State Key Laboratory of Applied Organic Chemistry, and Department of Chemistry, Lanzhou University, Lanzhou, China.
School of Pharmacy, Lanzhou University, Lanzhou, China.
Chem Biol Drug Des. 2018 Jan;91(1):162-171. doi: 10.1111/cbdd.13067. Epub 2017 Aug 14.
The accumulation of intrinsically disordered α-synuclein (αS) protein that can form β-sheet-rich fibrils is linked to Parkinson's disease. (-)-Epigallocatechin-3-gallate (EGCG) is the most abundant active component in green tea and can inhibit the fibrillation of αS. The elucidation of this molecular mechanism will be helpful to understand the inhibition mechanism of EGCG to the fibrillation of αS and also to find more potential small molecules that can inhibit the aggregation of αS. In this work, to study the influence of EGCG on the structure of β-sheet-rich fibrils of αS and identification of their possible binding mode, molecular dynamics simulations of pentamer and decamer aggregates of αS in complex with EGCG were performed. The obtained results indicate that EGCG can remodel the αS fibrils and break the initial ordered pattern by reducing the β-sheet content. EGCG can also break the Greek conformation of αS by the disappeared H-bond in the secondary structure of turn. The results from our study can not only reveal the specific interaction between EGCG and β-sheet-rich fibrils of αS, but also provide the useful guidance for the discovery of other potential inhibitors.
α-突触核蛋白（αS）的无序结构积累，可形成富含β-折叠的纤维，与帕金森病有关。表没食子儿茶素没食子酸酯（EGCG）是绿茶中最丰富的活性成分，可抑制αS 的纤维形成。阐明这一分子机制将有助于理解 EGCG 抑制 αS 纤维形成的机制，并发现更多潜在的可抑制 αS 聚集的小分子。在这项工作中，为了研究 EGCG 对富含β-折叠的 αS 纤维结构的影响并确定其可能的结合模式，对 EGCG 与五聚体和十聚体 αS 聚集体的分子动力学模拟进行了研究。结果表明，EGCG 可以通过降低β-折叠含量来重塑 αS 纤维并破坏初始有序模式。EGCG 还可以通过破坏二级结构中的氢键使 αS 希腊构象消失。我们的研究结果不仅可以揭示 EGCG 与富含β-折叠的 αS 纤维之间的特定相互作用，还可以为发现其他潜在抑制剂提供有用的指导。
