Disclosing the Mechanism of Spontaneous Aggregation and Template-Induced Misfolding of the Key Hexapeptide (PHF6) of Tau Protein Based on Molecular Dynamics Simulation
Disclosing the Mechanism of Spontaneous Aggregation and Template-Induced Misfolding of the Key Hexapeptide (PHF6) of Tau Protein Based on Molecular Dynamics Simulation
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基于分子动力学模拟揭示Tau蛋白关键六肽（PHF6）自发聚集和模板诱导错误折叠机制
DOI：
10.1021/acschemneuro.9b00488
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发表时间：
2019-12-01
影响因子：
5
通讯作者：
Yao, Xiaojun
中科院分区：
文献类型：
--
作者：
Liu, Hongli;Zhong, Haiyang;Yao, Xiaojun
微管相关蛋白 tau 对于神经系统的发育和维持至关重要。 Tau 功能障碍与多种称为 tau 蛋白病的神经退行性疾病有关，其特征是由异常聚集的 tau 蛋白形成的神经原纤维缠结。研究tau蛋白的聚集机制对于阐明tau蛋白病的病因具有重要意义。 R3 的六肽 (306)VQIVYK(311) (PHF6) 已被证明在促进 tau 聚集中发挥重要作用。本研究通过在显式溶剂中进行长期全原子分子动力学模拟，研究了PHF6的自发聚集和模板诱导错误折叠的机制，并通过马尔可夫状态模型（MSM）进一步具体分析了成核早期的二聚化。我们的结果表明，PHF6 可以自发聚集形成富含 β-折叠结构的多聚体，并且多聚体中的 β-折叠更倾向于以平行方式存在。据观察，PHF6 单体可以被诱导在模板的两侧形成 β-折叠结构，但方式不同。具体来说，左侧更容易形成β-折叠结构，但延伸性较差，但在右侧，单体可以形成延伸的β-折叠结构。此外，MSM分析表明二聚体的形成主要发生在三个步骤。首先，分离的单体以随机方向相互碰撞，然后形成N端具有短β-折叠结构的二聚体；最后，β-折叠延伸形成延伸的平行β-折叠二聚体。在这些过程中，多个中间状态被识别，并且多个路径可以从无序的线圈结构形成平行的β-折叠二聚体。此外，残基1308、V309和Y310在二聚化中起着重要作用。总之，我们的研究结果从原子水平揭示了PHF6的聚集和错误折叠机制，可为合理设计有效的tau蛋白病治疗药物提供有用的理论指导。
The microtubule-associated protein tau is critical for the development and maintenance of the nervous system. Tau dysfunction is associated with a variety of neurodegenerative diseases called tauopathies, which are characterized by neurofibrillary tangles formed by abnormally aggregated tau protein. Studying the aggregation mechanism of tau protein is of great significance for elucidating the etiology of tauopathies. The hexapeptide (306)VQIVYK(311) (PHF6) of R3 has been shown to play a vital role in promoting tau aggregation. In this study, long-term all-atom molecular dynamics simulations in explicit solvent were performed to investigate the mechanisms of spontaneous aggregation and template-induced misfolding of PHF6, and the dimerization at the early stage of nucleation was further specifically analyzed by the Markov state model (MSM). Our results show that PHF6 can spontaneously aggregate to form multimers enriched with beta-sheet structure and the beta-sheets in multimers prefer to exist in a parallel way. It is observed that PHF6 monomer can be induced to form a beta-sheet structure on either side of the template but in a different way. In detail, the beta-sheet structure is easier to form on the left side but does not extend well, but on the right side, the monomer can form the extended beta-sheet structure. Furthermore, MSM analysis shows that the formation of dimer mainly occurs in three steps. First, the separated monomers collide with each other at random orientations, and then a dimer with short beta-sheet structure at the N-terminal forms; finally, beta-sheets elongate to form an extended parallel beta-sheet dimer. During these processes, multiple intermediate states are identified and multiple paths can form a parallel beta-sheet dimer from the disordered coil structure. Moreover, the residues 1308, V309, and Y310 play an essential role in the dimerization. In a word, our results uncover the aggregation and misfolding mechanism of PHF6 from the atomic level, which can provide useful theoretical guidance for rational design of effective therapeutic drugs against tauopathies.