Phosphorylation Promotes Aβ25-35 Peptide Aggregation within the DMPC Bilayer.

Area of Science:

• Biochemistry
• Molecular Biology
• Computational Biophysics

Background:

• Amyloid-beta (Aβ) peptides are implicated in neurodegenerative diseases.
• Post-translational modifications, like phosphorylation, can alter Aβ behavior.
• The impact of Aβ25-35 phosphorylation at Ser26 on aggregation remains uncharacterized.

Purpose of the Study:

• To investigate the effects of Ser26 phosphorylation on Aβ25-35 peptide binding to lipid bilayers.
• To elucidate the impact of phosphorylation on the aggregation pathways of Aβ25-35.
• To understand the molecular mechanisms underlying altered Aβ25-35 aggregation due to phosphorylation.

Main Methods:

• All-atom replica exchange molecular dynamics simulations.
• Probing peptide-bilayer interactions using dimyristoyl phosphatidylcholine (DMPC) models.
• Comparative analysis with previously studied unmodified Aβ25-35 peptides.

Main Results:

• Phosphorylation at Ser26 moderately decreases helical propensity and DMPC bilayer binding affinity.
• Phosphorylation preserves bimodal binding (inserted and surface states) and favors inserted dimers.
• A new aggregation 'hot spot' is formed via cross-bridging involving pSer26, strengthening interpeptide interactions.
• Phosphorylation eliminates monomers, diversifies aggregated species, and promotes pathways to stable inserted dimers.

Conclusions:

• Phosphorylation of Aβ25-35 at Ser26 alters its binding and aggregation mechanisms.
• The identified cross-bridging mechanism explains experimental observations of increased low molecular weight oligomers and cytotoxicity.
• These findings provide a molecular basis for the role of phosphorylated Aβ in disease pathogenesis.