pH-Induced Misfolding Mechanism of Prion Protein: Insights from Microsecond-Accelerated Molecular Dynamics Simulations
pH-Induced Misfolding Mechanism of Prion Protein: Insights from Microsecond-Accelerated Molecular Dynamics Simulations
复制标题
pH 诱导的朊病毒蛋白错误折叠机制：微秒加速分子动力学模拟的见解
DOI：
10.1021/acschemneuro.8b00582
复制
发表时间：
2019
影响因子：
5
通讯作者：
Liu Huanxiang
中科院分区：
文献类型：
--
作者：
Zhou Shuangyan;Shi Danfeng;Liu Xuewei;Yao Xiaojun;Da Lin-Tai;Liu Huanxiang
Prion蛋白(PrP)从天然PrPc到病理PrPcc的构象转变是人类和动物许多PrP疾病的主要原因。因此，了解PrP构象转换的分子基础对于揭示PrP相关疾病的病因学具有重要意义。在这里，为了探索PrP在酸性条件下可能的错误折叠机制，即促进PrP错误折叠并引发其聚集，进行了常规和加速分子动力学(MD)模拟并结合马尔可夫状态模型(MSM)分析。常规的分子动力学模拟表明，在酸性pH条件下，PrP的球状结构域部分展开，特别是α2 C末端。对MSM获得的关键宏观状态的结构分析表明，α2的C末端和β2-α2环可能是pH诱导的PrP错误折叠的重要部位。同时，α1也可能通过离开α2-α3亚区参与pH诱导的结构转换。值得注意的是，对关键亚稳态的动力学网络分析表明，质子化的H187削弱了α2 C-末端、α1-β2环和α2-α3环之间的相互作用，导致这些结构域，特别是α2 C-末端变得不稳定，并开始错误折叠。因此，PrP2C末端在α错误折叠过程中起着关键作用，是药物靶向的潜在靶点。总之，我们的发现可以加深对PrP相关发病机制的理解，并为未来的药物开发提供有益的指导。
The conformational transition of prion protein (PrP) from a native form PrPCto a pathological isoform PrPScis the main cause of a number of prion diseases in human and animals. Thus, understanding the molecular basis of conformational transition of PrP will be valuable for unveiling the etiology of PrP-related diseases. Here, to explore the potential misfolding mechanism of PrP under the acidic condition, which is known to promote PrP misfolding and trigger its aggregation, the conventional and accelerated molecular dynamics (MD) simulations combined with the Markov state model (MSM) analysis were performed. The conventional MD simulations reveal that, at an acidic pH, the globular domain of PrP is partially unfolded, particularly for the α2 C-terminus. Structural analysis of the key macrostates obtained by MSM indicates that the α2 C-terminus and the β2-α2 loop may serve as important sites for the pH-induced PrP misfolding. Meanwhile, the α1 may also participate in the pH-induced structural conversion by moving away from the α2-α3 subdomain. Notably, dynamical network analysis of the key metastable states indicates that the protonated H187 weakens the interactions between the α2 C-terminus, α1-β2 loop, and α2-α3 loop, leading these domains, especially the α2 C-terminus, to become unstable and to begin to misfold. Therefore, the α2 C-terminus plays a key role in the PrP misfolding process and serves as a potential site for drug targeting. Overall, our findings can deepen the understanding of the pathogenesis related to PrP and provide useful guidance for the future drug discovery.