Department of Theoretical Chemistry and Biology, Royal Institute of Technology (KTH), AlbaNova University Center, Stockholm 10691, Sweden.
Division of Clinical Geriatrics, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Center for Alzheimer Research, Stockholm 17177, Sweden.
ACS Chem Neurosci. 2020 Mar 18;11(6):900-908. doi: 10.1021/acschemneuro.9b00578. Epub 2020 Feb 28.
Abnormal deposition of hyperphosphorylated tau as neurofibrillary tangles (NFTs) is an important pathological hallmark of Alzheimer's disease (AD) and of other neurodegenerative disorders. A noninvasive positron emission tomography (PET) tracer that quantifies neurofibrillary tangles can enhance the clinical diagnosis of AD and can also be used to evaluate the efficacy of therapeutics aimed at reducing the abnormal aggregation of the tau fibril in the brain. In this paper, we study the binding profile of fibrillar tau aggregates with a PET tracer PI2620, which is a new second generation tau PET tracer that is presently experimentally and clinically studied. The target structure for the tau fibril is based on cryo-electron microscopy (cryo-EM) structure. A multiscale simulation workflow including molecular docking, molecular dynamics simulation, metadynamics simulation, and free energy calculations was implemented. We find that PI2620 can bind to eight surface binding sites, three core binding sites, and one entry site. The binding at the core sites and entry site is found to be much more favorable than that on the surface sites due to stronger hydrophobic interactions and less solvent exposure. Furthermore, the entry site which is formed by the terminal β-sheets of the fibril is found to have the highest binding affinity to PI2620. Importantly, the binding capacity at the entry site can be much higher than that at other core sites, due to its easy accessibility. Therefore, the entry site is believed to be the major binding site for PI2620. A previous computational study on tracers with tau fibrils reports a maximum of four binding sites. Through use of methods that allow us to locate "cryptic binding sites", we report here additional core sites available for binding and we address the limitation of using the cryo-EM structure alone for structure-based tracer design. Our results could be helpful for elucidating the binding mechanism of imaging tracers with the fibrillar form of tau, a knowledge that in turn can be used to guide the development of compounds with higher affinity and selectivity for tau using structure-based design strategies.
异常磷酸化的 tau 沉积形成神经原纤维缠结（NFTs）是阿尔茨海默病（AD）和其他神经退行性疾病的重要病理标志。一种非侵入性的正电子发射断层扫描（PET）示踪剂可以定量 NFTs，可以增强 AD 的临床诊断，也可以用于评估旨在减少脑内 tau 纤维异常聚集的治疗药物的疗效。在本文中，我们研究了一种新型第二代 tau PET 示踪剂 PI2620 与纤维状 tau 聚集体的结合谱，该示踪剂目前正在进行实验和临床研究。tau 纤维的靶结构基于低温电子显微镜（cryo-EM）结构。我们实施了包括分子对接、分子动力学模拟、元动力学模拟和自由能计算的多尺度模拟工作流程。我们发现 PI2620 可以结合到 8 个表面结合位点、3 个核心结合位点和 1 个进入位点。由于更强的疏水相互作用和更少的溶剂暴露，核心位点和进入位点的结合比表面位点更有利。此外，我们发现由纤维末端β-片层形成的进入位点与 PI2620 具有最高的结合亲和力。重要的是，由于其易于接近，进入位点的结合能力可以远高于其他核心位点。因此，进入位点被认为是 PI2620 的主要结合位点。以前的 tau 纤维示踪剂的计算研究报告了最多 4 个结合位点。通过使用允许我们定位“隐匿结合位点”的方法，我们在这里报告了更多可用于结合的核心结合位点，并解决了仅使用 cryo-EM 结构进行基于结构示踪剂设计的局限性。我们的研究结果有助于阐明成像示踪剂与 tau 纤维形式的结合机制，而这反过来又可以用于指导使用基于结构的设计策略开发具有更高亲和力和选择性的 tau 化合物。
