Membrane Complexity and Phase Behavior Dictate the Stability of Membrane‐Inserted A β 42 Hexamers

Protein-membrane interactions are vital to Alzheimer's pathogenesis, as lipid environments modulate both the aggregation and toxicity of amyloid-β (Aβ) peptides. Using atomistic molecular dynamics simulations, this study investigates the stability of an NMR-derived hexameric Aβ42 β-barrel in aqueous solution, a fluid 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) bilayer, and a complex neuronal membrane. While the hexamer is unstable and conformationally heterogeneous in water, lipid environments provide essential structural reinforcement. Notably, the multicomponent neuronal membrane offers superior stabilization compared to POPC, supporting the β-barrel in a stable transmembrane conformation. This superior stability is driven by the rigid scaffolding of the liquid-ordered phase alongside specific electrostatic anchoring between the ethanolamine headgroups of the POPE component and the acidic Aβ42 residues E22/D23. We characterize a reciprocal relationship where the membrane stabilizes the β-barrel architecture, while the peptide induces localized lipid disorder and flip-flop translocation. Our findings demonstrate how membrane complexity and phase behavior dictate the stability of toxic Aβ42 oligomers, offering key insights into the membrane-mediated mechanisms of neurotoxicity.