Computational Insights Into the Inhibition Mechanism of Proanthocyanidin B2 on Tau Hexapeptide (PHF6) Oligomer.
Computational Insights Into the Inhibition Mechanism of Proanthocyanidin B2 on Tau Hexapeptide (PHF6) Oligomer.
复制标题
DOI：
10.3389/fchem.2021.666043
复制
发表时间：
2021
影响因子：
5.5
通讯作者：
Liu H
中科院分区：
文献类型：
--
作者：
Li Q;Xiong C;Liu H;Ge H;Yao X;Liu H
从Tau形成淀粉样蛋白原纤维是阿尔茨海默病（AD）的关键致病特征。干扰Tau聚集体的形成被认为是治疗AD的一种有前景的策略。最近，天然产物原花青素B2（PB 2）被证实不仅抑制Tau聚集，而且使Tau原纤维解聚。为了探索PB 2对Tau原纤维的抑制机制，为药物设计和发现提供有用的信息，我们对有序Tau六肽PHF 6寡聚体在PB 2存在和不存在下进行了全原子分子动力学模拟。结果表明，PB 2可以使PHF 6寡聚体由β-折叠结构转变为无序结构。聚类分析和结合自由能计算表明S3位点是最有潜力的结合位点。在S3位点，通过疏水和氢键作用，残基V309、Y310和K311是与PB 2结合所必需的，尤其是K311。本研究揭示了PB 2抑制PHF 6聚集的分子机制，为开发Tau聚集抑制剂提供了有价值的信息。
The formation of amyloid fibrils from Tau is a key pathogenic feature of Alzheimer’s disease (AD). To disturb the formation of Tau aggregates is considered as a promising therapeutic strategy for AD. Recently, a natural product proanthocyanidin B2 (PB2) was confirmed to not only inhibit Tau aggregation, but also disaggregate Tau fibrils. Herein, to explore the inhibition mechanism of PB2 against Tau fibril and to provide the useful information for drug design and discovery, all-atom molecular dynamics simulations were carried out for the ordered Tau hexapeptide PHF6 oligomer in the presence and absence of PB2. The obtained result shows that PB2 can transform PHF6 oligomer from the ordered β-sheet structure into disordered one. Moreover, the clustering analysis and binding free energy calculations identify that S3 site is the most potential binding site. At S3 site, by hydrophobic and hydrogen bond interactions, the residues V309, Y310 and K311 are essential for binding with PB2, especially K311. In a word, our study reveals the molecular mechanism of PB2 inhibiting PHF6 aggregation and it will provide some valuable information for the development of Tau aggregation inhibitors.
登录
查看更多内容
影响因子：
9.8
作者：
Landau M;Sawaya MR;Faull KF;Laganowsky A;Jiang L;Sievers SA;Liu J;Barrio JR;Eisenberg D
通讯作者：
Eisenberg D
影响因子：
14
作者：
通讯作者：
--
影响因子：
4.8
作者：
Goux, WJ;Kopplin, L;Kirschner, DA
通讯作者：
Kirschner, DA
DOI：
10.1073/pnas.121119298
发表时间：
2001-06-05
影响因子：
11.1
作者：
Alonso, AD;Zaidi, T;Iqbal, K
通讯作者：
Iqbal, K
DOI：
10.1016/j.bbrc.2007.03.056
发表时间：
2007-06-22
影响因子：
3.1
作者：
Crowe, Alex;Ballatore, Carlo;Lee, Virginia M. -Y.
通讯作者：
Lee, Virginia M. -Y.