Inhibition of Aβ_16-22 Peptide Aggregation by Small Molecules and Their Permeation through POPC Lipid Bilayer: Insight from Molecular Dynamics Simulation Study.

Alzheimer's Disease is a rapidly progressing irreversible neurodegenerative disorder characterized by neuronal cell deterioration that endangers human health. With its proper therapeutic treatment being unavailable, several research groups throughout the world are involved in designing efficient drug molecules. However, the elusive mechanism of action of the drugs as well as their debilitating side effects pose major challenges in this regard. In the present article, we investigated the inhibitory effect of an indanone-carbamate-based molecule on Aβ_16-22 peptide aggregation by employing a series of all-atom molecular dynamics simulation study. To gain explicit insights, we studied the role of inhibitor molecules on the disruption of highly arranged β-sheet of peptides by various types of analyses such as structural analysis, Cα-Cα-atom distance, residue-wise contact map, and solvent accessible surface area. The results obtained from various analyses revealed that the inhibitor molecules interacted with Aβ_16-22 peptides to destabilize its arranged β-sheet conformer via hydrophobic interaction. To further comprehend the effect of inhibitors on amyloid aggregation, we also determined interaction energy, hydration number, radial distribution function, hydrogen bonding, and potential of mean forces. In addition, the permeability of the inhibitors through model POPC lipid bilayer via passive diffusion was also analyzed. Our study is noteworthy in that it elucidates the strong interaction between inhibitors and the central hydrophobic core of peptides comprising aromatic phenylalanine residues, as well as the passive translocation of inhibitors across POPC lipid bilayers.