Major Reaction Coordinates Linking Transient Amyloid-β Oligomers to Fibrils Measured at Atomic Level
Major Reaction Coordinates Linking Transient Amyloid-β Oligomers to Fibrils Measured at Atomic Level
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DOI：
10.1016/j.bpj.2017.06.068
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发表时间：
2017-08-22
影响因子：
3.4
通讯作者：
Madhu, Perunthiruthy K.
中科院分区：
文献类型：
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作者：
Chandra, Bappaditya;Bhowmik, Debanjan;Madhu, Perunthiruthy K.
与成熟原纤维相比，淀粉样蛋白生成肽的低聚中间体的更高毒性的结构基础目前仍然未知。低聚物的瞬时性质和异质性使得难以遵循其结构。在这里，使用振动和固态核磁共振光谱，和分子动力学模拟，我们表明，在生理溶液中自由聚集的A β（40）低聚物具有分子内反平行配置，这是不同于在成熟的原纤维中观察到的分子间平行β-片层结构。分子内氢键网络翻转近90度，每个单体单元的两条β链分开，在成熟原纤维中产生众所周知的分子间对齐平行β折叠结构。固态核磁共振距离测量捕获链间分离的单体单元从低聚物的原纤维形式的过渡期间。我们进一步发现，D23-K28盐桥，A β（40）原纤维的主要特征和与早发性阿尔茨海默病相关的突变焦点，在小寡聚体中检测不到。分子动力学模拟捕获D23-K28距离的变化与反平行和平行β-折叠结构之间的单体二级结构的翻转之间的相关性。总的来说，我们提出链间分离和盐桥形成作为描述小A β（40）寡聚体向原纤维结构转变的关键反应坐标。
The structural underpinnings for the higher toxicity of the oligomeric intermediates of amyloidogenic peptides, compared to the mature fibrils, remain unknown at present. The transient nature and heterogeneity of the oligomers make it difficult to follow their structure. Here, using vibrational and solid-state nuclear magnetic resonance spectroscopy, and molecular dynamics simulations, we show that freely aggregating A beta(40) oligomers in physiological solutions have an intramolecular antiparallel configuration that is distinct from the intermolecular parallel beta-sheet structure observed in mature fibrils. The intramolecular hydrogen-bonding network flips nearly 90 degrees, and the two beta-strands of each monomeric unit move apart, to give rise to the well-known intermolecular in-register parallel beta-sheet structure in the mature fibrils. Solid-state nuclear magnetic resonance distance measurements capture the interstrand separation within monomer units during the transition from the oligomer to the fibril form. We further find that the D23-K28 salt-bridge, a major feature of the A beta(40) fibrils and a focal point of mutations linked to early onset Alzheimer's disease, is not detectable in the small oligomers. Molecular dynamics simulations capture the correlation between changes in the D23-K28 distance and the flipping of the monomer secondary structure between antiparallel and parallel beta-sheet architectures. Overall, we propose interstrand separation and salt-bridge formation as key reaction coordinates describing the structural transition of the small A beta(40) oligomers to fibrils.