for example, only 20 natural amino acids) and from weak bonding (for example, hydrogen bonding), and are typically formed under severe energy constraints 24 . Because amyloid materials consist of generic assemblies of normally soluble proteins bound together in a simple periodic structure defined by main-chain hydrogen-bonding constraints, studying them should shed new light on the material selection criteria that shape more complex proteinaceous materials in nature. Nanomechanics of amyloid materials Mechanical properties are critical to our understanding of how materials contribute to a biological or synthetic system. These properties include the strength of adhesive forces between fibrils or their surrounding, their rigidity, or the maximum stress that they can sustain without breaking. In common with many biological materials, amyloid materials have hierarchical structures (Fig. 1a) from the molecular to the macroscopic scale. Mechanical testing on the nanoscale allows the study of amyloid materials on the single fibril level and provides the ability to directly probe the forces that bind individual proteins together in such materials. Nanomechanical testing can be performed by using atomic force microscopy (AFM) to carry out indentation measurements with high lateral resolution. Measurements of the contact stiffness of phenylalanine nanofibrils using this method showed that they are characterized by a Young's modulus (E) of 19 GPa (ref. 25), implying a comparatively high stiffness (Fig. 3) . This type of nanomechanical manipulation by AFM also allows the miniaturization of standard three-point bending testing. To this effect, the nanofibril structures are suspended over nanoscale gaps and an AFM tip is used to load the beam 26,27 . Experiments probing fibrils assembled from the protein insulin yield E = 3.3 ± 0.4 GPa (ref. 28). For nanofibrils with smaller diameters of only a few nanometres, it can be more challenging to probe their mechanical properties by directly applying a force and measuring resulting displacements because they are more fragile and flexible. Therefore, alternative methods to probe mechanical properties have been applied.
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