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Crucial role of nonspecific interactions in amyloid nucleation.



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Šarić, Anđela 
Chebaro, Yassmine C 
Knowles, Tuomas PJ 


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.



amyloid, coarse-grained simulations, neurodegeneration, protein aggregation, protein oligomers, Amyloid, Models, Molecular, Molecular Dynamics Simulation, Protein Aggregates, Protein Conformation

Journal Title

Proc Natl Acad Sci U S A

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Proceedings of the National Academy of Sciences
Engineering and Physical Sciences Research Council (EP/I001352/1)
Engineering and Physical Sciences Research Council (EP/I000844/1)
The Royal Society (wm072834)
Biotechnology and Biological Sciences Research Council (BB/J002119/1)
European Research Council (227758)