Department of Chemistry and Biochemistry, University of California, Santa Barbara, California.
Department of Chemistry and Biochemistry, University of California, Santa Barbara, California; Department of Physics, University of California, Santa Barbara, California.
Biophys J. 2012 Aug 8;103(3):550-557. doi: 10.1016/j.bpj.2012.07.008.
Congo red (CR) is a commonly used histological amyloid dye and a weak amyloid inhibitor. There is currently no experimentally available structure of CR bound to an amyloid fibril and the binding modes, and the mechanisms governing its inhibitory and optical properties are poorly understood. In this work, we present the first, to our knowledge, atomistically detailed picture of CR binding to protofibrils of the Alzheimer Aβ(9-40) peptide. We identify three major binding modes, with the primary mode residing in the grooves formed by the β-sheets, and observe a restriction of the torsional rotation of the CR molecule upon binding. Our simulations reveal a novel, to our knowledge, electrostatic steering mechanism that plays an important role in the initial recognition and binding of CR to the positively charged surface residues of the fibril. Our simulations provide new, to our knowledge, insights into the striking spectrophotometric and inhibitory properties of CR. In particular, we show that birefringence upon CR binding is due to the anisotropic orientation of the CR dipoles resulting from the spatial ordering of these molecules in the grooves along the fibril axis. The fluorescent enhancement of the bound CR, in turn, is associated with the torsional restriction of this molecule upon binding.
刚果红（CR）是一种常用的组织学淀粉样蛋白染料，也是一种弱淀粉样蛋白抑制剂。目前尚无实验可获得的 CR 与淀粉样纤维结合的结构，其结合模式和调控其抑制和光学性质的机制也知之甚少。在这项工作中，我们首次提供了（据我们所知）原子细节的刚果红与阿尔茨海默氏症 Aβ（9-40）肽原纤维结合的图像。我们确定了三种主要的结合模式，主要模式位于β-折叠形成的凹槽中，并观察到 CR 分子在结合时扭转旋转受到限制。我们的模拟揭示了一种新颖的、据我们所知的静电引导机制，该机制在 CR 与纤维的带正电荷表面残基的初始识别和结合中起着重要作用。我们的模拟为 CR 的显著分光光度和抑制特性提供了新的、据我们所知的见解。特别是，我们表明，CR 结合后的双折射是由于这些分子在纤维轴上的凹槽中沿纤维轴的各向异性取向导致的 CR 偶极子的各向异性取向。结合后 CR 的荧光增强则与该分子的扭转限制有关。
