Out-of-Register Aβ 42 Assemblies as Models for Neurotoxic Oligomers and Fibrils

We propose a variant of the recently found S-shaped Aβ -motif that is characterized by out-of-register C-terminal β-strands. We show that chains with this structure can form not only fibrils that are compatible with the NMR signals but also barrel-shaped oligomers that resemble the ones formed by th...

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Bibliographic Details
Published in:Journal of chemical theory and computation 2018-02, Vol.14 (2), p.1099-1110
Main Authors: Xi, Wenhui, Vanderford, Elliott K, Hansmann, Ulrich H E
Format: Article
Language:English
Subjects:
Amyloid beta-Peptides - chemistry
Molecular Dynamics Simulation
Neurotoxins - chemistry
Nuclear Magnetic Resonance, Biomolecular
Peptide Fragments - chemistry
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Summary:We propose a variant of the recently found S-shaped Aβ -motif that is characterized by out-of-register C-terminal β-strands. We show that chains with this structure can form not only fibrils that are compatible with the NMR signals but also barrel-shaped oligomers that resemble the ones formed by the much smaller cylindrin peptides. By running long all-atom molecular dynamics simulations at physiological temperatures with an explicit solvent, we study the stability of these constructs and show that they are plausible models for neurotoxic oligomers. After analyzing the transitions between different assemblies, we suggest a mechanism for amyloid formation in Alzheimer's disease.
ISSN:1549-9618
1549-9626
DOI:10.1021/acs.jctc.7b01106