Simulations of cross-amyloid aggregation of amyloid-β and islet amyloid polypeptide fragments.

Autor: Kawecki GE; Department of Biochemistry, Virginia Tech, Blacksburg, Virginia., King KM; Department of Biochemistry, Virginia Tech, Blacksburg, Virginia., Cramer NA; Department of Biochemistry, Virginia Tech, Blacksburg, Virginia., Bevan DR; Department of Biochemistry, Virginia Tech, Blacksburg, Virginia; Center for Drug Discovery, Virginia Tech, Blacksburg, Virginia., Brown AM; Department of Biochemistry, Virginia Tech, Blacksburg, Virginia; Center for Drug Discovery, Virginia Tech, Blacksburg, Virginia; University Libraries, Virginia Tech, Blacksburg, Virginia. Electronic address: ambrown7@vt.edu.
Jazyk: angličtina
Zdroj: Biophysical journal [Biophys J] 2022 Jun 07; Vol. 121 (11), pp. 2002-2013. Date of Electronic Publication: 2022 May 10.
DOI: 10.1016/j.bpj.2022.05.007
Abstrakt: Amyloid-β (Aβ) and islet amyloid polypeptide (IAPP) are small peptides, classified as amyloids, that have the potential to self-assemble and form cytotoxic species, such as small soluble oligomers and large insoluble fibrils. The formation of Aβ aggregates facilitates the progression of Alzheimer's disease (AD), while IAPP aggregates induce pancreatic β-cell apoptosis, leading to exacerbation of type 2 diabetes (T2D). Cross-amyloid interactions between Aβ and IAPP have been described both in vivo and in vitro, implying the role of Aβ or IAPP as modulators of cytotoxic self-aggregation of each species, and suggesting that Aβ-IAPP interactions are a potential molecular link between AD and T2D. Using molecular dynamics (MD) simulations, "hotspot" regions of the two peptides were studied to understand the formation of hexamers in a heterogeneous and homogeneous peptide-containing environment. Systems of only Aβ (16-22) peptides formed antiparallel, β-barrel-like structures, while systems of only IAPP (20-29) peptides formed stacked, parallel β-sheets and had relatively unstable aggregation structures after 2 μs of simulation time. Systems containing both Aβ and IAPP (1:1 ratio) hexamers showed antiparallel, β-barrel-like structures, with an interdigitated arrangement of Aβ (16-22) and IAPP (20-29) . These β-barrel structures have features of cytotoxic amyloid species identified in previous literature. Ultimately, this work seeks to provide atomistic insight into both the mechanism behind cross-amyloid interactions and structural morphologies of these toxic amyloid species.
(Copyright © 2022 Biophysical Society. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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