Met35 Oxidation Hinders Aβ25-35 Peptide Aggregation within the Dimyristoylphosphatidylcholine Bilayer.

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.