Conformational transition from the normal cellular form of prion protein (PrPC) to the pathogenic "scrapie" form (PrPSc) is considered to be a key event in the occurrence of prion disease. Additionally, the H2 C-terminus is widely 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 conditions and H187R mutation can facilitate PrP misfolding by decreasing free energy barriers for conformational transition and forming energy stable conformational states. Further analyses aimed at H2 C-terminus show that due to the increase of positive charge on residue 187 in both acidic and H187R systems, the electrostatic repulsion of residue 187 and R136/R156 increases greatly, which disrupts the electrostatic interaction network around H2 C-terminus and exposes the hydrophobic core to the solvent. Taken together, acidic conditions and H187R mutation can accelerate PrP misfolding mainly by forming more energetically 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 quantitative insight into the related function of the H2 C-terminus in the PrP misfolding process, which may guide H2 C-terminus mediated drug design in the future.

中文翻译：

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通过元动力学模拟揭示Pri病毒H2 C末端错折叠的分子机理。

从正常细胞形式的病毒蛋白（PrPC）到病原性“刮rap”形式（PrPSc）的构象转变被认为是病毒疾病发生的关键事件。此外，H2 C端被广泛认为是PrP构象转变的重要位点，可以用作探讨PrP错折叠潜在机制的重要区域。因此，为了研究PrP的错误折叠机制，通过关注PrP的H2 C末端进行了500 ns合理的元动力学模拟。为了进行比较，总共设计了三个系统，包括中性和酸性条件下的PrP以及H187R突变体。从元动力学模拟中获得的自由能表面（FES）显示，酸性条件和H187R突变可通过减少构象转变的自由能垒并形成能量稳定的构象态来促进PrP错折叠。针对H2 C末端的进一步分析表明，由于酸性和H187R系统中残基187上正电荷的增加，残基187和R136 / R156的静电排斥力大大增加，这破坏了H2 C-周围的静电相互作用网络。末端，并使疏水核暴露于溶剂。总之，酸性条件和H187R突变可以加速PrP错折叠，主要是通过形成能量更稳定且具有较低自由能垒的亚稳构象，涉及残留物187的静电网络破坏驱动了H2 C末端的初始错折叠。这项研究提供定量了解PrP错折叠过程中H2末端的相关功能，这可能在将来指导H2 C末端介导的药物设计。