The binding of thioflavin T and its neutral analog BTA-1 to protofibrils of the Alzheimer's disease Abeta(16-22) peptide probed by molecular dynamics simulations.
The binding of thioflavin T and its neutral analog BTA-1 to protofibrils of the Alzheimer's disease Abeta(16-22) peptide probed by molecular dynamics simulations.
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DOI：
10.1016/j.jmb.2008.09.062
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发表时间：
2008-12-19
影响因子：
5.6
通讯作者：
Shea, Joan-Emma
中科院分区：
文献类型：
--
作者：
Wu, Chun;Wang, Zhixiang;Lei, Hongxing;Duan, Yong;Bowers, Michael T.;Shea, Joan-Emma
关键词：
硫磺素T（ThT）是一种常用于染色淀粉样蛋白斑块的荧光染料，然而，这种染料在原纤维上的结合位点的特征很差。我们提出了ThT及其中性类似物BTA-1与阿尔茨海默淀粉样蛋白Aβ16-22肽的模型原纤维结合的分子动力学模拟。我们的模拟揭示了位于β-折叠表面的凹槽和β-折叠末端的两种结合模式。这些模拟为最近的实验工作提供了新的见解，并使我们能够将实验中观察到的高容量微摩尔亲和力位点表征为与β折叠表面凹槽结合，将低容量纳摩尔亲和力位点表征为与原纤维的β折叠末端结合。的结构-活性关系（SAR）突变带电的ThT中性BTA-1在增加的亲油性和结合亲和力方面进行了研究，计算的溶剂化自由能和结合能被发现是定性的协议与实验测量。
Thioflavin T (ThT) is a fluorescent dye commonly used to stain amyloid plaques, however, the binding sites of this dye onto fibrils are poorly characterized. We present molecular dynamics simulations of the binding of ThT and its neutral analog BTA-1 to model protofibrils of the Alzheimer Amyloid Aβ16-22 peptide. Our simulations reveal two binding modes located at the grooves of the β-sheet surfaces and at the ends of the β-sheet. These simulations provide new insight into recent experimental work and allow us to characterize the high-capacity, micromolar-affinity site seen in experiment as binding to the β-sheet surface grooves and the low-capacity, nanomolar-affinity site as binding to the β-sheet extremities of the fibril. The structure-activity relationship (SAR) upon mutating charged ThT to neutral BTA-1 in terms of increased lipophilicity and binding affinity was studied, with calculated solvation free energies and binding energies found to be in qualitative agreement with the experimental measurements.
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