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See detailNeurotoxic Amyloidogenic Peptides Identified in the Proteome of SARS-COV2: Potential Implications for Neurological Symptoms in COVID-19
Islam, Saba; Charnley, Mirren; Bindra, Guneet et al

E-print/Working paper (2021)

COVID-19 is primarily known as a respiratory disease caused by the virus SARS-CoV-2. However, neurological symptoms such as memory loss, sensory confusion, cognitive and psychiatric issues, severe ... [more ▼]

COVID-19 is primarily known as a respiratory disease caused by the virus SARS-CoV-2. However, neurological symptoms such as memory loss, sensory confusion, cognitive and psychiatric issues, severe headaches, and even stroke are reported in as many as 30% of cases and can persist even after the infection is over (so-called ‘long COVID’). These neurological symptoms are thought to be caused by brain inflammation, triggered by the virus infecting the central nervous system of COVID-19 patients, however we still don’t fully understand the mechanisms for these symptoms. The neurological effects of COVID-19 share many similarities to neurodegenerative diseases such as Alzheimer’s and Parkinson’s in which the presence of cytotoxic protein-based amyloid aggregates is a common etiological feature. Following the hypothesis that some neurological symptoms of COVID-19 may also follow an amyloid etiology we performed a bioinformatic scan of the SARS-CoV-2 proteome, detecting peptide fragments that were predicted to be highly amyloidogenic. We selected two of these peptides and discovered that they do rapidly self-assemble into amyloid. Furthermore, these amyloid assemblies were shown to be highly toxic to a neuronal cell line. We introduce and support the idea that cytotoxic amyloid aggregates of SARS-CoV-2 proteins are causing some of the neurological symptoms commonly found in COVID-19 and contributing to long COVID, especially those symptoms which are novel to long COVID in contrast to other post-viral syndromes. [less ▲]

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See detailAmyloid Evolution: Antiparallel Replaced by Parallel
Hakami Zanjani, Ali Asghar UL; Reynolds, Nicholas; Zhang, Afang et al

in Biophysical Journal (2020), 118

Several atomic structures have now been found for micrometer-scale amyloid fibrils or elongated microcrystals using a range of methods, including NMR, electron microscopy, and X-ray crystallography, with ... [more ▼]

Several atomic structures have now been found for micrometer-scale amyloid fibrils or elongated microcrystals using a range of methods, including NMR, electron microscopy, and X-ray crystallography, with parallel beta-sheet appearing as the most common secondary structure. The etiology of amyloid disease, however, indicates nanometer-scale assemblies of only tens of peptides as significant agents of cytotoxicity and contagion. By combining solution X-ray with molecular dynamics, weshow that antiparallel structure dominates at the first stages of aggregation for a specific set of peptides, being replaced by parallel at large length scales only. This divergence in structure between small and large amyloid aggregates should inform future design of molecular therapeutics against nucleation or intercellular transmission of amyloid. Calculations and an overview from the literature argue that antiparallel order should be the first appearance of structure in many or most amyloid aggregation processes, regardless of the endpoint. Exceptions to this finding should exist, depending inevitably on the sequence and on solution conditions. [less ▲]

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See detailKinetic Control of Parallel versus Antiparallel Amyloid Aggregation via Shape of the Growing Aggregate
Hakami Zanjani, Ali Asghar UL; Reynolds, Nicholas; Zhang, Afang et al

in Nature Scientific Reports (2019)

By combining atomistic and higher-level modelling with solution X-ray diffraction we analyse self-assembly pathways for the IFQINS hexapeptide, a bio-relevant amyloid former derived from human lysozyme ... [more ▼]

By combining atomistic and higher-level modelling with solution X-ray diffraction we analyse self-assembly pathways for the IFQINS hexapeptide, a bio-relevant amyloid former derived from human lysozyme. We verify that (at least) two metastable polymorphic structures exist for this system which are substantially different at the atomistic scale, and compare the conditions under which they are kinetically accessible. We further examine the higher-level polymorphism for these systems at the nanometre to micrometre scales, which is manifested in kinetic differences and in shape differences between structures instead of or as well as differences in the small-scale contact topology. Any future design of structure based inhibitors of the IFQINS steric zipper, or of close homologues such as TFQINS which are likely to have similar structures, should take account of this polymorphic assembly. [less ▲]

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See detailCompetition between crystal and fibril formation in molecular mutations of amyloidogenic peptides
Reynolds, Nicholas; Adamcik, Jozef; Berryman, Josh UL et al

in Nature Communications (2017), 8

Amyloidogenic model peptides are invaluable for investigating assembly mechanisms in disease related amyloids and in protein folding. During aggregation, such peptides can undergo bifurcation leading to ... [more ▼]

Amyloidogenic model peptides are invaluable for investigating assembly mechanisms in disease related amyloids and in protein folding. During aggregation, such peptides can undergo bifurcation leading to fibrils or crystals, however the mechanisms of fibril-to-crystal conversion are unclear. We navigate herein the energy landscape of amyloidogenic peptides by studying a homologous series of hexapeptides found in animal, human and disease related proteins. We observe fibril-to-crystal conversion occurring within single aggregates via untwisting of twisted ribbon fibrils possessing saddle-like curvature and cross-sectional aspect ratios approaching unity. Changing sequence, pH or concentration shifts the growth towards larger aspect ratio species assembling into stable helical ribbons possessing mean-curvature. By comparing atomistic calculations of desolvation energies for association of peptides we parameterise a kinetic model, providing a physical explanation of fibril-to-crystal interconversion. These results shed light on the self-assembly of amyloidogenic peptides, suggesting amyloid crystals, not fibrils, represent the ground state of the protein folding energy landscape. [less ▲]

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See detailILQINS hexapeptide, identified in lysozyme left-handed helical ribbons and nanotubes, forms right-handed helical ribbons and crystals.
Lara, Cecile; Reynolds, Nicholas; Berryman, Josh UL et al

in Journal of the American Chemical Society (2014), 136(12), 4732-4739

Amyloid fibrils are implicated in over 20 neurodegenerative diseases. The mechanisms of fibril structuring and formation are not only of medical and biological importance but are also relevant for ... [more ▼]

Amyloid fibrils are implicated in over 20 neurodegenerative diseases. The mechanisms of fibril structuring and formation are not only of medical and biological importance but are also relevant for material science and nanotechnologies due to the unique structural and physical properties of amyloids. We previously found that hen egg white lysozyme, homologous to the disease-related human lysozyme, can form left-handed giant ribbons, closing into nanotubes. By using matrix-assisted laser desorption ionization mass spectrometry analysis, we here identify a key component of such structures: the ILQINS hexapeptide. By combining atomic force microscopy and circular dichorism, we find that this fragment, synthesized by solid-phase peptide synthesis, also forms fibrillar structures in water at pH 2. However, all fibrillar structures formed possess an unexpected right-handed twist, a rare chirality within the corpus of amyloid experimental observations. We confirm by small- and wide-angle X-ray scattering and molecular dynamics simulations that these fibrils are composed of conventional left-handed β-sheets, but that packing stresses between adjacent sheets create this twist of unusual handedness. We also show that the right-handed fibrils represent a metastable state toward β-sheet-based microcrystals formation. [less ▲]

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