Molecular chirality mediated amyloid formation on phospholipid surfaces

One of the neuropathological features of Alzheimer's disease (AD) is the misfolding of amyloid-beta to form amyloid aggregates, a process highly associated with biological membranes. However, how molecular chirality affects the amyloid formation on phospholipid surfaces has seldom been reported. Here,l- andd-aspartic acid-modified 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine (l-/d-Asp-DPPE) is synthesized to construct chiral phospholipid bilayers. We discover that thel-Asp-DPPE liposomes slightly inhibit the A beta(1-40) nucleation process but cannot affect the oligomer elongation process. By contrast, thed-Asp-DPPE liposomes strongly inhibit both nucleation and elongation of the peptide. Notably,l- andd-Asp-DPPE liposomes not only have good biocompatibility but can also rescue A beta(1-40)-aggregation induced cytotoxicity with significant chiral discrimination, in which the cell viability is higher in the presence ofd-Asp-DPPE liposomes. Mechanism analysis and molecular dynamics simulation clearly demonstrate that differential electrostatic interactions of Lys16 in A beta(1-40) withl- ord-Asp on the phospholipid contribute to the remarkable chiral discrimination. This study provides a deeper understanding of the crucial amyloidosis process from the perspective of the chiral interface and reveals that the convergence ofd-amino acids with the liposomes might be a feasible route for AD prevention.