Amyloid β Peptides Aggregation in a Mixed Membrane Bilayer: A Molecular Dynamics Study

Zhao, Li; Chiu, See‐Wing; Benoit, Jérôme; Chew, Lock Yue; Mu, Yuguang

doi:10.1021/jp2065985

Cited by 68 publications

(83 citation statements)

References 58 publications

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“…Some β-strands were tending to be curved (Figure 6), perhaps lacking enough interactions to stabilize the flat extended sheets observed in mature fibrils. In a recent study the formation of a short segment of parallel intermolecular β-sheet was reported during assembly of three Aβ peptides in a mixed bilayer [33]. The small oligomers of Aβ do not have β-sheet structure characteristics of fibril, rather are composed of several shorter and loosely aggregated stands, which might polymerize in later stages during fibrillization [5].…”

Section: Resultsmentioning

confidence: 99%

Binding, Conformational Transition and Dimerization of Amyloid-β Peptide on GM1-Containing Ternary Membrane: Insights from Molecular Dynamics Simulation

Manna

Mukhopadhyay

2013

PLoS ONE

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Interactions of amyloid-β (Aβ) with neuronal membrane are associated with the progression of Alzheimer’s disease (AD). Ganglioside GM1 has been shown to promote the structural conversion of Aβ and increase the rate of peptide aggregation; but the exact nature of interaction driving theses processes remains to be explored. In this work, we have carried out atomistic-scale computer simulations (totaling 2.65 µs) to investigate the behavior of Aβ monomer and dimers in GM1-containing raft-like membrane. The oligosaccharide head-group of GM1 was observed to act as scaffold for Aβ-binding through sugar-specific interactions. Starting from the initial helical peptide conformation, a β-hairpin motif was formed at the C-terminus of the GM1-bound Aβ-monomer; that didn’t appear in absence of GM1 (both in fluid POPC and liquid-ordered cholesterol/POPC bilayers and also in aqueous medium) within the simulation time span. For Aβ-dimers, the β-structure was further enhanced by peptide-peptide interactions, which might influence the propensity of Aβ to aggregate into higher-ordered structures. The salt-bridges and inter-peptide hydrogen bonds were found to account for dimer stability. We observed spontaneous formation of intra-peptide D23-K28 salt-bridge and a turn at V24GSN27 region - long been accepted as characteristic structural-motifs for amyloid self-assembly. Altogether, our results provide atomistic details of Aβ-GM1 and Aβ-Aβ interactions and demonstrate their importance in the early-stages of GM1-mediated Aβ-oligomerisation on membrane surface.

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Section: Resultsmentioning

confidence: 99%

Binding, Conformational Transition and Dimerization of Amyloid-β Peptide on GM1-Containing Ternary Membrane: Insights from Molecular Dynamics Simulation

Manna

Mukhopadhyay

2013

PLoS ONE

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“…49-51 In our previous simulations, we modeled two truncated Aβ barrels, Aβ 17-42 (p3) and Aβ 9-42 (N9), 21 using U-shaped peptides with the β-strand-turn-β-strand motif. 34,35 To model the full sequence Aβ 1-42 barrels, we again employ the U-shaped peptides as the membrane embedded portion and adopt the N-terminal structure from the Aβ 1-16 (coordinates taken from PDB code: 1ZE7) 36 as the extramembranous portion.…”

Section: Resultsmentioning

confidence: 99%

Atomic Force Microscopy and MD Simulations Reveal Pore-Like Structures of All-d-Enantiomer of Alzheimer’s β-Amyloid Peptide: Relevance to the Ion Channel Mechanism of AD Pathology

et al. 2012

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Alzheimer’s disease (AD) is a protein misfolding disease characterized by a build-up of β-amyloid (Aβ) peptide as senile plaques, uncontrolled neurodegeneration, and memory loss. AD pathology is linked to the destabilization of cellular ionic homeostasis and involves Aβ peptide-plasma membrane interactions. In principle, there are two possible ways through which disturbance of the ionic homeostasis can take place: directly, where the Aβ peptide either inserts into the membrane and creates ion-conductive pores or destabilizes the membrane organization; or, indirectly, where the Aβ peptide interacts with existing cell membrane receptors. To distinguish between these two possible types of Aβ-membrane interactions, we took advantage of the biochemical tenet that ligand-receptor interactions are stereospecific; L-amino acid peptides, but not their D-counterparts, bind to cell membrane receptors. However, with respect to the ion channel-mediated mechanism, like L-amino acids, D-amino acid peptides will also form ion channel-like structures. Using atomic force microscopy (AFM) we imaged the structures of both D- and L-enantiomers of the full length Aβ1-42 when reconstituted in lipid bilayers. AFM imaging shows that both L- and D-Aβ isomers form similar channel-like structures. Molecular dynamics (MD) simulations support the AFM imaged 3D structures. Earlier we have shown that D-Aβ1-42 channels conduct ions similarly to their L-counter parts. Taken together, our results support the direct mechanism of Aβ ion channel-mediated destabilization of ionic homeostasis rather than the indirect mechanism through Aβ interaction with membrane receptors.

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“…The influence of Chol embedded in POPC or dipalmitoylphosphatidylcholine (DPPC) membranes has been investigated in some studies. 22,23) Only a few studies employed the calculation models that included GM1 and Chol in the lipid membrane. 21,24) We have developed a modeling technique and simulation method for mixed membranes.…”

Section: )mentioning

confidence: 99%

Simulation Study on Complex Conformations of Aβ<sub>42</sub> Peptides on a GM1 Ganglioside-Containing Lipid Membrane

Vahed

Neya

Hoshino

2018

CHEMICAL & PHARMACEUTICAL BULLETIN

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Aggregation and complex formation of amyloid beta (Aβ) peptides on a neuronal cell membrane is a hallmark of neuro-disturbance diseases. In this work, we performed molecular dynamics (MD) simulations to investigate the initial stage of interactions of multiple Aβ 42 peptides on a GM1 ganglioside-containing membrane that mimics a micro-domain on the neuronal cell surface. Conformational changes of Aβs due to adhesion on the membrane and subsequent molecular interactions among the Aβs were monitored. It was suggested from results of the two 1.0 µs simulation trials that stable complexes of Aβ peptides were not rapidly generated but that a steady binding of two Aβs was gradually formed. Observation of two Aβs that will be a complex with steady binding revealed that one Aβ was bound to the membrane surface, while the other was attached to the first one without strong contact with the membrane. The motion of the first one was restricted and its conformational change was limited, with the basic side-chains of Arg5 and Lys28 working as anchors to hold the Aβ helix region on the membrane. In contrast, the second one had high flexibility and showed diversity in its conformation. The second Aβ can search for an energetically favorable binding position on the first one. A parallel β-sheet structure was formed between the C-terminal sides of the two Aβs. Ala30 was critically important to lead the stable β-sheet conformation at the C-terminal hydrophobic domains of Aβs. In the N-terminal sides, helix structures were kept in both Aβs.Key words amyloid beta peptide; molecular dynamics simulation; membrane surface; molecular interaction; conformational change; complex structure Aggregation of amyloid beta (Aβ)-peptides is closely linked to several neurodegeneration diseases including Alzheimer's disease (AD).1-3) Aβ is a small peptide consisting of typically 39-43 amino acid residues and it is a normal product of cellular metabolism from amyloid precursor protein (APP) due to the successive proteolytic action by β-and γ-secretases. 4,5) Aggregation and resultant transformation of Aβ peptides into insoluble misfolding proteins is a pathological hallmark of neurodegeneration diseases in the brain.4) The most commonly observed forms of toxic Aβs are comprised of 40 and/or 42 residues. Both of them show an affinity to a lipid membrane, but Aβ 42 (a.a. 1-42) is more likely to form amyloid fibrils. 6)This strong tendency of Aβ 42 to aggregate is related to two additional hydrophobic amino acids at its C-terminal end. 7)According to an in vivo study, 8) soluble Aβ oligomers were sequestered from brain interstitial fluid onto brain membranes more rapidly than non-toxic monomers and they were strongly bound to GM1-ganglioside on the cellular membranes. GM1 is likely to form a cluster on a membrane containing sphingomyelin (SM) and cholesterol (Chol). A GM1 cluster has a hydrophobic surface and a negatively charged area due to the condensation of glycans. Many in vitro studies have shown an acceleration of Aβ aggregation on lipid micro-d...

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Amyloid β Peptides Aggregation in a Mixed Membrane Bilayer: A Molecular Dynamics Study

Cited by 68 publications

References 58 publications

Binding, Conformational Transition and Dimerization of Amyloid-β Peptide on GM1-Containing Ternary Membrane: Insights from Molecular Dynamics Simulation

Binding, Conformational Transition and Dimerization of Amyloid-β Peptide on GM1-Containing Ternary Membrane: Insights from Molecular Dynamics Simulation

Atomic Force Microscopy and MD Simulations Reveal Pore-Like Structures of All-d-Enantiomer of Alzheimer’s β-Amyloid Peptide: Relevance to the Ion Channel Mechanism of AD Pathology

Simulation Study on Complex Conformations of Aβ<sub>42</sub> Peptides on a GM1 Ganglioside-Containing Lipid Membrane

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