Authors:
M.H. Dehabadi; A. Caflisch; I.M. Ilie; R. Firouzi

Journal: J. Phys. Chem. B
Year: 2022
Volume: 126
Issue: 39
Pages: 7627-7637
DOI: 10.1021/acs.jpcb.2c05846
Type of Publication: Journal Article

Keywords:
Alzheimer Disease; Amyloid beta-Peptides; Benzaldehydes; Curcumin; Humans; Molecular Dynamics Simulation; Peptide Fragments

Abstract:

Amyloid-β (Aβ) dimers are the smallest toxic species along the amyloid-aggregation pathway and among the most populated oligomeric accumulations present in the brain affected by Alzheimer's disease (AD). A proposed therapeutic strategy to avoid the aggregation of Aβ into higher-order structures is to develop molecules that inhibit the early stages of aggregation, i.e., dimerization. Under physiological conditions, the Aβ dimer is highly dynamic and does not attain a single well-defined structure but is rather characterized by an ensemble of conformations. In a recent study, a highly heterogeneous library of conformers of the Aβ dimer was generated by an efficient sampling method with constraints based on ion mobility mass spectrometry data. Here, we make use of the Aβ dimer library to study the interaction with two curcumin degradation products, ferulic aldehyde and vanillin, by molecular dynamics (MD) simulations. Ensemble docking and MD simulations are used to provide atomistic detail of the interactions between the curcumin degradation products and the Aβ dimer. The simulations show that the aromatic residues of Aβ, and in particular FF, interact with ferulic aldehyde and vanillin through π-π stacking. The binding of these small molecules induces significant changes on the KLVFF region.