Molecular interactions of Alzheimer amyloid-β oligomers with neutral and negatively charged lipid bilayers
| Autor: | Xiang Yu, Qiuming Wang, Jie Zheng, Feimeng Zhou, Qingfen Pan |
|---|---|
| Rok vydání: | 2013 |
| Předmět: |
Membrane permeability
Pentamer Membrane lipids Lipid Bilayers Molecular Sequence Data General Physics and Astronomy Molecular Dynamics Simulation Protein Structure Secondary Article chemistry.chemical_compound Alzheimer Disease Humans Organic chemistry Amino Acid Sequence Lipid bilayer phase behavior Physical and Theoretical Chemistry Lipid bilayer POPC Amyloid beta-Peptides Chemistry Bilayer Lipid bilayer fusion Phosphatidylglycerols Peptide Fragments Phosphatidylcholines Biophysics Calcium lipids (amino acids peptides and proteins) |
| Zdroj: | Physical Chemistry Chemical Physics. 15:8878 |
| ISSN: | 1463-9084 1463-9076 |
| DOI: | 10.1039/c3cp44448a |
| Popis: | Interaction of p3 (Aβ17-42) peptides with cell membrane is crucial for the understanding of amyloid toxicity associated with Alzheimer’s disease (AD). Such p3-membrane interactions are considered to induce the disruption of membrane permeability and integrity, but the exact mechanisms of how p3 aggregates, particularly small p3 oligomers, induce receptor-independent membrane disruption are not yet completely understood. Here, we investigate the adsorption, orientation, and surface interaction of the p3 pentamer with lipid bilayers composed of both pure zwitterionic POPC (palmitoyl-oleyl-phosphatidylcholine) and mixed anionic POPC/POPG (palmitoyl-oleyl-phosphatidylglycerol) (3:1) lipids using explicit-solvent molecular dynamics (MD) simulations. MD simulation results show that the p3 pentamer has much stronger interactions with mixed POPC/POPG lipids than pure POPC lipids, consistent with experimental observation that Aβ adsorption and fibrililation are enhanced on anionic lipid bilayers. Although electrostatic interactions are main attractive forces to drive the p3 to adsorb on the bilayer surface, the adsorption of the p3 pentamer on the lipid bilayer with a preferential C-terminal β-strands facing toward the bilayer surface is a net outcome of different competitions between p3 peptides-lipid bilayer and ions-p3-bilayer interactions. More importantly, Ca2+ ions are found to form ionic bridges to associate negatively charged residues of p3 with anionic headgroups of the lipid bilayer, resulting in Aβ–Ca2+–PO4− complexes. Intensive Ca2+ bound to lipid bilayer and Ca2+ ionic bridges may lead to the alternation of Ca2+ hemostasis responsible for neuronal dysfunction and death. This work provides insights into the mutual structure, dynamics, and interactions of both Aβ peptides and lipid bilayer at the atomic level, which expand our understanding of the complex behavior of amyloid-induced membrane disruption. |
| Databáze: | OpenAIRE |
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