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2014 ; 111
(50
): 17869-74
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Crucial role of nonspecific interactions in amyloid nucleation
#MMPMID25453085
?ari? A
; Chebaro YC
; Knowles TP
; Frenkel D
Proc Natl Acad Sci U S A
2014[Dec]; 111
(50
): 17869-74
PMID25453085
show ga
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
?-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.
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