A Coarse-Grained Molecular Dynamics Investigation on Spontaneous Binding of Aβ9-40 Fibril with Cholesterol-mixed DPPC Bilayer

Alzheimers disease is the most common form of dementia. Its aetiology is characterized by the misfolding and aggregation of amyloid-{beta} (A{beta}) peptides into {beta}-sheet-rich A{beta} oligomers/fibrils. Whereas experimental studies have suggested that A{beta} oligomers/fibrils interact with the cell membranes and perturb their structures and dynamics, the molecular mechanism of this interaction is still not fully understood. In the present work, we have performed a total of 120 s-long simulations to investigate the interaction between trimeric or hexameric A{beta}1-40 fibrils with either a 100% DPPC bilayer, a 70% DPPC-30% cholesterol bilayer or a 50% DPPC-50 % cholesterol bilayer. Our simulation data capture the spontaneous binding of the aqueous A{beta}1-40 fibrils with the membranes and show that the central hydrophobic amino acid cluster, the lysine residue adjacent to it and the C-terminal hydrophobic residues are all involved in the process. Moreover, our data show that while the A{beta}1-40 fibril does not bind to the 100% DPPC bilayer, its binding affinity for the membrane increases with the amount of cholesterol. Overall, our data suggest that two clusters of hydrophobic residues and one lysine help A{beta}1-40 fibrils establish stable interactions with a cholesterol-rich DPPC bilayer. These residues are likely to represent potential target regions for the design of inhibitors, thus opening new avenues in structure-based drug design against A{beta} oligomer/fibril-membrane interaction.