Molecular mechanisms of resveratrol and EGCG in the inhibition of Aβ aggregation and disruption of Aβ protofibril: similarities and differences.

The aggregation of amyloid-β protein (Aβ) into fibrillary deposits is implicated in Alzheimer's disease (AD), and inhibiting Aβ aggregation and clearing Aβ fibrils are considered as promising strategies to treat AD. It has been reported that resveratrol (RSV) and epigallocatechin-3-gallate (EGCG), two of the most extensively studied natural polyphenols, are able to inhibit Aβ fibrillization and remodel the preformed fibrillary aggregates into amorphous, non-toxic species. However, the mechanisms by which RSV inhibits Aβ aggregation and disrupts Aβ protofibril, as well as the inhibitory/disruptive mechanistic similarities and differences between RSV and EGCG, remain mostly elusive. Herein, we performed extensive all-atom molecular dynamics (MD) simulations on Aβ dimers (the early aggregation state of Aβ) and protofibrils (the intermediate of Aβ fibril formation and elongation) in the absence/presence of RSV or EGCG molecules. Our simulations show that both RSV and EGCG can bind with Aβ monomers and inhibit the dimerization of Aβ. The binding of RSV with Aβ peptide is mostly viaπ-π stacking interactions, while the binding of EGCG with Aβ is mainly through hydrophobic, π-π stacking, and hydrogen-bonding interactions. Moreover, both RSV and EGCG disrupt the β-sheet structure and K28-A42 salt bridges, leading to a disruption of Aβ protofibril structure. RSV mainly binds with residues whose side-chains point inwards from the surface of the protofibril, while EGCG mostly binds with residues whose side-chains point outwards from the surface of the protofibril. Furthermore, RSV interacts with Aβ protofibrils mostly viaπ-π stacking interactions, while EGCG interacts with Aβ protofibrils mainly via hydrogen-bonding and hydrophobic interactions. For comparison, we also explore the effects of RSV/EGCG molecules on the aggregation inhibition and protofibril disruption of the Iowa mutant (D23N) Aβ. Our findings may pave the way for the design of more effective drug candidates as well as the utilization of cocktail therapy using RSV and EGCG for the treatment of AD.