Oligomerization Mechanism of Amyloid-β Peptides at Hydrophobic Interfaces Revealed by Molecular Dynamics Simulations

Molecular dynamics simulations of Amyloid-β (Aβ) peptides in water were conducted to calculate the free energy profiles of their dissociation in bulk water and at a hydrophobic interface, as well as their transfer from the bulk to the interface, in order to discuss the thermodynamic cycle of oligomerization. The air/water interface was introduced as a typical hydrophobic interface, and the free energy associated with the process in which two Aβ monomers associate to form a dimer in bulk water, either directly or via the interface, was analyzed. The results show that the Aβ₄₂ monomer is stabilized at the interface by 6.9 kcal/mol, while the dimer and trimer become progressively less stable at the interface. This indicates that a hydrophobic interface can serve as a catalytic reaction field for Aβ oligomerization. Additionally, the model dependence of Aβ (Aβ₄₂, Aβ₄₀, Aβ_17-42, Aβ_15-23) on the free energy profile from the bulk to the interface, as well as the orientational structures of the Aβ₄₂ monomer, dimer, and trimer near the interface, were also discussed.