State Key Laboratory of Microbial Metabolism, Department of Bioinformatics and Biostatistics, SJTU-Yale Joint Center for Biostatistics, National Experimental Teaching Center for Life Sciences and Biotechnology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China.
Shanghai Center for Bioinformation Technology, Shanghai, China.
Chem Biol Drug Des. 2019 Mar;93(3):242-253. doi: 10.1111/cbdd.13407. Epub 2018 Oct 17.
Microtubule-associated Tau protein plays a key role in assembling microtubule and modulating the functional organization of the neuron and developing axonal morphology, growth, and polarity. The pathological Tau can aggregate into cross-beta amyloid as one of the hallmarks for Alzheimer's disease (AD). Therefore, one of the top priorities in AD research is to figure out the structural model of Tau aggregation and to screen the inhibitors. The latest generation intrinsically disordered protein specific force field ff14IDPSFF significantly improved the distributions of heterogeneous conformations for intrinsically disordered proteins (IDPs). Here, the molecular dynamics (MD) simulations with three force fields of ff14SB, ff14IDPs, and ff14IDPSFF were employed to investigate the secondary structures transition of Tau (267-312) fragment. The results indicate that ff14IDPSFF can generate more heterogeneous conformers, and the predicted secondary structural distribution is closer to that of the experimental observation. In addition, predicted secondary chemical shifts from ff14IDPSFF are the most approach to those of experiment. Secondary structures transition kinetics for Tau(267-312) with ff14IDPSFF shows that the secondary structures were gradually transformed from α-helix to β-strand and the β-strand located at the regions of the residues 274-280 and residues 305-311. Besides, the driving force for the secondary structures transition of Tau(267-312) is mainly hydrophobic interactions which located at hexa-peptides VQIINK and VQIVYK . Secondary structure transition of Tau protein can give insight into the aggregation mechanism for AD.
微管相关 Tau 蛋白在组装微管和调节神经元的功能组织以及发育轴突形态、生长和极性方面发挥着关键作用。病理性 Tau 可以聚集形成交叉-β淀粉样蛋白，这是阿尔茨海默病 (AD) 的标志之一。因此，AD 研究的首要任务之一是确定 Tau 聚集的结构模型，并筛选抑制剂。最新一代的固有无序蛋白特定力场 ff14IDPSFF 显著改善了固有无序蛋白 (IDP) 的异质构象分布。在这里，采用 ff14SB、ff14IDPs 和 ff14IDPSFF 三种力场的分子动力学 (MD) 模拟来研究 Tau（267-312）片段的二级结构转变。结果表明，ff14IDPSFF 可以产生更多的异质构象，并且预测的二级结构分布更接近实验观察结果。此外，ff14IDPSFF 预测的二级化学位移最接近实验值。Tau（267-312）的二级结构转变动力学研究表明，二级结构逐渐从α-螺旋转变为β-折叠，β-折叠位于残基 274-280 和残基 305-311 区域。此外，Tau（267-312）二级结构转变的驱动力主要是位于六肽 VQIINK 和 VQIVYK 的疏水相互作用。Tau 蛋白的二级结构转变可以深入了解 AD 的聚集机制。
