Molecular Insights into Aβ Oligomers and their Interactions with Lipid Bilayers

Abstract

Amyloid-β (Aβ) oligomers exhibit many distinct structural morphology at the early aggregate stage, some of which are biological relevant to the pathogenesis of Alzheimer's disease (AD). Considerably less is known about the molecular structure of Aβ oligomers and their relation to amyloid fibril formation and amyloid neurotoxicity. In this work, we develop a computational platform including conformational search, structural optimization, potential energy evaluation, and all-atom molecular dynamics (MD) to predict and model a series of atomic structures of Aβ oligomers (i.e. micelles, globulomers, triangulars, annulars, and linears) in solution. Simulation results show that although different oligomers are assembled by distinct peptide packing, the formation of these Aβ oligomers is mainly driven by hydrophobic interactions largely involving hydrophobic C-terminal residues and central hydrophobic cluster residues of L17VFFA21 at the N-terminal. We further study the interactions of Aβ oligomer with lipid bilayers to examine membrane-damaging effects by varying oligomers, lipid compositions, cholesterol contents, and position and orientation of Aβ relative to lipid bilayers. Simulation results reveal that Aβ-lipid interactions are greatly enhanced as cholesterol contents and anionic headgroups of lipids increase, highlighting electrostatic interactions are dominated force to control Aβ adsorption and orientation on the lipid bilayers. Several Aβ adsorption scenarios coupled with energetic and structural analysis will be discussed. In addition, due to the complex nature of cell membranes, we also alternatively employ self-assembled monolayers as model systems to study the aggregation and conformational changes of Aβ peptides using an integrated simulation and experimental approach. The complementary results from simulations and experiments will provide valuable insights into structural transition and underlying driving forces from aqueous solution to lipid/SAM surfaces, as well as Aβ-membrane interactions, which are essential for understanding the origin of the toxicity of Aβ oligomers.