Abstract
Oligomers populated during the early amyloid aggregation process are more toxic than mature fibrils, but pinpointing the exact toxic species among highly dynamic and heterogeneous aggregation intermediates remains a major challenge. β-barrel oligomers, structurally-determined recently for a slow-aggregating peptide derived from αB crystallin, are attractive candidates for exerting amyloid toxicity due to their well-defined structures as therapeutic targets and compatibility to the “amyloid-pore” hypothesis of toxicity. To assess whether β-barrel oligomers are common intermediates to amyloid peptides - a necessary step toward associating β-barrel oligomers with general amyloid cytotoxicity, we computationally studied the oligomerization and fibrillization dynamics of seven well-studied fragments of amyloidogenic proteins with different experimentally-determined aggregation morphologies and cytotoxicity. In our molecular dynamics simulations, β-barrel oligomers were only observed in five peptides self-assembling into the characteristic cross-β aggregates, but not the other two that formed polymorphic β-rich aggregates as reported experimentally. Interestingly, the latter two peptides were previously found nontoxic. Hence, the observed correlation between β-barrel oligomers formation and cytotoxicity supports the hypothesis of β-barrel oligomers as the common toxic intermediates of amyloid aggregation.
Highlights
Computational study combining coarse-grained and all-atom simulations[26]
We computationally investigated the aggregation dynamics of several well-studied peptides derived from various amyloidogenic proteins
Consistent with experimentally observed morphologies of final aggregates[27], hIAPP19–29 and its S20G mutant tended to form two-layer β-sheets face-to-face with hydrophobic side-chains packed against each other in our simulations; but the β-sheets of hIAPP15–25 and the S20G mutant were polymorphic with different bent conformations that did not form the mated β-sheet packing
Summary
Computational study combining coarse-grained and all-atom simulations[26] These β-barrel oligomers capable of spanning across the lipid bilayer and compatible to the “amyloid-pore” hypothesis of amyloid toxicity[15,16,17] have been postulated as the early aggregation intermediates exerting toxic effects on cells[11]. The connection of β-barrel oligomers with the general amyloid cytotoxicity in amyloid diseases remains to be fully established It is unclear whether the formation of β-barrel oligomer as intermediates is common and yet specific to the aggregation of toxic amyloid peptides. The inter-conversion between closed β-barrels and open β-sheets with single or double layers was observed in DMD simulations For these five peptides, the final aggregates in simulations of large molecular systems resembled the cross-β protofibrils consistent with the experimentally-observed mated β-sheets. We postulate that β-barrel oligomers are common aggregation intermediates towards the final formation of cross-β aggregates and these β-barrel oligomer intermediates, among many other factors[38,39], may contribute to the cytotoxicity of amyloid aggregation
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