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

Alzheimer’s disease is the most common form of dementia. Its aetiology is characterized by misfolding and aggregation of amyloid-β (Aβ) peptides into β-sheet-rich Aβ oligomers/fibrils. Whereas experimental studies have suggested that Aβ 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 8 μs-long simulations of an Aβ9-40 fibril hexamer with a cholesterol-rich DPPC bilayer. Our simulation data captures the spontaneous binding of the aqueous Aβ9-40 fibril hexamer with the membrane and shows that both the middle region and the C-terminal residues of the fibril play an important role in this event. A decrease in the number of water molecules around the Aβ9-40 fibril and an increase in the number of lipids occurs as the distance between the Aβ9-40 fibril and the membrane decreases. We also detected that binding of the Aβ9-40 fibril appears to cause the localized thinning of the membrane at the point of contact. The identified binding residues of the Aβ fibril could serve as a potential target region for the design of new inhibitors, thus opening new avenues in structure-based drug design against Aβ oligomer/fibril-membrane interaction.