School of Physical Science and Technology, Ningbo University, Ningbo 315211, China.
Department of Physics and Astronomy, Clemson University, Clemson, South Carolina 29634, United States.
J Chem Inf Model. 2021 Jun 28;61(6):2916-2925. doi: 10.1021/acs.jcim.1c00217. Epub 2021 May 25.
Pathological aggregation of intrinsically disordered tau protein, driven by the interactions between microtubule-binding (MTB) domains, is associated with Alzheimer's disease. The MTB domain contains either three or four repeats with sequence similarities. Compared to amyloid β, many aspects of the misfolding and aggregation mechanisms of tau are largely unknown. In this study, we systematically investigated the dynamics of monomer misfolding and dimerization of each MTB repeat using atomistic discrete molecular dynamic simulations. Our results revealed that all the four repeat monomers (R1-R4) were very dynamic, featuring frequent conformational conversion and lacking stable conformations. While R1, R2, and R4 monomers occasionally adopted partially helical conformations, R3 monomers frequently formed β-sheets. In dimerization simulations, R3 displayed the strongest aggregation propensity with high β-sheet contents, while R1 was the least prone to aggregation. The R2 and R4 dimers contained both helix and β-sheet structures. The β-sheets in R4 assemblies were dominant with β-hairpin conformation. In R2 and R3 dimers, intermolecular β-sheets were mainly driven by residues around the paired helical filament (PHF) regions. Residues around the PHF6* in R2 and PHF6 in R3 had significantly higher intermolecular contacts than other regions, suggesting that these residues play a key role in the amyloid aggregation of tau. Our results on the structural ensembles and early aggregation dynamics of each tau MTB repeat will help understand the nucleation and fibrillization of tau.
tau 蛋白的无序结构域内在的病理性聚集，是由微管结合（MTB）结构域之间的相互作用驱动的，与阿尔茨海默病有关。MTB 结构域包含三个或四个重复序列，具有相似的序列相似性。与淀粉样β蛋白相比，tau 蛋白错误折叠和聚集机制的许多方面在很大程度上尚不清楚。在这项研究中，我们使用原子离散分子动力学模拟系统地研究了每个 MTB 重复的单体错误折叠和二聚化的动力学。我们的结果表明，所有四个重复单体（R1-R4）都非常活跃，频繁发生构象转换，缺乏稳定的构象。虽然 R1、R2 和 R4 单体偶尔会采用部分螺旋构象，但 R3 单体经常形成β-折叠。在二聚化模拟中，R3 显示出最强的聚集倾向，具有较高的β-折叠含量，而 R1 则最不易聚集。R2 和 R4 二聚体包含螺旋和β-折叠结构。R4 组装体中的β-折叠以β-发夹构象为主。在 R2 和 R3 二聚体中，分子间β-折叠主要由配对螺旋丝（PHF）区域周围的残基驱动。R2 中的 PHF6*和 R3 中的 PHF6 周围的残基与其他区域相比具有显著更高的分子间接触，表明这些残基在 tau 淀粉样聚集中发挥关键作用。我们对每个 tau MTB 重复的结构集合和早期聚集动力学的研究结果将有助于理解 tau 的成核和原纤维形成。
