An S-Shaped Aβ42 Cross-β Hexamer Embedded into a Lipid Bilayer Reveals Membrane Disruption and Permeability

Abstract

The interactions of amyloid oligomers with membranes are known to contribute to cellular toxicity. Numerous in vitro experimental studies reported on the insertion of oligomers of different sizes that can induce cell membrane disruption, extract lipids, and form ion-permeable transmembrane pores. The current repertoire of amyloid-beta (Aβ) membrane-inserted folds that was subject to high-resolution structure NMR spectroscopy and computer simulations is devoid of any cross-β fibrillar structure. In this study, we explored the dynamics of an S-shaped Aβ42 cross-β hexamer model inserted into a lipid bilayer membrane by two atomistic molecular dynamics simulations. The initial model is characterized by the hydrophobic residues at the central hydrophobic core (residues 17–21, CHC) and the C-terminus (residues 30–42) embedded into the membrane. We observed major structural secondary, tertiary, and quaternary rearrangements leading to two distinct species, hexamer and two trimers, accompanied by membrane disruption and water permeation. The simulations show that some configurations, but not the majority, have the CHC and C-terminus hydrophobic residues exposed to the solvent. Overall, our computational results offer new perspectives to understand the relationship between Aβ42 assemblies and membrane permeability.

Interactions between Lipid Vesicle Membranes and Single Amino Acid Fibrils: Probable Origin of Specific Neurological Disorders

“…On the other hand, Nguyen et al established an S-shaped Aβ42 cross-β hexamer that embeds into the lipid bilayer, leading to membrane disruption. 100 Strikingly, how amyloid-β peptide (Aβ) behaves differently in the aqueous phase and the membrane has been recently explored by Fatafta et al 101 They proved that Aβ undergoes a rapid transition from the random coil to β-sheet in the aqueous phase; however, such a transition is not seen in the membrane. Specifically, on the neuronal membrane, they found that Aβ oligomers introduce toxicity to the neuronal membrane by damaging the membrane via hampering the membrane integrity, resulting in severe disruption of the neurons.…”

“…Based on the typical trajectory, they concluded that the peptide, prior to its final adsorption on the membrane, undergoes several binding and unbinding sequences, the extent of which mostly depends on the net charge, hydrophobicity, and polarity of the peptides. On the other hand, Nguyen et al established an S-shaped Aβ42 cross-β hexamer that embeds into the lipid bilayer, leading to membrane disruption . Strikingly, how amyloid-β peptide (Aβ) behaves differently in the aqueous phase and the membrane has been recently explored by Fatafta et al They proved that Aβ undergoes a rapid transition from the random coil to β-sheet in the aqueous phase; however, such a transition is not seen in the membrane.…”

Recent Computational Advances Regarding Amyloid-β and Tau Membrane Interactions in Alzheimer’s Disease

“…In a recent study, the dynamics of an S-shaped Aβ42 cross-β hexamer model inserted into a lipid bilayer membrane were explored by Nguyen and Derreumaux using two atomistic MD simulations, each two microseconds long [70]. The initial model was characterized by the CHC and residues 30-42 embedded into a DOPC bilayer membrane (Figure 2).…”

“…View in the x direction, parallel to the fibril axis.We show the ribbon structure of the hexamer, the phosphate atoms (tan), and the O21 and O22 atoms of the glycerol (black). Also shown are the Cα atom of V12 (yellow), Q15 (blue), V18 (orange), E22 (purple), and K28 (red)[70].…”