Molecular Mechanism of Cyanidin-3-O-Glucoside Disassembling Aβ Fibril In Silico

The deposition of beta-amyloid (A beta) in the brain leads to neurotoxic effects and subsequent Alzheimer's disease (AD). While AD is becoming more and more prevalent in modern society, therapeutic efforts targeting A beta could be a promising solution. Currently, two natural products are reported to disintegrate preformed A beta fibril in vitro. Meanwhile, the chemical driving force behind this phenomenon remains unknown. Taking cyanidin-3-O-glucoside (Cy-3G) as an example, here we studied its interaction with different A beta polymorphs in silico. Negative charges on different A beta polymorphs draw the interaction with the flavylium cation on Cy-3G. Our results show that A beta in a single peptide form in solution exposed more hydrophobic solvent accessible surface area than its fibril structure (per protomer), and Cy-3G interacts more intensively with the single peptide form than fibril as indicated by more hydrogen bonding formed and more amino acid residues involved in their hydrophobic interactions. Thus, the single A beta peptide aggregation into fibril and fibril dissociation into single peptide equilibrium could be disturbed by the preferential binding of Cy-3G to the monomeric A beta peptide, which leads to the disassembly of the pathogenic A beta fibril. This study offers a novel perspective of Cy-3G alleviated AD syndrome beyond its dogmatic antioxidant activity.