The inhibitory mechanisms of PGG, a natural polyphenol enriched with gallate moieties, against Aβ42 amyloid aggregation: A unified experimental and molecular dynamics simulation study.

Alzheimer's disease currently affects over 44 million individuals worldwide. Inhibiting Aβ aggregation and preventing the formation of toxic Aβ oligomers were regarded as promising therapeutic approaches. Experimental studies demonstrated that 1,2,3,4,6-Penta-O-galloyl-β-d-glucopyranose (PGG), a natural polyphenol enriched with gallate moieties, significantly inhibited Aβ42 oligomerization and amyloid formation both in vitro and in vivo, underscoring its potential as a promising lead compound for AD therapy. Nevertheless, the detailed molecular mechanisms remained mostly unknown. Herein, we employed relevant biophysical methods to investigate the inhibitory effects of PGG and its analogs on Aβ42 amyloid aggregation, particularly on oligomer formation, providing direct evidence for the influence of gallate moiety number on its inhibitory activity against Aβ42 amyloid aggregation. Moreover, we further conducted 1500 ns all-atom MD simulations to explore how PGG inhibited Aβ amyloid aggregation. The simulations revealed that PGG promoted the adoption of a more loosely packed conformation of the Aβ42 dimer, and completely prevented the helix-to-β-sheet conformational change. Moreover, the binding of PGG molecules to the Aβ42 dimer resulted in the disruption of the inter-peptide interactions, and dramatically weakened the intra-peptide contacts. We observed that, apart from the usual hydrogen bonds and hydrophobic interactions, both π-π and cation-π interactions were also detected between specific residues of the Aβ42 dimer and the gallate moieties of PGG. We believed that these results might provide novel insights into the mechanisms underlying the inhibitory effects of PGG on Aβ42 amyloid aggregation and further support its potential for AD prevention and treatment.