Exploring the binding kinetics and behaviors of self-aggregated beta-amyloid oligomers to phase-separated lipid rafts with or without ganglioside-clusters.

Lipid binding kinetics and energetics of self-aggregated and disordered beta-amyloid oligomers of various sizes, from solution to lipid raft surfaces, were investigated using MD simulations. Our systems include small (monomers to tetramers) and larger (octamers and dodecamers) oligomers. Our lipid rafts contain saturated and unsaturated phosphatidylcholine (PC), cholesterol, and with or without asymmetrically distributed monosialotetrahexosylganglioside (GM1). All rafts exhibited dynamic and structurally diversified domains including liquid-ordered (Lo), liquid-disordered (Ld), and interfacial Lod domains. For rafts without GM1, all oligomers bound to the Lod domain. For GM1-containing rafts, all small oligomers and most larger oligomers bound specifically to the GM1-clusters embedded in the Lo domain. Lipid-protein binding energies followed an order of GM1 >> unsaturated PC > saturated PC > cholesterol for all rafts. In addition, protein-induced membrane structural disruption increased progressively with the size of the oligomer for the annular lipids surrounding the membrane-bound protein in non-GM1-containing rafts. We propose that the tight binding of beta-amyloid oligomers to the GM1-clusters and the structural perturbation of lipids surrounding the membrane-bound proteins at the Lod domain are early molecular events of the beta-amyloid aggregation process on neuronal membrane surfaces that trigger the onset of Alzheimer's.