Metastable alpha‐rich and beta‐rich conformations of small Aβ42 peptide oligomers

Nguyen, Phuong H.; Sterpone, Fabio; Derreumaux, Philippe

doi:10.1002/prot.26495

Cited by 5 publications

(1 citation statement)

References 88 publications

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“…Recently, Berardet et al found that the initial state of conformation, oligomerization, and quality of the hIAPP can greatly impact the aggregation kinetics . Different oligomeric conformations have been predicted using several analytical techniques like TEM, thioflavin T (ThT) fluorescence spectroscopy, or the machine-learning AlphaFold2 method. , …”

Section: Results and Discussionmentioning

confidence: 99%

Molecular Insights into the Self-Assembly of a Full-Length hIAPP Trimer: β-Protofibril Formed by β-Hairpin Lateral or Longitudinal Association

et al. 2023

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The fibrillar protein deposits of the human islet amyloid polypeptide (hIAPP) in the pancreatic islet of Langerhans are pathological hallmark of type II diabetes. Extensive experimental studies have revealed that the oligomeric formations of the hIAPP are more toxic than the mature fibrils. Exploring the oligomeric conformations in the early aggregation state is valuable for effective therapeutics. In this work, using the all-atom explicit-solvent replica exchange molecular dynamic (REMD) simulations, we investigated the structural features and the assembly mechanisms of the full-length hIAPP trimer in solution.The hIAPP trimer adopted more β-sheets than a-helix conformations, and three types of ordered conformations including open β-barrel, single-layer, and doublelayer U-shaped β-sheet structures with five β-strands were captured in our simulations. A representative single-layer β-sheet conformation with a CCS value of 1400 Å 2 in our simulations matches exactly the experimentally ESI-IMS-MS-derived hIAPP trimer sample. These five β-strand conformations formed via the β-hairpin lateral and longitudinal association, respectively, showing two βprotofibril formation models. To the best of our knowledge, it is the first time to reveal two routes to β-sheet formation in the hIAPP trimers on the atomic level. The contact probabilities between pairs of the β-stranded residue show that the hydrophobic interactions between the residues F 15 ∼ V 17 and A 25 ∼ L 27 are responsible for the inter-and intra-peptide β-hairpin formations. All of these results indicate that the β-sheet formation is the first step in the conformational changes toward pathological aggregation and provides evidence of the β-sheet assembly mechanism into hIAPP aggregation.

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Section: Results and Discussionmentioning

confidence: 99%

Molecular Insights into the Self-Assembly of a Full-Length hIAPP Trimer: β-Protofibril Formed by β-Hairpin Lateral or Longitudinal Association

et al. 2023

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Survey of the Aβ-peptide structural diversity: molecular dynamics approaches

Tolstova,

Adzhubei,

Strelkova

et al. 2024

Biophys Rev

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Structural Insight into Melatonin’s Influence on the Conformation of Aβ₄₂ Dimer Studied by Molecular Dynamics Simulation

Kang,

Lu,

Etaka

et al. 2024

J. Phys. Chem. B

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The accumulation of amyloid-beta (Aβ) oligomers is recognized as a potential culprit in Alzheimer's disease (AD). Experimental studies show that melatonin, a hormone that mainly regulates circadian rhythm and sleep, can interact with Aβ peptides and disrupt the formation of oligomers. However, how melatonin inhibits the oligomerization of soluble Aβ is unclear. Here, by computational simulations, we investigate the effect of different levels of melatonin on the conformation of the Aβ 42 dimer. We find that the conformation of the Aβ 42 dimer is dependent on melatonin levels. When melatonin is absent, the dimer mainly forms a parallel β-sheet in the CHC region.When one melatonin molecule is present, the overall conformation of the dimer does not change much, but the N-terminal of the dimer tends to adopt antiparallel β-sheets. When two melatoinin molecules are present, the Aβ 42 dimer exhibits significant structural change, especially in its central region, resulting in a more compact conformation, and forms parallel β-sheets in the C-terminal. This conformational difference induced by different levels of melatoinin can shed light on the protective role of melatonin.

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Metastable alpha‐rich and beta‐rich conformations of small Aβ42 peptide oligomers

Cited by 5 publications

References 88 publications

Molecular Insights into the Self-Assembly of a Full-Length hIAPP Trimer: β-Protofibril Formed by β-Hairpin Lateral or Longitudinal Association

Molecular Insights into the Self-Assembly of a Full-Length hIAPP Trimer: β-Protofibril Formed by β-Hairpin Lateral or Longitudinal Association

Survey of the Aβ-peptide structural diversity: molecular dynamics approaches

Structural Insight into Melatonin’s Influence on the Conformation of Aβ₄₂ Dimer Studied by Molecular Dynamics Simulation

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Metastable alpha‐rich and beta‐rich conformations of small Aβ42 peptide oligomers

Cited by 5 publications

References 88 publications

Molecular Insights into the Self-Assembly of a Full-Length hIAPP Trimer: β-Protofibril Formed by β-Hairpin Lateral or Longitudinal Association

Molecular Insights into the Self-Assembly of a Full-Length hIAPP Trimer: β-Protofibril Formed by β-Hairpin Lateral or Longitudinal Association

Survey of the Aβ-peptide structural diversity: molecular dynamics approaches

Structural Insight into Melatonin’s Influence on the Conformation of Aβ42 Dimer Studied by Molecular Dynamics Simulation

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Product

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Structural Insight into Melatonin’s Influence on the Conformation of Aβ₄₂ Dimer Studied by Molecular Dynamics Simulation