Early aggregation mechanism of Aβ16-22 revealed by Markov state models

A beta(16-22 )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 A beta(16-22) peptides. The identified dimeric form adopted either globular random-coil or extended beta-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 beta-sheets. The inter-state transitions were very frequent ranges from few to hundred nanoseconds. More strikingly, those states which contain fraction of beta 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 beta sheets, occurred by multiple pathways with the formation of an obligatory intermediates. We proposed that these states might facilitate the A beta(16-22 ) 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 beta sheet structures is critical for oligomerization, and at the same time provided a flat geometry to seed the ordered beta-strand packing of the fibrils. Our findings hint at reorganization of this part of the molecule as a potentially critical step in A beta aggregation and will insight into early oligomerization for large beta amyloids.

Automated summary

By using molecular dynamics simulations and Markov state model, the early oligomerization mechanism of A beta(16-22) peptides was investigated. It was found that the dimeric form of the peptides adopted globular random-coil or extended beta-strand like conformations, and intermolecular antiparallel beta-sheets were the most common type of secondary structure in the observed dimers. The states containing beta secondary structure and extended coiled structures were majorly involved in aggregation.