Impact of Au144 metal clusters on the structural and inhibitory mechanism of Aβ42 peptide: A theoretical approach

Abstract

One of the main causes for Alzheimer disease is the abnormal self-assembly of the amyloid-beta (Aβ) peptide, which in turn forms a toxic β-rich aggregation. A recent study suggests that gold nanoparticles (AuNPs) can inhibit the Aβ aggregation. Nevertheless, the effects of AuNPs on Aβ peptide system are still ambiguous and needs exploration that is more detailed. Molecular dynamics simulations have been carried out to investigate the aggregation mechanism of Aβ₄₂ peptide for 500 ns. During simulation, C-terminus regions of Met 35-Ala42 residues exhibits β-sheet conformations. Meanwhile, the Au₁₄₄MC coordination induces substantial α-helical character, both α-helix and 3₁₀-helix structure at 0-500ns, in the region of Asp1-Arg5 and Val36-Ile41 residues. The Au₁₄₄MC strongly coordinates with Asp1, Ala2, Glu3, Phe4, Asp7, Tyr10 and Gln15 residues that plays the significant effects to loss the β-sheet geometry in the N-terminal region and it converted into random α-helix, turn and bend conformation. On comparing the RMSF of the Aβ₄₂ peptide and Aβ₄₂-Au₁₄₄MC complex shows that the coordination of Au₁₄₄MC results in greater rigidity of the Aβ₄₂ peptide backbone regions with exemptions for the Asp1, Ala2, Glu3, Leu34, Ile41 and Ala42 residues due to the strong binding between the metal cluster and the CHC (Leu17-Ala21) region. The structural stability of the Aβ₄₂ peptide and Aβ₄₂-Au₁₄₄MC complex is enhanced by the several intermolecular and intramolecular interactions and it was visibly revealed in the H-bond. From the above results, it is very evident that the Au₁₄₄MC can be used as inhibitor agent for the oligomerization of Aβ₄₂.

Keywords: Aggregation; Alzheimer disease; Inhibitors; Metal cluster; Molecular dynamics simulation.