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Binding of protofibrillar A? trimers to lipid bilayer surface enhances A? structural stability and causes membrane thinning.

ABSTRACT: Alzheimer's disease, a common neurodegenerative disease, is characterized by the aggregation of amyloid-? (A?) peptides. The interactions of A? with membranes cause changes in membrane morphology and ion permeation, which are responsible for its neurotoxicity and can accelerate fibril growth. However, the A?-lipid interactions and how these induce membrane perturbation and disruption at the atomic level and the consequences for the A? organization are not entirely understood. Here, we perform multiple atomistic molecular dynamics simulations on three protofibrillar A?9-40 trimers. Our simulations show that, regardless of the morphologies and the initial orientations of the three different protofibrillar A?9-40 trimers, the N-terminal ?-sheet of all trimers preferentially binds to the membrane surface. The POPG lipid bilayers enhance the structural stability of protofibrillar A? trimers by stabilizing inter-peptide ?-sheets and D23-K28 salt-bridges. The interaction causes local membrane thinning. We found that the trimer structure related to Alzheimer's disease brain tissue () is the most stable both in water solution and at membrane surface, and displays slightly stronger membrane perturbation capability. These results provide mechanistic insights into the membrane-enhanced structural stability of protofibrillar A? oligomers and the first step of A?-induced membrane disruption at the atomic level.

SUBMITTER: Dong X

PROVIDER: S-EPMC5647258 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Binding of protofibrillar Aβ trimers to lipid bilayer surface enhances Aβ structural stability and causes membrane thinning.

Dong Xuewei X Sun Yunxiang Y Wei Guanghong G Nussinov Ruth R Ma Buyong B

Physical chemistry chemical physics : PCCP 20171001 40

Alzheimer's disease, a common neurodegenerative disease, is characterized by the aggregation of amyloid-β (Aβ) peptides. The interactions of Aβ with membranes cause changes in membrane morphology and ion permeation, which are responsible for its neurotoxicity and can accelerate fibril growth. However, the Aβ-lipid interactions and how these induce membrane perturbation and disruption at the atomic level and the consequences for the Aβ organization are not entirely understood. Here, we perform mu ...[more]

PMID: 28979963

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Project description:The development of next-generation transmembrane protein-based biosensors relies heavily on the use of black lipid membranes (BLMs); however, electrical, mechanical, and temporal instability of BLMs poses a limiting challenge to biosensor development. In this work, micrometer-sized glass apertures were modified with silanes of different chain length and fluorine composition, including 3-cyanopropyldimethychlorosilane (CPDCS), ethyldimethylchlorosilane (EDCS), n-octyldimethylchlorosilane (ODCS), (tridecafluoro-1, 1, 2, 2-tetrahydrooctyl)dimethylchlorosilane (PFDCS), or (heptadecafluoro-1,1,2,2-tetrahydrodecyl)dimethylchlorosilane (PFDDCS), to explore the effect of substrate surface energy on BLM stability. Low energy silane-modified surfaces promoted enhanced lipid-substrate interactions that facilitate the formation of low-leakage, stable BLMs. The surface energies of silane-modified substrates were 30 ± 3, 16 ± 1, 14 ± 2, 11 ± 1, and 7.1 ± 2 mJ m(-2) for CDCS, EDCS, ODCS, PFDCS, and PFDDCS, respectively. Decreased surface energy directly correlated to improved electrical, mechanical, and temporal BLM stability. Amphiphobic perfluorinated surface modifiers yielded superior performance compared to traditional hydrocarbon modifiers in terms of stability and BLM formation, with only marginal effects on BLM membrane permeability. Leakage currents obtained for PFDCS and PFDDCS BLMs were elevated only 10-30%, though PFDDCS modification yielded >5-fold increase in electrical stability as indicated by breakdown voltage (> 2000 mV vs 418 ± 73 mV), and >25-fold increase in mechanical stability as indicated by air-water transfers (> 50 vs 2 ± 0.2) when compared to previously reported CPDCS modification. Importantly, the dramatically improved membrane stabilities were achieved with no deleterious effects on reconstituted ion channel function, as evidenced by ?-hemolysin activity. Thus, this approach provides a simple, low cost, and broadly applicable alternative for BLM stabilization and should contribute significantly toward the development of next-generation ion-channel-functionalized biosensors.

Dataset Information

Binding of protofibrillar A? trimers to lipid bilayer surface enhances A? structural stability and causes membrane thinning.

Publications

Binding of protofibrillar Aβ trimers to lipid bilayer surface enhances Aβ structural stability and causes membrane thinning.

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