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Distinct oligomerization and fibrillization dynamics of amyloid core sequences of amyloid-beta and islet amyloid polypeptide

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Abstract

A direct observation of amyloid aggregation from isolated peptides to cross-β fibrils is crucial for understanding the nucleation-dependence process, but the corresponding macroscopic timescales impose a major computational challenge. Using rapid all-atom discrete molecular dynamics simulations, we capture the oligomerization and fibrillization dynamics of the amyloid core sequences of amyloid-β (Aβ) in Alzheimer's disease and islet amyloid polypeptide (IAPP) in type-2 diabetes, namely Aβ16–22 and IAPP22–28. Both peptides and their mixture spontaneously assemble into cross-β aggregates in silico, but follow distinct pathways. Aβ16–22 is highly aggregation-prone with a funneled free energy basin toward multi-layer β-sheet aggregates. IAPP22–28, on the other hand, features the accumulation of unstructured oligomers before the nucleation of β-sheets and growth into double-layer β-sheet aggregates. In the presence of Aβ16–22, the aggregation of IAPP22–28 is promoted by forming co-aggregated multi-layer β-sheets. Our study offers a detailed molecular insight to the long-postulated oligomerization-nucleation process in the amyloid aggregations.

Graphical abstract: Distinct oligomerization and fibrillization dynamics of amyloid core sequences of amyloid-beta and islet amyloid polypeptide

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Publication details

The article was received on 20 Aug 2017, accepted on 11 Oct 2017 and first published on 11 Oct 2017


Article type: Paper
DOI: 10.1039/C7CP05695H
Citation: Phys. Chem. Chem. Phys., 2017, Advance Article
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    Distinct oligomerization and fibrillization dynamics of amyloid core sequences of amyloid-beta and islet amyloid polypeptide

    Y. Sun, B. Wang, X. Ge and F. Ding, Phys. Chem. Chem. Phys., 2017, Advance Article , DOI: 10.1039/C7CP05695H

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