{"keyword":["multidisciplinary"],"oa":1,"language":[{"iso":"eng"}],"main_file_link":[{"open_access":"1","url":"https://www.pnas.org/content/111/50/17869"}],"publication_identifier":{"eissn":["1091-6490"],"issn":["0027-8424"]},"_id":"10382","pmid":1,"doi":"10.1073/pnas.1410159111","publication":"Proceedings of the National Academy of Sciences","quality_controlled":"1","user_id":"8b945eb4-e2f2-11eb-945a-df72226e66a9","external_id":{"arxiv":["1412.0897"],"pmid":["25453085"]},"title":"Crucial role of nonspecific interactions in amyloid nucleation","issue":"50","article_type":"original","status":"public","article_processing_charge":"No","author":[{"first_name":"Anđela","id":"bf63d406-f056-11eb-b41d-f263a6566d8b","full_name":"Šarić, Anđela","orcid":"0000-0002-7854-2139","last_name":"Šarić"},{"full_name":"Chebaro, Yassmine C.","last_name":"Chebaro","first_name":"Yassmine C."},{"first_name":"Tuomas P. J.","last_name":"Knowles","full_name":"Knowles, Tuomas P. J."},{"first_name":"Daan","full_name":"Frenkel, Daan","last_name":"Frenkel"}],"year":"2014","type":"journal_article","citation":{"short":"A. Šarić, Y.C. Chebaro, T.P.J. Knowles, D. Frenkel, Proceedings of the National Academy of Sciences 111 (2014) 17869–17874.","apa":"Šarić, A., Chebaro, Y. C., Knowles, T. P. J., &#38; Frenkel, D. (2014). Crucial role of nonspecific interactions in amyloid nucleation. <i>Proceedings of the National Academy of Sciences</i>. National Academy of Sciences. <a href=\"https://doi.org/10.1073/pnas.1410159111\">https://doi.org/10.1073/pnas.1410159111</a>","ista":"Šarić A, Chebaro YC, Knowles TPJ, Frenkel D. 2014. Crucial role of nonspecific interactions in amyloid nucleation. Proceedings of the National Academy of Sciences. 111(50), 17869–17874.","chicago":"Šarić, Anđela, Yassmine C. Chebaro, Tuomas P. J. Knowles, and Daan Frenkel. “Crucial Role of Nonspecific Interactions in Amyloid Nucleation.” <i>Proceedings of the National Academy of Sciences</i>. National Academy of Sciences, 2014. <a href=\"https://doi.org/10.1073/pnas.1410159111\">https://doi.org/10.1073/pnas.1410159111</a>.","mla":"Šarić, Anđela, et al. “Crucial Role of Nonspecific Interactions in Amyloid Nucleation.” <i>Proceedings of the National Academy of Sciences</i>, vol. 111, no. 50, National Academy of Sciences, 2014, pp. 17869–74, doi:<a href=\"https://doi.org/10.1073/pnas.1410159111\">10.1073/pnas.1410159111</a>.","ama":"Šarić A, Chebaro YC, Knowles TPJ, Frenkel D. Crucial role of nonspecific interactions in amyloid nucleation. <i>Proceedings of the National Academy of Sciences</i>. 2014;111(50):17869-17874. doi:<a href=\"https://doi.org/10.1073/pnas.1410159111\">10.1073/pnas.1410159111</a>","ieee":"A. Šarić, Y. C. Chebaro, T. P. J. Knowles, and D. Frenkel, “Crucial role of nonspecific interactions in amyloid nucleation,” <i>Proceedings of the National Academy of Sciences</i>, vol. 111, no. 50. National Academy of Sciences, pp. 17869–17874, 2014."},"date_created":"2021-11-29T13:09:53Z","extern":"1","intvolume":"       111","acknowledgement":"We thank Michele Vendruscolo, Iskra Staneva, and William M. Jacobs, for helpful discussions. A.Š. acknowledges support from the Human Frontier Science Program and Emmanuel College. Y.C.C. and D.F. are supported by Engineering and Physical Sciences Research Council Programme Grant EP/I001352/1. T.P.J.K. acknowledges the Frances and Augustus Newman Foundation, the European Research Council, and the Biotechnology and Biological Sciences Research Council. D.F. acknowledges European Research Council Advanced Grant 227758.","scopus_import":"1","date_updated":"2021-11-29T13:29:05Z","publisher":"National Academy of Sciences","day":"01","volume":111,"oa_version":"Published Version","publication_status":"published","month":"12","abstract":[{"text":"Protein oligomers have been implicated as toxic agents in a wide range of amyloid-related diseases. However, it has remained unsolved whether the oligomers are a necessary step in the formation of amyloid fibrils or just a dangerous byproduct. 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 nonspecific 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 nonphysiologically high peptide concentrations. At low peptide concentrations, which mimic the physiologically relevant regime, attractive interpeptide 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 also, create an environment that facilitates the conversion of monomers into the β-sheet–rich form characteristic of fibrils. Nucleation typically does not proceed through the most prevalent oligomers but through 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 with increases in both concentration and interpeptide interactions, which is in direct contrast with predictions from classical nucleation theory.","lang":"eng"}],"date_published":"2014-12-01T00:00:00Z","page":"17869-17874"}