Structure, Orientation, and Surface Interaction of Alzheimer Amyloid-β Peptides on the Graphite

The misfolding and aggregation of amyloid-beta (A beta) peptides into amyloid fibrils in solution and on the cell membrane has been linked to the pathogenesis of Alzheimer's disease. Although it is well-known that the presence of different surfaces can accelerate the aggregation of A beta peptides into fibrils, surface-induced conformation, orientation, aggregation, and adsorption of A beta peptides have not been well understood at the atomic level. Here, we perform all-atom explicit-water molecular dynamics (MD) simulations to study the orientation change, conformational dynamics, surface interaction of small A beta aggregates with different sizes (monomer to tetramer), and conformations (alpha-helix and beta-hairpin) upon adsorption on the graphite surface, in comparison with A beta structures in bulk solution. Simulation results show that hydrophobic graphite induces the quick adsorption of A beta peptides regardless of their initial conformations and sizes. Upon the adsorption, A beta prefers to adopt random structure for monomers and to remain beta-rich-structure for small oligomers, but not helical structures. More importantly, due to the amphiphilic sequence of A beta and the hydrophobic nature of graphite, hydrophobic C-terminal residues of higher-order A beta oligomers appear to have preferential interactions with the graphite surface for facilitating A beta fibril formation and fibril growth. In combination of atomic force microscopy (AFM) images and MD simulation results, a postulated mechanism is proposed to describe the structure and kinetics of A beta aggregation from aqueous solution to the graphite surface, providing parallel insights into A beta aggregation on biological cell membranes.