Abstract
Amyloid-β (Aβ) is a macromolecular structure of great interest because its misfolding and aggregation, along with changes in the secondary structure, have been correlated with its toxicity in various neurodegenerative diseases. Small drug-like molecules can modulate the amyloid secondary structure and therefore have raised significant interest in applications to active and passive therapies ...
Abstract
Amyloid-β (Aβ) is a macromolecular structure of great interest because its misfolding and aggregation, along with changes in the secondary structure, have been correlated with its toxicity in various neurodegenerative diseases. Small drug-like molecules can modulate the amyloid secondary structure and therefore have raised significant interest in applications to active and passive therapies targeting amyloids. In this study, we investigate the interactions of epigallocatechin-3-gallate (EGCG), found in green tea, with Aβ polypeptides, using a combination of in vitro immuno-infrared sensor measurements, docking, molecular dynamics simulations, and ab initio calculations. We find that the interactions of EGCG are dominated by only a few residues in the fibrils, including hydrophobic π-π interactions with aromatic rings of side chains and hydrophilic interactions with the backbone of Aβ, as confirmed by extended (1-μs-long) molecular dynamics simulations. Immuno-infrared sensor data are consistent with degradation of Aβ fibril induced by EGCG and inhibition of Aβ fibril and oligomer formation, as manifested by the recovery of the amide-I band of monomeric Aβ, which is red-shifted by 26 cm−1 when compared to the amide-I band of the fibrillar form. The shift is rationalized by computations of the infrared spectra of Aβ42 model structures, suggesting that the conformational change involves interchain hydrogen bonds in the amyloid fibrils that are broken upon binding of EGCG.
Altmetric