Aβ16-22 is believed to have critical role in early aggregation of full length amyloids that are associated with the Alzheimer's disease and can aggregate to form amyloid fibrils. However, the early aggregation mechanism is still unsolved. Here, multiple long-term molecular dynamics simulations combining with Markov state model were used to probe the early oligomerization mechanism of Aβ16-22 peptides. The identified dimeric form adopted either globular random-coil or extended β-strand like conformations. The observed dimers of these variants shared many overall conformational characteristics but differed in several aspects at detailed level. In all cases, the most common type of secondary structure was intermolecular antiparallel β-sheets. The inter-state transitions were very frequent ranges from few to hundred nanoseconds. More strikingly, those states which contain fraction of β secondary structure and significant amount of extended coiled structures, therefore exposed to the solvent, were majorly participated in aggregation. The assembly of low-energy dimers, in which the peptides form antiparallel β sheets, occurred by multiple pathways with the formation of an obligatory intermediates. We proposed that these states might facilitate the Aβ16-22 aggregation through a significant component of the conformational selection mechanism, because they might increase the aggregates population by promoting the inter-chain hydrophobic and the hydrogen bond contacts. The formation of early stage antiparallel β sheet structures is critical for oligomerization, and at the same time provided a flat geometry to seed the ordered β-strand packing of the fibrils. Our findings hint at reorganization of this part of the molecule as a potentially critical step in Aβ aggregation and will insight into early oligomerization for large β amyloids.
Keywords: Aggregation mechanism; Amyloid; Markov state model.
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