Modulation of the phospholipid dynamics and bilayer water accessibility with the membrane-associated nucleation of β-amyloid (Aβ) peptides.

Ahead of the membrane curve: in silico insights into amyloid-β aggregation

Impact of Lipid Composition and Synergistic Effect on Aβ42 Oligomer-Induced Changes in Membrane Conductance and Microviscosity

The accumulation of the Aβ42 peptide is one of the key factors in the progression of Alzheimer’s disease, as it disrupts synaptic signaling and impairs neuronal function. Although the peptide is known to compromise plasma membrane integrity, the detailed mechanisms underlying bilayer alterations and lipid–Aβ42 interactions remain unclear. In the present study, electrochemical impedance spectroscopy and fluorescence lifetime imaging microscopy were employed to investigate the impact of oligomeric Aβ42 on model membranes that mimic the lipid composition of the outer leaflet of the neuronal plasma membrane. Our results demonstrate that the presence of SM or GM1 within a DOPC/Chol backbone is enough to facilitate Aβ42 interaction with the membrane, as evidenced by increased membrane microviscosity; however, this interaction alone is insufficient to induce permeability-enhancing defects in the membrane. Extensive disruption of bilayer integrity required the complete lipid ensemble present in the outer leaflet of the neuronal membrane-mimicking composition, indicating that not only specific lipids but also their cooperative interplay and organization within the lipid bilayer are essential for Aβ42-induced membrane permeabilization.

Membrane Complexity and Phase Behavior Dictate the Stability of Membrane‐Inserted Aβ 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.

Molecular dynamics simulations of a complex plasma membrane reveal finely-tuned sphingolipid hydrogen bonds.

The study of lipid bilayers has lagged behind that of other complex molecular assemblies due to the dynamic nature of lipid bilayers and the paucity of experimental techniques to study them in atomic detail. This is particularly true when analyzing interactions between lipid components of membranes. We now report a multi-resolution in silico analysis of a lipid bilayer based on the asymmetric lipid composition of the human erythrocyte plasma membrane. Our approach combines a coarse-grained bilayer simulation with resolution transformation to multiple smaller all-atom simulations. The coarse-grained simulation was consistent with previously published studies, as demonstrated by analysis of cholesterol translocation and neighbor enrichment. Subsequently, small patches from the coarse-grained simulations were transformed to all-atom resolution; quality control analysis of this data was again consistent with area per lipid and chain orientational order measurements of model bilayers. All-atom simulations permitted us to examine intermolecular and intramolecular hydrogen-bonding with a particular focus on sphingolipids, which unlike glycerophospholipids, donate hydrogen bonds in the bilayer interface region. We determined the relative contribution of each donor and acceptor hydrogen bond in lipid-lipid interactions and took advantage of atomic level resolution to study hydrogen-bonding for d-erythro-, 3-keto-, phyto- and dihydro-sphingolipids. Removing one of the hydrogen bond donors in sphingomyelin (SM) (by modeling 3-keto-SM rather than d-erythro-SM) resulted in an unexpected compensatory increase in hydrogen bond donation by the amide proton to neighboring SM. Phyto-SM increased hydrogen-bonding by the 3-position hydroxyl, while dihydro-SM reduced donation to cholesterol. Our results not only illustrate the usefulness of all-atom simulations to reveal membrane interactions less accessible by other methods, but also strengthen our recent suggestions that lipid bilayers are finely-tuned molecular assemblies in which atomic interactions play critical roles in maintaining and regulating membrane structure and function.

Membrane Phase, Charge, and Curvature Regulate α-Synuclein Binding Dynamics.

α-Synuclein (αSyn) is an intrinsically disordered protein whose interactions with lipid membranes are central to both its physiological function and its role in synucleopathies. While membrane charge, phase, and curvature are each known to influence αSyn binding, these properties are typically examined independently, leaving their combined effects on both equilibrium and dynamic membrane association unresolved. Here, we systematically investigate how membrane phase and charge jointly regulate αSyn binding, curvature sensitivity, and exchange dynamics using fluorescence microscopy, circular dichroism spectroscopy, and fluorescence recovery after photobleaching (FRAP), complemented by coarse-grained molecular dynamics simulations. Under zwitterionic conditions, αSyn preferentially binds highly curved gel-phase membranes, driven by curvature-dependent enrichment of packing defects arising from faceted vesicle morphologies. Incorporation of anionic lipids selectively enhances binding in liquid-phase membranes while attenuating curvature-dependent partitioning in gel-phase membranes. Dynamic measurements reveal that membrane phase and charge also govern the stability of membrane-associated αSyn, with gel-phase membranes and anionic lipids promoting kinetically stabilized states. Simulations show that curvature-induced defect formation is strongly amplified in gel-phase membranes but largely insensitive to charge. These findings establish that αSyn-membrane interactions are governed by a cooperative interplay between membrane phase, curvature, and charge and highlight the importance of resolving both thermodynamic and kinetic contributions to protein-membrane binding.

The Molecular Interplay Between Lipids, Cholesterol and Membrane Hydration Layer.