Distinct disruption mechanisms of green tea extracts EGC and EGCG on ATTR fibrils: a molecular simulation study

Abstract

Transthyretin amyloidosis cardiomyopathy (ATTR-CM) is a life-threatening disease caused by misfolded TTR amyloid fibril deposition. Disaggregating these fibrils is a promising treatment method. While epigallocatechin-3-gallate (EGCG) has shown efficacy in disrupting ATTR aggregates, its molecular mechanism and comparison with related catechins remain unclear. Herein, we have investigated the detailed interactions between two most common catechins (EGCG and EGC (lacking an extra gallic acid ester group compared to EGCG)) and ATTR fibrils by performing microsecond molecular dynamic simulations. Our results indicate that both EGC and EGCG can disrupt the stability of ATTR fibrils and reduce their β-sheet contents, especially in the cavity region (residue 57–84). The cavity is mainly stabilized by L58–I84, T59–A81, E61–K80 and E66–K70 interactions. EGCG predominantly targets L58–I84, opening the cavity entrance and destabilizing other interactions. EGC binds to V65, pulling the G57–Y69 region outward to weaken critical salt bridges (E61–K80 and E66–K70). Owing to the presence of an additional gallic acid ester group, EGCG exhibits stronger hydrophobicity and a more three-dimensional structure compared to EGC, and therefore a stronger destructive effect on ATTR fibrils. Our simulation results provide atomic-level insights into the different mechanisms by which EGC and EGCG disrupt ATTR fibrils, which could be useful for designing amyloid inhibitors.