?-barrel Oligomers as Common Intermediates of Peptides Self-Assembling into Cross-? Aggregates.

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. ?-barrel oligomers, structurally-determined recently for a slow-aggregating peptide derived from ?B 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 ?-barrel oligomers are common intermediates to amyloid peptides - a necessary step toward associating ?-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, ?-barrel oligomers were only observed in five peptides self-assembling into the characteristic cross-? aggregates, but not the other two that formed polymorphic ?-rich aggregates as reported experimentally. Interestingly, the latter two peptides were previously found nontoxic. Hence, the observed correlation between ?-barrel oligomers formation and cytotoxicity supports the hypothesis of ?-barrel oligomers as the common toxic intermediates of amyloid aggregation.

SUBMITTER: Sun Y 

PROVIDER: S-EPMC6037789 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature