Department of Theoretical Chemistry and Biology, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH Royal Institute of Technology, SE-106 91 Stockholm, Sweden.
Leibniz University Hannover, Institute of Physical Chemistry and Electrochemistry, Callinstr. 3A, 30167 Hannover, Germany.
J Phys Chem B. 2021 Oct 28;125(42):11628-11636. doi: 10.1021/acs.jpcb.1c06019. Epub 2021 Oct 13.
The bi-thiophene-vinylene-benzothiazole (bTVBT4) ligand developed for Alzheimer's disease (AD)-specific detection of amyloid tau has been studied by a combination of several theoretical methods and experimental spectroscopies. With reference to the cryo-EM tau structure of the tau protofilament ( 2017, 547, 185), a periodic model system of the fibril was created, and the interactions between this fibril and bTVBT4 were studied with nonbiased molecular dynamics simulations. Several binding sites and binding modes were identified and analyzed, and the results for the most prevailing fibril site and ligand modes are presented. A key validation of the simulation work is provided by the favorable comparison of the theoretical and experimental absorption spectra of bTVBT4 in solution and bound to the protein. It is conclusively shown that the ligand-protein binding occurs at the hydrophobic pocket defined by the residues Ile360, Thr361, and His362. This binding site is not accessible in the Pick's disease (PiD) fold, and fluorescence imaging of bTVBT4-stained brain tissue samples from patients diagnosed with AD and PiD provides strong support for the proposed tau binding site.
用于阿尔茨海默病（AD）特异性检测淀粉样tau 的双噻吩-亚乙烯基-苯并噻唑（bTVBT4）配体已通过几种理论方法和实验光谱学的组合进行了研究。参考 tau 原丝的冷冻电镜结构（2017，547，185），创建了纤维的周期性模型系统，并通过无偏分子动力学模拟研究了纤维与 bTVBT4 之间的相互作用。确定并分析了几个结合位点和结合模式，并呈现了最流行的纤维位点和配体模式的结果。模拟工作的一个关键验证是理论和实验吸收光谱的有利比较bTVBT4 在溶液中和与蛋白质结合时的光谱。结论表明，配体-蛋白质的结合发生在由残基 Ile360、Thr361 和 His362 定义的疏水性口袋中。该结合位点在 Pick 氏病（PiD）折叠中不可用，并且对来自被诊断患有 AD 和 PiD 的患者的 bTVBT4 染色脑组织样本的荧光成像为所提出的 tau 结合位点提供了强有力的支持。
