A coarse-grained molecular dynamics investigation on spontaneous binding of Aβ1-40 fibrils with cholesterol-mixed DPPC bilayers

Alzheimer's 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. Although multiple ex-perimental 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 mu 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.(c) 2023 The Authors. Published by Elsevier B.V. on behalf of Research Network of Computational and Structural Biotechnology. This is an open access article under the CC BY-NC-ND license (http://creative-commons.org/licenses/by-nc-nd/4.0/).

Automated summary

Alzheimer's disease, characterized by the misfolding and aggregation of amyloid-beta (A beta) peptides, remains poorly understood in terms of its molecular mechanism of interaction with cell membranes. In this study, simulations were conducted to investigate the interaction between A beta 1-40 fibrils and different bilayers composed of DPPC and cholesterol. The results show the involvement of hydrophobic amino acid clusters, lysine residues, and C-terminal hydrophobic residues in the binding process. Furthermore, the data suggest that the binding affinity of A beta 1-40 fibrils to the membrane increases with the presence of cholesterol. These findings provide insights into potential target regions for the development of inhibitors against A beta oligomer/fibril-membrane interaction.