A theoretical study of polymorphism in VQIVYK fibrils.
A theoretical study of polymorphism in VQIVYK fibrils.
复制标题
VQIVYK原纤维多态性的理论研究。
DOI：
10.1016/j.bpj.2021.01.032
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发表时间：
2021
影响因子：
3.4
通讯作者：
Singer,SherwinJ
中科院分区：
文献类型：
--
作者：
Yang,Jaehoon;Agnihotri,MithilaV;Huseby,CarolJ;Kuret,Jeff;Singer,SherwinJ
来自Tau蛋白的VQIVYK片段，也称为PHF6，对于Tau聚集成与神经退行性疾病相关的神经原纤维病变至关重要。VQIVYK本身形成由成对β片组成的淀粉样原纤维。因此，完整的Tau蛋白和VQIVYK原纤维已被深入研究。这些研究的中心问题是多态性，即蛋白质折叠成多种结构的能力。利用全原子分子模拟，我们生成了5个稳定的VQIVYK原纤维多晶型，利用伞形采样方法确定了它们的相对自由能，并确定了提供稳定性的侧链相互作用。两种最稳定的多晶，具有几乎相等的自由能，是由β-片的大部分疏水性的VIY“面”侧的交叉形成的。另一种稳定的多晶型是由QVK“背面”的交叉形成的。当我们对取自患病患者或体外生成的Tau细丝进行低温电子显微镜实验时，我们发现在两个最稳定的面对面和背靠背多态性中发现的侧链相互作用模式在完整蛋白质的淀粉样蛋白结构中得到了再现。因此，我们的研究表明，稳定PHF6原纤维的相互作用解释了全Tau蛋白中VQIVYK基序的淀粉样变性，并为使用VQIVYK原纤维作为设计识别或抑制淀粉样结构的分子的实验平台提供了理由。
The VQIVYK fragment from the Tau protein, also known as PHF6, is essential for aggregation of Tau into neurofibrillary lesions associated with neurodegenerative diseases. VQIVYK itself forms amyloid fibrils composed of pairedβ-sheets. Therefore, the full Tau protein and VQIVYK fibrils have been intensively investigated. A central issue in these studies is polymorphism, the ability of a protein to fold into more than one structure. Using all-atom molecular simulations, we generate five stable polymorphs of VQIVYK fibrils, establish their relative free energy with umbrella sampling methods, and identify the side chain interactions that provide stability. The two most stable polymorphs, which have nearly equal free energy, are formed by interdigitation of the mostly hydrophobic VIY "face" sides of theβ-sheets. Another stable polymorph is formed by interdigitation of the QVK "back" sides. When we turn to examine structures from cryo-electron microscopy experiments on Tau filaments taken from diseased patients or generated in vitro, we find that the pattern of side chain interactions found in the two most stable face-to-face as well as the back-to-back polymorphs are recapitulated in amyloid structures of the full protein. Thus, our studies suggest that the interactions stabilizing PHF6 fibrils explain the amyloidogenicity of the VQIVYK motif within the full Tau protein and provide justification for the use of VQIVYK fibrils as a test bed for the design of molecules that identify or inhibit amyloid structures.