Crucial role of non-specific interactions in amyloid nucleation
  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 pre-nucleation 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 $\beta$-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. 
An{\dj}ela \v{S}ari\'c, Yassmine C. Chebaro, Tuomas P. J. Knowles and   Daan Frenkel
q-bio.BM cond-mat.soft physics.bio-ph