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Epigallocatechin Gallate Destabilizes α-Synuclein Fibril by Disrupting the E46-K80 Salt-Bridge and Inter-protofibril Interface.

Abstract：

:The accumulation and deposition of fibrillar aggregates of α-synuclein (α-syn) into Lewy bodies are the major hallmarks of Parkinson's disease (PD) for which there is no cure yet. Disrupting preformed α-syn fibrils is considered one of the rational therapeutic strategies to combat PD. Experimental studies reported that epigallocatechin gallate (EGCG), a polyphenol extracted from green tea, can disrupt α-syn fibrils into benign amorphous aggregates. However, the molecular mechanism of action is poorly understood. Herein, we performed molecular dynamics simulations on a newly released Greek-key-like α-syn fibril with or without EGCG to investigate the influence of EGCG on α-syn fibril. Our simulations show that EGCG disrupts the local β-sheet structure, E46-K80 salt-bridge crucial for the stabilization of the Greek-key-like structure, and hydrophobic interactions stabilizing the inter-protofibril interface and destabilizes the global structure of the α-syn fibril. Interaction analyses reveal that hydrophobic and hydrogen-bonding interactions between EGCG and α-syn fibrils play important roles in the destabilization of the fibril. We find that the disruption of the E46-K80 salt-bridge closely correlates with the formation of hydrogen-bonds (H-bonds) between EGCG and E46/K80. Our results provide mechanistic insights into the disruption modes of α-syn fibril by EGCG, which may pave the way for designing drug candidates targeting α-syn fibrillization to treat PD.

journal_name

ACS Chem Neurosci

journal_title

ACS chemical neuroscience

authors

Yao Y,Tang Y,Wei G

doi

10.1021/acschemneuro.0c00598

subject

Has Abstract

pub_date

2020-12-16 00:00:00

pages

4351-4361

issue

24

issn

1948-7193

journal_volume

11

pub_type

杂志文章

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