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) A beta 25-35 peptides into dimers mediated by the zwitterionic dimyristoylphosphatidylcholine (DMPC) lipid bilayer. By comparing oxA beta 25-35 aggregation with that observed for reduced and phosphorylated A beta 25-35 peptides, we elucidated plausible impact of post-translational modifications on cytotoxicity of A beta peptides involved in Alzheimer's disease. We found that Met35 oxidation reduces helical propensity in oxA beta 25-35 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 oxA beta 25-35 dimer becomes partially expelled from the DMPC bilayer and as a result inflicts limited disruption to the bilayer structure compared to wild-type A beta 25-35. 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.

Automated summary

Using molecular dynamics simulations, this study investigated the aggregation of oxidized A beta 25-35 peptides mediated by a lipid bilayer and found that oxidation reduces helical propensity and increases backbone fluctuations, leading to destabilization of the dimer interface and decreased aggregation propensity. On the other hand, phosphorylation has an opposite effect, preserving the wild-type aggregation interface and enhancing aggregation propensity.