Effects of anthocyanidins on the conformational transition of Aβ(1-42) peptide: Insights from molecular docking and molecular dynamics simulations

Recent evidence from in vitro and in vivo studies has shown that anthocyanins and anthocyanidins can reduce and inhibit the amyloid beta (Aβ) species, one of the hallmarks of Alzheimer's disease (AD). However, their inhibition mechanisms on Aβ species at molecular details remain elusive. Therefore, in the present study, molecular modelling methods were employed to investigate their inhibitory mechanisms on Aβ(1-42) peptide. The results highlighted that anthocyanidins effectively inhibited the conformational transitions of helices into beta-sheet (β-sheet) conformation within Aβ(1-42) peptide by two different mechanisms: 1) the obstruction of two terminals from coming into contact due to the binding of anthocyanidins with residues of N- and second hydrophobic core (SHC)-C-terminals, and 2) the prevention of the folding process due to the binding of anthocyanidin with the central polar (Asp23 and Lys28) and native helix (Asp23, Lys28, and Leu34) residues. These new findings on the inhibition of β-sheet formation by targeting both N- and SHC-C-terminals, and the long-established target, D23-K28 salt bridge residues, not with the conventional central hydrophobic core (CHC) as reported in the literature, might aid in designing more potent inhibitors for AD treatment.