Crucial role of non-specific interactions in amyloid nucleation
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Publication Date
2014-12-16Journal Title
Proceedings of the National Academy of Sciences (PNAS)
ISSN
0027-8424
Publisher
National Academy of Sciences
Volume
111
Pages
17869-17874
Language
English
Type
Article
Metadata
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Šarić, A., Chebaro, Y., Knowles, T., & Frenkel, D. (2014). Crucial role of non-specific interactions in amyloid nucleation. Proceedings of the National Academy of Sciences (PNAS), 111 17869-17874. https://doi.org/10.1073/pnas.1410159111
Abstract
Protein oligomers have been implicated as toxic agents in a wide range of amyloid-related diseases.
Yet it has remained unsolved whether the oligomers are a necessary step in the formation of
amyloid fibrils, or just a dangerous by-product. Analogously, it has not been resolved if the amyloid
nucleation process is a classical one-step nucleation process, or a two-step process involving prenucleation
clusters. We use coarse-grained computer simulations to study the effect of non-specific
attractions between peptides on the primary nucleation process underlying amyloid fibrillization.
We find that for peptides that do not attract, the classical one-step nucleation mechanism is possible,
but only at non-physiologically high peptide concentrations. At low peptide concentrations,
which mimic the physiologically relevant regime, attractive inter-peptide interactions are essential
for fibril formation. Nucleation then inevitably takes place through a two-step mechanism involving
prefibrillar oligomers. We show that oligomers not only help peptides meet each other, but create an
environment that facilitates the conversion of monomers into the β-sheet rich form characteristic of
fibrils. Nucleation typically does not proceed via the most prevalent oligomers, but via an oligomer
size that is only observed in rare fluctuations, which is why such aggregates might be hard to capture
experimentally. Finally, we find that the nucleation of amyloid fibrils cannot be described by
classical nucleation theory: in the two-step mechanism the critical nucleus size increases both with
an increase in concentration and in the inter-peptide interactions, in direct contrast with predictions
from classical nucleation theory.
Sponsorship
EPSRC (EP/I001352/1)
BBSRC (BB/J002119/1)
European Research Council (227758)
Royal Society (wm072834)
EPSRC (EP/I000844/1)
Identifiers
External DOI: https://doi.org/10.1073/pnas.1410159111
This record's URL: https://www.repository.cam.ac.uk/handle/1810/246671
Rights
Attribution-NonCommercial 2.0 UK: England & Wales
Licence URL: http://creativecommons.org/licenses/by-nc/2.0/uk/
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