Transition Networks Unveil Disorder-to-Order Transformations in AIβ/I Caused by Glycosaminoglycans or Lipids

The aggregation of amyloid-β (Aβ) peptides, particularly of Aβ[sub.1−42], has been linked to the pathogenesis of Alzheimer’s disease. In this study, we focus on the conformational change of Aβ[sub.1−42] in the presence of glycosaminoglycans (GAGs) and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine...

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Bibliographic Details
Published in:International journal of molecular sciences 2023-07, Vol.24 (14)
Main Authors: Schäffler, Moritz, Samantray, Suman, Strodel, Birgit
Format: Article
Language:English
Subjects:
Lipids
Proteins
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Summary:The aggregation of amyloid-β (Aβ) peptides, particularly of Aβ[sub.1−42], has been linked to the pathogenesis of Alzheimer’s disease. In this study, we focus on the conformational change of Aβ[sub.1−42] in the presence of glycosaminoglycans (GAGs) and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) lipids using molecular dynamics simulations. We analyze the conformational changes that occur in Aβ by extracting the key structural features that are then used to generate transition networks. Using the same three features per network highlights the transitions from intrinsically disordered states ubiquitous in Aβ[sub.1−42] in solution to more compact states arising from stable β-hairpin formation when Aβ[sub.1−42] is in the vicinity of a GAG molecule, and even more compact states characterized by a α-helix or β-sheet structures when Aβ[sub.1−42] interacts with a POPC lipid cluster. We show that the molecular mechanisms underlying these transitions from disorder to order are different for the Aβ[sub.1−42]/GAG and Aβ[sub.1−42]/POPC systems. While in the latter the hydrophobicity provided by the lipid tails facilitates the folding of Aβ[sub.1−42], in the case of GAG there are hardly any intermolecular Aβ[sub.1−42]–GAG interactions. Instead, GAG removes sodium ions from the peptide, allowing stronger electrostatic interactions within the peptide that stabilize a β-hairpin. Our results contribute to the growing knowledge of the role of GAGs and lipids in the conformational preferences of the Aβ peptide, which in turn influences its aggregation into toxic oligomers and amyloid fibrils.
ISSN:1422-0067
1422-0067
DOI:10.3390/ijms241411238