Structural Remodeling Mechanism of the Toxic Amyloid Fibrillary Mediated by Epigallocatechin-3-gallate

Numerous therapeutic agents and strategies were designed targeting the therapies of Alzheimer's disease, but many have been suspended due to their severe clinical side effects (such as encephalopathy) on patients. The attractiveness for small molecules with good biocompatibility is therefore restarted. Epigallocatechin-3gallate (EGCG), extracted from green tea, is expected to be a promising small-molecule drug candidate, which can remodel the structure of preformed ss-sheet-rich oligomers/fibrils and then effectively interfere with neurodegenerative processes. However, as the structure of nonfibrillary aggregates cannot be directly characterized, the atomic details of the underlying inhibitory and destructive mechanisms still remain elusive to date. Here, all-atom molecular dynamics simulations and experiments were carried out to elucidate the EGCG-induced remodeling mechanism of amyloid ss (A ss) fibrils. We showed that EGCG was indeed an effective A ss fibril inhibitor. EGCG was capable of mediating conformational rearrangement of A ss 1- 42 fibrils (from a ss-sheet to a random coil structure) and triggering the disintegration of fibrils in a dose-dependent manner. EGCG redirected the structure of A ss by breaking the ss-sheet structure and hydrogen bonds between peptide chains within the A ss protofibrils, especially the parallel ss-strand (L(17)VFFAEDVGS(26)). Moreover, reduced solvent exposure and multisite binding patterns all tended to induce the conformation conversion of A ss(17- 42) pentameric protofibrils, destroying pre-formed fibrils and inhibiting continued fibril growth. Detailed data analysis revealed that structural features of EGCG with abundant benzene ring and phenolic hydroxyl moieties preferentially interact with the parallel ss-strands to effectually hinder the interaction of the interpeptide chain and the growth of the ordered ss-sheet structure. Furthermore, experimental studies confirmed that EGCG was able to disaggregate the preformed fibrils and alter the protein structure. This study will enable a deeper understanding of fundamental principles for design of structural-based inhibitors.

Automated summary

Epigallocatechin-3gallate (EGCG) extracted from green tea is a promising small-molecule drug candidate for Alzheimer's disease. This study used molecular dynamics simulations and experiments to investigate the mechanism of EGCG-induced remodeling of Aβ fibrils.