The consequences of phosphorylation of the Aβ25-35 peptide at the position Ser26 on its aggregation have not been examined. To investigate them, we performed all-atom replica exchange simulations probing the binding of phosphorylated Aβ25-35 (pAβ25-35) peptides to the dimyristoyl phosphatidylcholine (DMPC) bilayer and their subsequent aggregation. As a control, we used our previous study of unmodified peptides. We found that phosphorylation moderately reduces the helical propensity in pAβ25-35 and its binding affinity to the DMPC bilayer. Phosphorylation preserves the bimodal binding observed for unmodified Aβ25-35, which features a preferred inserted state and a less probable surface bound state. Phosphorylation also retains the inserted dimer with a head-to-tail helical aggregation interface as the most thermodynamically stable state. Importantly, this post-translation modification strengthens interpeptide interactions by adding a new aggregation "hot spot" created by cross-bridging phosphorylated Ser26 with water, cationic ions, or Lys28. The cross-bridging constitutes the molecular mechanism behind most structural phosphorylation effects. In addition, phosphorylation eliminates pAβ25-35 monomers and diversifies the pool of aggregated species. As a result, it changes the binding and aggregation mechanism by multiplying pathways leading to stable inserted dimers. These findings offer a plausible molecular rationale for experimental observations, including enhanced production of low molecular weight oligomers and cytotoxicity of phosphorylated Aβ peptides.
Keywords: Alzheimer’s disease; Aβ peptide; Lipid bilayer; Molecular dynamics; Replica exchange with solute tempering.