Bunce, SJ, Wang, Y, Stewart, KL et al. (4 more authors) (2019) Molecular insights into the surface-catalyzed secondary nucleation of amyloid-β₄₀ (Aβ₄₀) by the peptide fragment Aβ₁₆-₂₂. Science Advances, 5 (6). eaav8216. ISSN 2375-2548
Abstract
Understanding the structural mechanism by which proteins and peptides aggregate is crucial given the role of fibrillar aggregates in debilitating amyloid diseases and bioinspired materials. Yet, this is a major challenge given assembly involves multiple heterogeneous and transient intermediates. Here, we analyze the co-aggregation of Aβ40 and Aβ16-22, two widely studied peptide fragments of Aβ42 implicated in Alzheimer’s disease. We demonstrate that Aβ16-22 increases the aggregation rate of Aβ40 through a surface catalyzed secondary nucleation mechanism. Discontinuous molecular dynamics simulations allowed aggregation to be tracked from the initial random coil monomer to the catalysis of nucleation on the fibril surface. Together, the results provide insight into how dynamic interactions between Aβ40 monomers/oligomers on the surface of pre-formed Aβ16-22 fibrils nucleate Aβ40 amyloid assembly. This new understanding may facilitate development of surfaces designed to enhance or suppress secondary nucleation and hence to control the rates and products of fibril assembly.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | (c) 2019, The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY). |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Engineering & Physical Sciences (Leeds) > School of Chemistry (Leeds) > Organic Chemistry (Leeds) The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Molecular and Cellular Biology (Leeds) > Biomolecular Mass Spectroscopy (Leeds) The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Molecular and Cellular Biology (Leeds) > Structural Molecular Biology (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 10 May 2019 15:16 |
Last Modified: | 25 Jun 2023 21:48 |
Status: | Published |
Publisher: | American Association for the Advancement of Science |
Identification Number: | 10.1126/sciadv.aav8216 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:145685 |