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Stability of transmembrane amyloid ?-peptide and membrane integrity tested by molecular modeling of site-specific A?42 mutations.

ABSTRACT: Interactions of the amyloid ?-protein (A?) with neuronal cell membranes, leading to the disruption of membrane integrity, are considered to play a key role in the development of Alzheimer's disease. Natural mutations in A?42, such as the Arctic mutation (E22G) have been shown to increase A?42 aggregation and neurotoxicity, leading to the early-onset of Alzheimer's disease. A correlation between the propensity of A?42 to form protofibrils and its effect on neuronal dysfunction and degeneration has been established. Using rational mutagenesis of the A?42 peptide it was further revealed that the aggregation of different A?42 mutants in lipid membranes results in a variety of polymorphic aggregates in a mutation dependent manner. The mutant peptides also have a variable ability to disrupt bilayer integrity. To further test the connection between A?42 mutation and peptide-membrane interactions, we perform molecular dynamics simulations of membrane-inserted A?42 variants (wild-type and E22G, D23G, E22G/D23G, K16M/K28M and K16M/E22G/D23G/K28M mutants) as ?-sheet monomers and tetramers. The effects of charged residues on transmembrane A?42 stability and membrane integrity are analyzed at atomistic level. We observe an increased stability for the E22G A?42 peptide and a decreased stability for D23G compared to wild-type A?42, while D23G has the largest membrane-disruptive effect. These results support the experimental observation that the altered toxicity arising from mutations in A? is not only a result of the altered aggregation propensity, but also originates from modified A? interactions with neuronal membranes.

SUBMITTER: Poojari C

PROVIDER: S-EPMC3820573 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Stability of transmembrane amyloid β-peptide and membrane integrity tested by molecular modeling of site-specific Aβ42 mutations.

Poojari Chetan C Strodel Birgit B

PloS one 20131107 11

Interactions of the amyloid β-protein (Aβ) with neuronal cell membranes, leading to the disruption of membrane integrity, are considered to play a key role in the development of Alzheimer's disease. Natural mutations in Aβ42, such as the Arctic mutation (E22G) have been shown to increase Aβ42 aggregation and neurotoxicity, leading to the early-onset of Alzheimer's disease. A correlation between the propensity of Aβ42 to form protofibrils and its effect on neuronal dysfunction and degeneration ha ...[more]

PMID: 24244308

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Project description:As the bacterial multidrug resistance crisis continues, membrane-active antimicrobial peptides are being explored as an alternate treatment to conventional antibiotics. In contrast to antimicrobial peptides, which function by a nonspecific membrane disruption mechanism, here we describe a series of transmembrane (TM) peptides that are designed to act as drug efflux inhibitors by aligning with and out-competing a conserved TM4-TM4 homodimerization motif within bacterial small multidrug resistance proteins. The peptides contain two terminal tags: a C-terminal lysine tag to direct the peptides toward the negatively charged bacterial membrane, and an uncharged N-terminal sarcosine (N-methyl-glycine) tag to promote membrane insertion. While effective at inhibiting efflux activity, ostensibly through their designed mechanism of action, the impact of the peptides on the bacterial inner membrane remains undetermined. To evaluate the extant peptide-membrane interactions, we performed a series of biophysical measurements. Circular dichroism spectroscopy and Trp fluorescence showed that the peptides insert into the membrane generally in helical form. Interestingly, differential scanning calorimetry of the peptides added to bacterial-like membranes (POPE:POPG 3:1) revealed the peptides' ability to demix the POPE and POPG lipids, creating two pools, one of which is likely a peptide-POPG conglomerate, and the other a POPE-rich component where the native POPG content has been depleted. However, dye leakage assays confirmed that these events occur without causing significant membrane disruption both in vitro and in vivo, indicating that the peptides can target the small multidrug resistance TM4-TM4 motif without nonspecific membrane disruption. In related studies, DiOC2(3) fluorescence indicated moderate peptide-mediated reduction of the proton motive force for all peptides, including control peptides that did not display inhibitory activity. The overall findings suggest that peptides designed with suitable tags, sequence hydrophobicity, and charge distribution can be directed more generally to impact proteins whose function involves membrane-embedded protein-protein interactions.

Dataset Information

Stability of transmembrane amyloid ?-peptide and membrane integrity tested by molecular modeling of site-specific A?42 mutations.

Publications

Stability of transmembrane amyloid β-peptide and membrane integrity tested by molecular modeling of site-specific Aβ42 mutations.

Similar Datasets

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