Monitoring and Inhibition of Insulin Fibrillation by a Small Organic Fluorogen with Aggregation-Induced Emission Characteristics
Monitoring and Inhibition of Insulin Fibrillation by a Small Organic Fluorogen with Aggregation-Induced Emission Characteristics
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DOI：
10.1021/ja208720a
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发表时间：
2012-01-25
影响因子：
15
通讯作者：
Tang, Ben Zhong
中科院分区：
文献类型：
--
作者：
Hong, Yuning;Meng, Luming;Tang, Ben Zhong
蛋白质的淀粉样纤颤与多种病理条件有关。开发能够监测淀粉样变性动力学和抑制纤维形成的新分子具有重要的诊断和治疗价值。在这项工作中，我们以胰岛素为模型蛋白，开发了一种生物相容分子，其功能是作为蛋白质纤颤的非原位监测和原位抑制。1，2-Bis[4-(3-sulfonatopropoxyl)phenyl]-1，2-diphenylethene盐(BSPOTPE)在孵化缓冲液中与天然胰岛素溶解时是不发射的，但当它与预制的胰岛素原纤维混合时开始发出荧光，从而实现了对淀粉样蛋白发生动力学的非原位监测和蛋白质纤维的高对比度荧光成像。另一方面，将BSPOTPE与胰岛素预混合会抑制成核过程，阻碍原纤维的形成。增加BSPOTPE的剂量可增强其抑制效力。分子动力学模拟和对接的理论模型表明，BSPOTPE易于通过BSPOTPE的苯环与暴露的胰岛素疏水残基的疏水作用与部分未折叠的胰岛素结合。这种结合被认为稳定了部分展开的胰岛素，并阻止了蛋白质纤维形成过程中关键低聚物种的形成。
Amyloid fibrillation of proteins is associated with a great variety of pathologic conditions. Development of new molecules that can monitor amyloidosis kinetics and inhibit fibril formation is of great diagnostic and therapeutic value. In this work, we have developed a biocompatible molecule that functions as an ex situ monitor and an in situ inhibitor for protein fibrillation, using insulin as a model protein. 1,2-Bis[4-(3-sulfonatopropoxyl)phenyl]-1,2-diphenylethene salt (BSPOTPE) is nonemissive when it is dissolved with native insulin in an incubation buffer but starts to fluoresce when it is mixed with preformed insulin fibril, enabling ex situ monitoring of amyloidogenesis kinetics and high-contrast fluorescence imaging of protein fibrils. Premixing BSPOTPE with insulin, on the other hand, inhibits the nucleation process and impedes the protofibril formation. Increasing the dose of BSPOTPE boosts its inhibitory potency. Theoretical modeling using molecular dynamics simulations and docking reveals that BSPOTPE is prone to binding to partially unfolded insulin through hydrophobic interaction of the phenyl rings of BSPOTPE with the exposed hydrophobic residues of insulin. Such binding is assumed to have stabilized the partially unfolded insulin and obstructed the formation of the critical oligomeric species in the protein fibrillogenesis process.