Binding of protofibrillar Aβ trimers to lipid bilayer surface enhances Aβ structural stability and causes membrane thinning

Abstract

Alzheimer’s disease (AD), a common neurodegenerative disease, is characterized by the aggregation of amyloid-β (Aβ) peptides. The interactions of Aβ with membranes cause changes in membrane morphology and ion permeation, which are responsible for its neurotoxicity and can accelerate fibril growth. However, the Aβ-lipid interactions and how these induce membrane perturbation and disruption at the atomic level and the consequences for the Aβ organization are not entirely understood. Here, we perform multiple atomistic molecular dynamics (MD) simulations on three protofibrillar Aβ9–40 trimers. Our simulations show that, regardless of the morphologies and the initial orientations of the three different protofibrillar Aβ9–40 trimers, the N-terminal β-sheet of all trimers preferentially binds to the membrane surface. The POPG lipid bilayers enhance the structural stability of protofibrillar Aβ trimers by stabilizing inter-peptide β-sheets and D23-K28 salt-bridges. The interaction causes local membrane thinning. We found that the trimer structure related to Alzheimer’s disease brain tissue (2M4J) is the most stable both in water solution and at membrane surface, and displays slightly stronger membrane perturbation capability. These results provide mechanistic insights into the membrane-enhanced structural stability of protofibrillar Aβ oligomers and the first step of Aβ-induced membrane disruption at the atomic level.

The Toxicity and Polymorphism of β-Amyloid Oligomers

“…High-MW aggregates elevate the intracellular Ca 2+ level by increasing the membrane lipid peroxidation reaction and changing the membrane structure and function, resulting in the suppression of LTP and neuronal death [ 65 ]. On the other hand, after binding to the β-sheets of the N-terminal residues of Aβos, lipid bilayers stabilize the structure of Aβos and accelerate fiber formation [ 66 ]. The molecular docking results showed that the U-shaped oligomers inserted into the membrane and formed ion-permeable pores [ 67 ], which is consistent with the report that Aβ can insert into lipid bilayers and assemble into a β-barrel pore under optimized detergent micelle conditions [ 68 ].…”

Counting charges on membrane-bound peptides

“…Peptides and their interactions with biological and engineered membranes are of importance in the development of antimicrobial surfaces and therapeutics, 1 – 6 non-viral vectors, 7 – 12 layer-by-layer thin films, 13 – 15 and for understanding the progression of many neurodegenerative diseases. 16 , 17 Cell penetrating peptides containing cationic amino acids such as arginine and lysine can be used to cross cell membranes 18 and deliver compounds to the cell interior by exploiting the surface charge of biological membranes. 9 Small peptides also provide an opportunity to probe how short segments of polycations may interact with surfaces, with direct relevance to understanding how engineered nanomaterials, often manufactured with polycationic wrappings, interact with their environment.…”

Atomistic-level study of the interactions between hIAPP protofibrils and membranes: Influence of pH and lipid composition

“…Recently, Dong et al investigated systemically the adsorption dynamics, structural stability and membrane perturbation of protofibrillar Aβ trimers constructed using three different NMR-derived fibril structures, 2BEG, 2LMN and 2M4J. Their simulations showed that regardless of the morphologies and the initial orientations of the three different protofibrillar Aβ trimers, the N-terminal β-sheet of all trimers preferentially binds to the membrane surface [44]. …”