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Structures and dynamics of β-barrel oligomer intermediates of amyloid-beta16-22 aggregation
| Content Provider | Scilit |
|---|---|
| Author | Ge, Xinwei Sun, Yunxiang Ding, Feng |
| Copyright Year | 2018 |
| Description | Journal: Biochimica et Biophysica Acta (BBA) - Biomembranes Accumulating evidence suggests that soluble oligomers are more toxic than final fibrils of amyloid aggregations. Among the mixture of inter-converting intermediates with continuous distribution of sizes and secondary structures, oligomers in the β-barrel conformation – a common class of protein folds with a closed β-sheet – have been postulated as the toxic species with well-defined three-dimensional structures to perform pathological functions. A common mechanism for amyloid toxicity, therefore, implies that all amyloid peptides should be able to form β-barrel oligomers as the aggregation intermediates. Here, we applied all-atom discrete molecular dynamics (DMD) simulations to evaluate the formation of β-barrel oligomers and characterize their structures and dynamics in the aggregation of a seven-residue amyloid peptide, corresponding to the amyloid core of amyloid-β with a sequence of$ ^{16}KLVFFAE^{22}$ (Aβ16-22). We carried out aggregation simulations with various numbers of peptides to study the size dependence of aggregation dynamics and assembly structures. Consistent with previous computational studies, we observed the formation of β-barrel oligomers in all-atom DMD simulations. Using a network-based approach to automatically identify β-barrel conformations, we systematically characterized β-barrels of various sizes. Our simulations revealed the conformational inter-conversion between β-barrels and double-layer β-sheets due to increased structural strains upon forming a closed β-barrel while maximizing backbone hydrogen bonds. The potential of mean force analysis further characterized the free energy barriers between these two states. The obtained structural and dynamic insights of β-barrel oligomers may help better understand the molecular mechanism of oligomer toxicities and design novel therapeutics targeting the toxic β-barrel oligomers. This article is part of a Special Issue entitled: Protein Aggregation and Misfolding at the Cell Membrane Interface edited by Ayyalusamy Ramamoorthy |
| Related Links | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6145138/pdf https://www.sciencedirect.com/science/article/pii/S0005273618300919/pdfft?md5=f044c2f5310a3946ab7876be7096cff5&pid=1-s2.0-S0005273618300919-main.pdf |
| Ending Page | 1697 |
| Page Count | 11 |
| Starting Page | 1687 |
| ISSN | 00052736 |
| DOI | 10.1016/j.bbamem.2018.03.011 |
| Journal | Biochimica et Biophysica Acta (BBA) - Biomembranes |
| Issue Number | 9 |
| Volume Number | 1860 |
| Language | English |
| Publisher | Elsevier BV |
| Publisher Date | 2018-09-01 |
| Access Restriction | Open |
| Subject Keyword | Journal: Biochimica et Biophysica Acta (BBA) - Biomembranes Mathematical and Computational Biology Amyloid Aggregation Aggregation Oligomer Molecular Dynamics |
| Content Type | Text |
| Resource Type | Article |
| Subject | Cell Biology Biochemistry Biophysics |
