Aggregation of misfolded oligomeric amyloid-beta (Aβ) peptides on lipid membranes has been identified as a primary event in Alzheimer's pathogenesis. However, the structural and dynamical features of this membrane assisted Aβ aggregation have not been well characterized. The microscopic characterization of dynamic molecular-level interactions in peptide aggregation pathways has been challenging both computationally and experimentally. In this work, we explore differential patterns of membrane-induced Aβ 16–22 (K–L–V–F–F–A–E) aggregation from the microscopic perspective of molecular interactions. Physics-based coarse-grained molecular dynamics (CG-MD) simulations were employed to investigate the effect of lipid headgroup charge – zwitterionic (1-palmitoyl-2-oleoyl- sn-glycero -3-phosphocholine: POPC) and anionic (1-palmitoyl-2-oleoyl- sn-glycero -3-phospho- l -serine: POPS) – on Aβ 16–22 peptide aggregation. Our analyses present an extensive overview of multiple pathways for peptide absorption and biomechanical forces governing peptide folding and aggregation. In agreement with experimental observations, anionic POPS molecules promote extended configurations in Aβ peptides that contribute towards faster emergence of ordered β-sheet-rich peptide assemblies compared to POPC, suggesting faster fibrillation. In addition, lower cumulative rates of peptide aggregation in POPS due to higher peptide–lipid interactions and slower lipid diffusion result in multiple distinct ordered peptide aggregates that can serve as nucleation seeds for subsequent Aβ aggregation. This study provides an in-silico assessment of experimentally observed aggregation patterns, presents new morphological insights and highlights the importance of lipid headgroup chemistry in modulating the peptide absorption and aggregation process.
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Multivariate effects of pH, salt, and Zn2+ ions on Aβ40 fibrillation
Abstract Amyloid-β (Aβ) peptide aggregation plays a central role in the progress of Alzheimer’s disease (AD), of which Aβ-deposited extracellular amyloid plaques are a major hallmark. The brain micro-environmental variation in AD patients, like local acidification, increased ionic strength, or changed metal ion levels, cooperatively modulates the aggregation of the Aβ peptides. Here, we investigate the multivariate effects of varied pH, ionic strength and Zn 2+ on Aβ 40 fibrillation kinetics. Our results reveal that Aβ fibrillation kinetics are strongly affected by pH and ionic strength suggesting the importance of electrostatic interactions in regulating Aβ 40 fibrillation. More interestingly, the presence of Zn 2+ ions can further alter or even reserve the role of pH and ionic strength on the amyloid fibril kinetics, suggesting the importance of amino acids like Histidine that can interact with Zn 2+ ions. Both pH and ionic strength regulate the secondary nucleation processes, however regardless of pH and Zn 2+ ions, ionic strength can also modulate the morphology of Aβ 40 aggregates. These multivariate effects in bulk solution provide insights into the correlation of pH-, ionic strength- or Zn 2+ ions changes with amyloid deposits in AD brain and will deepen our understanding of the molecular pathology in the local brain microenvironment.
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- Award ID(s):
- 2015030
- NSF-PAR ID:
- 10401740
- Date Published:
- Journal Name:
- Communications Chemistry
- Volume:
- 5
- Issue:
- 1
- ISSN:
- 2399-3669
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1038/s42004-022-00786-1
