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Met35 Oxidation Hinders Aβ25-35 Peptide Aggregation within the Dimyristoylphosphatidylcholine Bilayer
Elias Khayat1, Christopher Lockhart1, Bryan M Delfing1
1School of Systems Biology, George Mason University, Manassas, Virginia 20110, United States.
Abstract:
Using all-atom explicit solvent replica exchange molecular dynamics simulations, we studied the aggregation of oxidized (ox) Aβ25-35 peptides into dimers mediated by the zwitterionic dimyristoylphosphatidylcholine (DMPC) lipid bilayer. By comparing oxAβ25-35 aggregation with that observed for reduced and phosphorylated Aβ25-35 peptides, we elucidated plausible impact of post-translational modifications on cytotoxicity of Aβ peptides involved in Alzheimer's disease. We found that Met35 oxidation reduces helical propensity in oxAβ25-35 peptides bound to the lipid bilayer and enhances backbone fluctuations. These factors destabilize the wild-type head-to-tail dimer interface and lower the aggregation propensity. Met35 oxidation diversifies aggregation pathways by adding monomeric species to the bound conformational ensemble. The oxAβ25-35 dimer becomes partially expelled from the DMPC bilayer and as a result inflicts limited disruption to the bilayer structure compared to wild-type Aβ25-35. Interestingly, the effect of Ser26 phosphorylation is largely opposite, as it preserves the wild-type head-to-tail aggregation interface and strengthens, not weakens, aggregation propensity. The differing effects can be attributed to the sequence locations of these post-translational modifications, since in contrast to Ser26 phosphorylation, Met35 oxidation directly affects the wild-type C-terminal aggregation interface. A comparison with experimental data is provided.
Insights
Oxidation of methionine-35 in amyloid-beta (Aβ) peptides reduces their aggregation and cytotoxicity. In contrast, serine-26 phosphorylation enhances Aβ aggregation, impacting Alzheimer's disease mechanisms.
Area of Science:
- Biochemistry
- Neuroscience
- Computational Biology
Background:
- Alzheimer's disease is linked to amyloid-beta (Aβ) peptide aggregation.
- Post-translational modifications (PTMs) like oxidation and phosphorylation can alter Aβ behavior.
- Understanding PTMs' impact on Aβ aggregation is crucial for disease mechanism insights.
Purpose of the Study:
- To investigate the aggregation of oxidized Aβ25-35 peptides.
- To compare the effects of Met35 oxidation versus Ser26 phosphorylation on Aβ aggregation.
- To elucidate the influence of PTMs on Aβ cytotoxicity and interaction with lipid bilayers.
Main Methods:
- All-atom explicit solvent replica exchange molecular dynamics simulations.
- Studying Aβ25-35 peptide aggregation on a dimyristoylphosphatidylcholine (DMPC) lipid bilayer.
- Comparing aggregation pathways of oxidized, reduced, and phosphorylated Aβ25-35 peptides.
Main Results:
- Met35 oxidation in Aβ25-35 reduces helical propensity and increases backbone fluctuations.
- Oxidation destabilizes the wild-type Aβ dimer interface, lowering aggregation propensity.
- Met35 oxidation leads to partial expulsion of the oxAβ25-35 dimer from the DMPC bilayer.
- Ser26 phosphorylation preserves the wild-type aggregation interface and enhances aggregation propensity.
- PTMs' differing effects correlate with their location within the Aβ sequence.
Conclusions:
- Met35 oxidation modulates Aβ aggregation and reduces its disruptive potential on lipid bilayers.
- Ser26 phosphorylation enhances Aβ aggregation, contrasting with Met35 oxidation effects.
- PTMs significantly influence Aβ aggregation pathways and cytotoxicity, offering insights into Alzheimer's disease.
- Computational simulations provide a valuable approach to study PTMs' effects on Aβ.
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