Unraveling the molecular mechanism of prion H2 C-terminus misfolding by metadynamics simulations.
Unraveling the molecular mechanism of prion H2 C-terminus misfolding by metadynamics simulations.
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DOI：
10.1021/acschemneuro.9b00679
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发表时间：
2020-02
影响因子：
5
通讯作者：
Zerong Xu;Hongli Liu;Shuo Wang;Qianqian Zhang;X. Yao;Shuangyan Zhou;Huanxiang Liu
中科院分区：
文献类型：
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作者：
Zerong Xu;Hongli Liu;Shuo Wang;Qianqian Zhang;X. Yao;Shuangyan Zhou;Huanxiang Liu
朊病毒蛋白（PrPC）从正常细胞形态向致病性瘙痒病形态（PrPSc）的构象转变被认为是朊病毒病发生的关键事件。此外，H2 C端被广泛认为是PrP构象转变的重要位点，可作为探讨PrP错误折叠机制的重要区域。因此，为了研究PrP的错误折叠机制，通过聚焦于PrP的H2 C-末端进行500 ns的良好回火的代谢模拟。为了比较，共设计了三个系统，包括中性和酸性条件下的PrP以及H187 R突变体。从代谢动力学模拟得到的自由能表面（FES）显示，酸性条件和H187 R突变可以促进PrP的错误折叠，通过降低构象转变的自由能垒，形成能量稳定的构象状态。针对H2 C端的进一步分析表明，由于187残基在酸性和H187 R体系中正电荷的增加，187残基与R136/R156之间的静电排斥作用大大增强，破坏了H2 C端周围的静电相互作用网络，使疏水核暴露于溶剂中。总之，酸性条件和H187 R突变可以加速PrP错误折叠主要是通过形成具有较低自由能垒的更能量稳定的亚稳态构象，并且涉及残基187的静电网络破坏驱动H2 C-末端的初始错误折叠。本研究定量分析了H2 C端在PrP错误折叠过程中的相关功能，为今后H2 C端介导的药物设计提供了指导。
Conformational transition from the normal cellular form of prion protein (PrPC) to pathogenic "Scrapie" form (PrPSc) is considered to be a key event to the occurrence of prion disease. Additionally, the H2 C-terminus is extensively considered to be a vital site for PrP conformational transition, which can be used as an important region to explore the potential mechanism of PrP misfolding. Therefore, to study the misfolding mechanism of PrP, 500 ns well-tempered metadynamics simulations were performed by focusing on the H2 C-terminus of PrP. For comparison, three systems were designed in total, including PrP in neutral and acidic conditions as well as H187R mutant. The resulting free energy surfaces (FESs) obtained from metadynamics simulations reveal that acidic condition and H187R mutation can facilitate PrP misfolding by decreasing free energy barriers for conformational transition and forming energy stable conformational states. Further analyses aiming at H2 C-terminus show that due to the increase of positive charge of residue 187 in both acidic and H187R systems, the electrostatic repulsion of residue 187 and R136/R156 increases largely, which disrupts the electrostatic interaction network around H2 C-terminus and makes the hydrophobic core exposed to the solvent. Taken together, the acidic condition and H187R mutation can accelerate PrP misfolding mainly by forming more energy stable metastable conformations with lower free energy barriers, and electrostatic network disruption involving residue 187 drives the initial misfolding of H2 C-terminus. This study provides a quantitative insight into the related function of the H2 C-terminus in the PrP misfolding process, which may guide the H2 C-terminus mediated drug design in the future.