Zou Huizhen, Zhou Shuangyan
Chongqing Key Laboratory of Big Data for Bio Intelligence, Chongqing University of Posts and Telecommunications, Chongqing 400065, China.
Int J Mol Sci. 2023 Sep 15;24(18):14146. doi: 10.3390/ijms241814146.
Transthyretin amyloidosis (ATTR) is a progressive and systemic disease caused by the misfolding and amyloid aggregation of transthyretin (TTR). Stabilizing the TTR tetramers and disrupting the formed TTR aggregation are treated as a promising strategy for the treatment of ATTR. Previous studies have reported that epigallocatechin gallate (EGCG) can participate in the whole process of TTR aggregation to prevent ATTR. However, the interaction mechanism of EGCG in this process is still obscure. In this work, we performed molecular dynamics simulations to investigate the interactions between EGCG and TTR tetramers, and between EGCG and TTR aggregates formed by the V30M mutation. The obtained results suggest that EGCG at the binding site of the V30M TTR tetramer can form stable hydrogen bonds with residues in the flexible AB-loop and EF-helix-loop, which reduces the structural mobility of these regions significantly. Additionally, the polyaromatic property of EGCG contributes to the increasement of hydrophobicity at the binding site and thus makes the tetramer difficult to be solvated and dissociated. For V30M-TTR-generated aggregates, EGCG can promote the dissociation of boundary β-strands by destroying key residue interactions of TTR aggregates. Moreover, EGCG is capable of inserting into the side-chain of residues of neighboring β-strands and disrupting the highly structured aggregates. Taken together, this study elucidates the role of EGCG in preventing TTR amyloidosis, which can provide important theoretical support for the future of drug design for ATTR.
转甲状腺素蛋白淀粉样变性病（ATTR）是一种由转甲状腺素蛋白（TTR）错误折叠和淀粉样聚集引起的进行性全身性疾病。稳定TTR四聚体并破坏已形成的TTR聚集物被视为治疗ATTR的一种有前景的策略。先前的研究报道，表没食子儿茶素没食子酸酯（EGCG）可以参与TTR聚集的全过程以预防ATTR。然而，EGCG在此过程中的相互作用机制仍不清楚。在这项工作中，我们进行了分子动力学模拟，以研究EGCG与TTR四聚体之间以及EGCG与由V30M突变形成的TTR聚集体之间的相互作用。获得的结果表明，位于V30M TTR四聚体结合位点的EGCG可以与柔性AB环和EF螺旋环中的残基形成稳定的氢键，这显著降低了这些区域的结构流动性。此外，EGCG的多芳族性质有助于增加结合位点的疏水性，从而使四聚体难以被溶剂化和解离。对于V30M-TTR产生的聚集体，EGCG可以通过破坏TTR聚集体的关键残基相互作用来促进边界β链的解离。此外，EGCG能够插入相邻β链残基的侧链并破坏高度结构化的聚集体。综上所述，本研究阐明了EGCG在预防TTR淀粉样变性病中的作用，可为未来ATTR药物设计提供重要的理论支持。
