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

ABSTRACT

Alzheimer's disease, a common neurodegenerative disease, is characterized by the aggregation of amyloid-ß (Aß) peptides. The interactions of Aß with membranes cause changes in membrane morphology and ion permeation, which are responsible for its neurotoxicity and can accelerate fibril growth. However, the Aß-lipid interactions and how these induce membrane perturbation and disruption at the atomic level and the consequences for the Aß organization are not entirely understood. Here, we perform multiple atomistic molecular dynamics simulations on three protofibrillar Aß9-40 trimers. Our simulations show that, regardless of the morphologies and the initial orientations of the three different protofibrillar Aß9-40 trimers, the N-terminal ß-sheet of all trimers preferentially binds to the membrane surface. The POPG lipid bilayers enhance the structural stability of protofibrillar Aß trimers by stabilizing inter-peptide ß-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 () 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 Aß oligomers and the first step of Aß-induced membrane disruption at the atomic level.