Neurotoxic amyloidogenic peptides in the proteome of SARS-COV2: potential implications for neurological symptoms in COVID-19

in Nature Communications (2022), 13

COVID-19 is primarily known as a respiratory disease caused by SARS-CoV-2. However, neurological symptoms such as memory loss, sensory confusion, severe headaches, and even stroke are reported in up to 30 ... [more ▼]

COVID-19 is primarily known as a respiratory disease caused by SARS-CoV-2. However, neurological symptoms such as memory loss, sensory confusion, severe headaches, and even stroke are reported in up to 30% of cases and can persist even after the infection is over (long COVID). These neurological symptoms are thought to be produced by the virus infecting the central nervous system, however we don’t understand the molecular mechanisms triggering them. The neurological effects of COVID-19 share similarities to neurodegenerative diseases in which the presence of cytotoxic aggregated amyloid protein or peptides is a common feature. Following the hypothesis that some neurological symptoms of COVID-19 may also follow an amyloid etiology we identified two peptides from the SARS-CoV-2 proteome that self-assemble into amyloid assemblies. Furthermore, these amyloids were shown to be highly toxic to neuronal cells. We suggest that cytotoxic aggregates of SARS-CoV-2 proteins may trigger neurological symptoms in COVID-19. [less ▲]

Neurotoxic Amyloidogenic Peptides Identified in the Proteome of SARS-COV2: Potential Implications for Neurological Symptoms in COVID-19

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 ▲]

First-principles modeling of chemistry in mixed solvents: Where to go from here?

in Journal of Chemical Physics (2020), 152

Mixed solvents (i.e., binary or higher order mixtures of ionic or nonionic liquids) play crucial roles in chemical syntheses, separations, and electrochemical devices because they can be tuned for ... [more ▼]

Mixed solvents (i.e., binary or higher order mixtures of ionic or nonionic liquids) play crucial roles in chemical syntheses, separations, and electrochemical devices because they can be tuned for specific reactions and applications. Apart from fully explicit solvation treatments that can be difficult to parameterize or computationally expensive, there is currently no well-established first-principles regimen for reliably modeling atomic-scale chemistry in mixed solvent environments. We offer our perspective on how this process could be achieved in the near future as mixed solvent systems become more explored using theoretical and computational chemistry. We first outline what makes mixed solvent systems far more complex compared to single-component solvents. An overview of current and promising techniques for modeling mixed solvent environments is provided. We focus on so-called hybrid solvation treatments such as the conductor-like screening model for real solvents and the reference interaction site model, which are far less computationally demanding than explicit simulations. We also propose that cluster-continuum approaches rooted in physically rigorous quasi-chemical theory provide a robust, yet practical, route for studying chemical processes in mixed solvents. [less ▲]

Kinetic Control of Parallel versus Antiparallel Amyloid Aggregation via Shape of the Growing Aggregate

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 ▲]

Competition between crystal and fibril formation in molecular mutations of amyloidogenic peptides

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 ▲]

AMBER 2015

Book published by University of California (2015)

ILQINS hexapeptide, identified in lysozyme left-handed helical ribbons and nanotubes, forms right-handed helical ribbons and crystals.

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 ▲]

The Flexible Rare Event Sampling Harness System (FRESHS)

in Computer Physics Communications (2014)

We present the software package FRESHS (http://www.freshs.org) for parallel simulation of rare events using sampling techniques from the ‘splitting’ family of methods. Initially, Forward Flux Sampling ... [more ▼]

We present the software package FRESHS (http://www.freshs.org) for parallel simulation of rare events using sampling techniques from the ‘splitting’ family of methods. Initially, Forward Flux Sampling (FFS) and Stochastic Process Rare Event Sampling (SPRES) have been implemented. These two methods together make rare event sampling available for both quasi-static and full non-equilibrium regimes. Our framework provides a plugin system for software implementing the underlying physics of the system of interest. At present, example plugins exist for our framework to steer the popular MD packages GROMACS, LAMMPS and ESPResSo, but due to the simple interface of our plugin system, it is also easy to attach other simulation software or self-written code. Use of our framework does not require recompilation of the simulation program. The modular structure allows the flexible implementation of further sampling methods or physics engines and creates a basis for objective comparison of different sampling algorithms. Our code is designed to make optimal use of available compute resources. System states are managed using standard database technology so as to allow checkpointing, scaling and flexible analysis. The communication within the framework uses plain TCP/IP networking and is therefore suited to high-performance parallel hardware as well as to distributed or even heterogeneous networks of inexpensive machines. For FFS we implemented an automatic interface placement that ensures optimal, nearly constant flux through the interfaces. We introduce ‘ghost’ (or ‘look-ahead’) runs that remedy the bottleneck which occurs when progressing to the next interface. FRESHS is open-source, providing a publicly available parallelized rare event sampling system. [less ▲]

Free Energies by Thermodynamic Integration Relative to an Exact Solution, Used to Find the Handedness-Switching Salt Concentration for DNA

in Journal of Chemical Theory and Computation (2012)

A general algorithm for sampling rare events in non-equilibrium and non-stationary systems

in Journal of Chemical Physics (2010), 133