Misfolding of the cellular prion protein (PrP^C) is associated with lethal neurodegeneration. PrP^C consists of a flexible tail (residues 23–123) and a globular domain (residues 124–231) whose C-terminal end is anchored to the cell membrane. The neurotoxic antibody POM1 and the innocuous antibody POM6 recognize the globular domain. Experimental evidence indicates that POM1 binding to PrP^C emulates the influence on PrP^C of the misfolded prion protein (PrP^Sc) while the binding of POM6 has the opposite biological response. Little is known about the potential interactions between flexible tail, globular domain, and the membrane. Here, we used atomistic simulations to investigate how these interactions are modulated by the binding of the Fab fragments of POM1 and POM6 to PrP^C and by interstitial sequence truncations to the flexible tail. The simulations show that the binding of the antibodies restricts the range of orientations of the globular domain with respect to the membrane and decreases the distance between tail and membrane. Five of the six sequence truncations influence only marginally this distance and the contact patterns between tail and globular domain. The only exception is a truncation coupled to a charge inversion mutation of four N-terminal residues, which increases the distance of the flexible tail from the membrane. The interactions of the flexible tail and globular domain are modulated differently by the two antibodies.

细胞朊病毒蛋白（PrP ^C）的错误折叠与致命的神经变性有关。PrP ^C由柔性尾部（残基 23-123）和球状结构域（残基 124-231）组成，其 C 末端锚定在细胞膜上。神经毒性抗体 POM1 和无害抗体 POM6 识别球状结构域。实验证据表明，POM1 与 PrP ^{C 的}结合模拟了错误折叠的朊病毒蛋白 (PrP ^{Sc ) 对 PrP C}的影响，而 POM6 的结合则具有相反的生物反应。关于柔性尾部、球状结构域和膜之间的潜在相互作用知之甚少。^{在这里，我们使用原子模拟来研究如何通过 POM1 和 POM6 的 Fab 片段与 PrP C}的结合以及通过间隙序列截断与柔性尾部来调节这些相互作用。模拟表明，抗体的结合限制了球状结构域相对于膜的方向范围，并减少了尾部和膜之间的距离。六个序列截断中的五个仅略微影响该距离以及尾部和球状结构域之间的接触模式。唯一的例外是与四个 N 端残基的电荷反转突变相结合的截断，这增加了柔性尾部与膜的距离。两种抗体对柔性尾部和球状结构域的相互作用进行不同的调节。