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dc.contributor.authorŠarić, Anđelaen
dc.contributor.authorChebaro, Yassmineen
dc.contributor.authorKnowles, Tuomasen
dc.contributor.authorFrenkel, Daanen
dc.date.accessioned2015-02-03T14:00:03Z
dc.date.available2015-02-03T14:00:03Z
dc.date.issued2014-12-16en
dc.identifier.citationProceedings of the National Academy of Sciences of the USA vol. 111 no. 50, 17869–17874. DOI: 10.1073/pnas.1410159111en
dc.identifier.issn0027-8424
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/246671
dc.description.abstractProtein 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.
dc.languageEnglishen
dc.language.isoenen
dc.publisherNational Academy of Sciences
dc.rightsAttribution-NonCommercial 2.0 UK: England & Wales*
dc.rights.urihttp://creativecommons.org/licenses/by-nc/2.0/uk/*
dc.titleCrucial role of non-specific interactions in amyloid nucleationen
dc.typeArticle
dc.description.versionThis is the accepted manuscript. The final published version is available from PNAS at http://www.pnas.org/content/111/50/17869.abstract.en
prism.endingPage17874
prism.publicationDate2014en
prism.publicationNameProceedings of the National Academy of Sciences (PNAS)en
prism.startingPage17869
prism.volume111en
dc.rioxxterms.funderEPSRC
dc.rioxxterms.funderERC
dc.rioxxterms.projectidEP/I001352/1
dc.rioxxterms.projectid227758
rioxxterms.versionofrecord10.1073/pnas.1410159111en
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2014-12-16en
dc.contributor.orcidKnowles, Tuomas [0000-0002-7879-0140]
dc.contributor.orcidFrenkel, Daan [0000-0002-6362-2021]
dc.identifier.eissn1091-6490
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idEPSRC (EP/I001352/1)
pubs.funder-project-idBBSRC (BB/J002119/1)
pubs.funder-project-idEuropean Research Council (227758)
pubs.funder-project-idRoyal Society (wm072834)
pubs.funder-project-idEPSRC (EP/I000844/1)
rioxxterms.freetoread.startdate2015-12-16


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Attribution-NonCommercial 2.0 UK: England & Wales
Except where otherwise noted, this item's licence is described as Attribution-NonCommercial 2.0 UK: England & Wales