Department of Pharmaceutical Sciences and Computational Chemical Genomics Screening Center, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, United States.
Department of Neuroscience, The Ohio State University Wexner Medical Center, Columbus, Ohio 43210, United States.
ACS Chem Neurosci. 2023 Jan 18;14(2):209-217. doi: 10.1021/acschemneuro.2c00381. Epub 2022 Dec 23.
Tau proteins not only have many important biological functions but also are associated with several neurodegenerative diseases, such as Parkinson's disease and Alzheimer's disease (AD). However, it is still a challenge to identify the atomic structure of full-length tau proteins due to their lengthy and disordered characteristics and the factor that there are no crystal structures of full-length tau proteins available. We performed multi- and large-scale molecular dynamics simulations of the full-length tau monomer (the 2N4R isoform and 441 residues) in aqueous solution under biological conditions with coarse-grained and all-atom force fields. The obtained atomic structures produced radii of gyration and chemical shifts that are in excellent agreement with those of experiment. The generated monomer structure ensemble would be very useful for further studying the oligomerization mechanism and discovering tau oligomerization inhibitors, which are important events in AD drug development.
tau 蛋白不仅具有许多重要的生物学功能，而且与几种神经退行性疾病有关，如帕金森病和阿尔茨海默病（AD）。然而，由于其长而无序的特性，以及没有全长 tau 蛋白的晶体结构可用，因此确定全长 tau 蛋白的原子结构仍然是一个挑战。我们使用粗粒化和全原子力场在生物条件下对全长 tau 单体（2N4R 异构体和 441 个残基）在水溶液中进行了多尺度和大规模的分子动力学模拟。得到的原子结构产生的旋转半径和化学位移与实验结果非常吻合。生成的单体结构集合将非常有助于进一步研究寡聚化机制和发现 tau 寡聚化抑制剂，这是 AD 药物开发中的重要事件。
