Künze Georg, Kümpfel Richy, Rullmann Michael, Barthel Henryk, Brendel Matthias, Patt Marianne, Sabri Osama
Institute for Drug Discovery, University of Leipzig, 04103 Leipzig, Germany.
Department of Nuclear Medicine, University of Leipzig, Leipzig 04103, Germany.
ACS Chem Neurosci. 2022 Jul 20;13(14):2222-2234. doi: 10.1021/acschemneuro.2c00291. Epub 2022 Jun 28.
Tauopathies are a class of neurodegenerative disorders characterized by the accumulation of tau protein filaments in the brain. On the basis of isoforms with three or four microtubule-binding repeats (3R or 4R) that constitute tau filaments, tauopathies can be divided into 3R, 4R, and 3R/4R tauopathies. [F]PI-2620 is a tau-positron emission tomography (PET) tracer that detects tau filaments in the 3R/4R tauopathy Alzheimer's disease (AD) and the 4R tauopathies corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP) with differential binding characteristics. A multiscale simulation workflow, including molecular docking, molecular dynamics simulation, metadynamics, and Brownian dynamics, was applied to uncover the molecular basis for the different binding properties of [F]PI-2620 in these tauopathies. The energetically best binding sites of [F]PI-2620 in the AD-tau filament are located in the C-shaped groove of the filament core structure that is accessible to the outside. The most favorable binding sites in CBD-tau and PSP-tau filaments are localized to cavities in the inner filament core. Sites on the outer surface have higher binding free energies, and interaction of [F]PI-2620 at these sites was short-lived in the molecular dynamics simulations. Computationally predicted associated rates of [F]PI-2620 with the groove sites in the AD-tau filament were higher than association rates with the cavity sites in the CBD- and PSP-tau filaments. The results indicate that tau filaments in AD combine favorable energetic and kinetic properties with regard to tracer binding, while the binding of [F]PI-2620 to filaments in CBD and PSP is kinetically restricted. Our findings reveal that distinct structural, energetic, and kinetic properties of tau filaments from AD, CBD, and PSP govern their interaction with PET tracers, which highlights the possibility to achieve tau isoform specificity in future tracer developments.
tau蛋白病是一类神经退行性疾病，其特征是tau蛋白细丝在大脑中积累。根据构成tau细丝的具有三个或四个微管结合重复序列（3R或4R）的异构体，tau蛋白病可分为3R、4R和3R/4R tau蛋白病。[F]PI-2620是一种tau正电子发射断层扫描（PET）示踪剂，可检测3R/4R tau蛋白病阿尔茨海默病（AD）以及4R tau蛋白病皮质基底节变性（CBD）和进行性核上性麻痹（PSP）中的tau细丝，且具有不同的结合特性。应用了包括分子对接、分子动力学模拟、元动力学和布朗动力学在内的多尺度模拟工作流程，以揭示[F]PI-2620在这些tau蛋白病中不同结合特性的分子基础。[F]PI-2620在AD-tau细丝中的能量最优结合位点位于细丝核心结构可通向外部的C形凹槽中。CBD-tau和PSP-tau细丝中最有利的结合位点位于细丝内部核心的腔中。外表面的位点具有更高的结合自由能，并且在分子动力学模拟中，[F]PI-2620在这些位点的相互作用是短暂的。计算预测的[F]PI-2620与AD-tau细丝中凹槽位点的结合速率高于与CBD-tau和PSP-tau细丝中腔位点的结合速率。结果表明，就示踪剂结合而言，AD中的tau细丝结合了有利的能量和动力学特性，而[F]PI-2620与CBD和PSP中细丝的结合在动力学上受到限制。我们的研究结果表明，来自AD、CBD和PSP的tau细丝具有独特的结构、能量和动力学特性，这些特性决定了它们与PET示踪剂的相互作用，这突出了在未来示踪剂开发中实现tau异构体特异性的可能性。
