School of Pharmacy , Lanzhou University , Lanzhou 730000 , China.
Chongqing Key Laboratory on Big Data for Bio Intelligence , Chongqing University of Posts and Telecommunications , Chongqing 400065 , China.
ACS Chem Neurosci. 2019 Jun 19;10(6):2718-2729. doi: 10.1021/acschemneuro.8b00582. Epub 2019 May 22.
The conformational transition of prion protein (PrP) from a native form PrP to a pathological isoform PrP is 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.
朊病毒蛋白（PrP）从天然构象向病理性构象的构象转变是许多人类和动物朊病毒病的主要原因。因此，了解 PrP 构象转变的分子基础对于揭示 PrP 相关疾病的病因将具有重要价值。在这里，为了探索酸性条件下 PrP 潜在的错误折叠机制，已知该条件可促进 PrP 错误折叠并引发其聚集，我们进行了常规和加速分子动力学（MD）模拟，并结合了马尔可夫状态模型（MSM）分析。常规 MD 模拟表明，在酸性 pH 值下，PrP 的球状结构域部分展开，特别是 α2 C 末端。MSM 获得的关键宏状态的结构分析表明，α2 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 也可能通过远离 α2-α3 亚结构域参与 pH 诱导的结构转换。值得注意的是，关键亚稳态的动力网络分析表明，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，使这些结构域，特别是 α2 C 末端，变得不稳定并开始错误折叠。因此，α2 C 末端在 PrP 错误折叠过程中起关键作用，并可作为药物作用的潜在靶点。总的来说，我们的研究结果可以加深对与 PrP 相关的发病机制的理解，并为未来的药物发现提供有用的指导。
