Hu Dingkun, Zhao Wei, Zhu Yong, Ai Hongqi, Kang Baotao
Shandong Provincial Key Laboratory of Fluorine Chemistry and Chemical Materials, School of Chemistry and Chemical Engineering, University of Jinan, No. 336, West Road of Nan Xinzhuang, Jinan, Shandong, 250022, P. R. China.
Hospital in University of Jinan, University of Jinan, No. 336, West Road of Nan Xinzhuang, Jinan, Shandong, 250022, P. R. China.
Chemistry. 2017 Nov 16;23(64):16257-16273. doi: 10.1002/chem.201702388. Epub 2017 Oct 24.
A growing body of evidence shows that soluble β-amyloid (Aβ) aggregates, oligomers, and even protofibrils, may be more neurotoxic than fibrils. Here, we employ a coarse grain model to investigate the aggregation of 75mer Aβ oligomers and the salt effect, the cornerstone of fibril evolution. We find that the oligomer morphologies generated by seventy-five monomers or mixed by both fifty monomers and five preset pentameric nuclei are different (spherical vs. bar-/disk-shaped) and are characterize by a full of coil content (former) and >70 % β-turn content (latter), indicating a novel role of the nuclei played in the early aggregation stage. The aggregation for the former oligomer adopts a master-nucleus mechanism, whereas for the latter combination of monomers and pentamers a multi-nuclei one is found. The random salt ions will distribute around the aggregates to form several ion shells as the aggregation develops. A unique two-fold gap between the shells is observed in the system containing 100 mm NaCl, endowing the physiological salt concentration with special implications. Meanwhile, an accurate ion-solute cutoff distance (0.66 nm) is predicted, and recommended to apply to many other aggregated biomolecular systems. The present distribution scenario of ions can be generalized to other aggregated systems, although it is strictly dependent on the identity of a specific aggregate, such as its charge and composition.
越来越多的证据表明，可溶性β-淀粉样蛋白（Aβ）聚集体、寡聚体，甚至原纤维，可能比纤维具有更强的神经毒性。在此，我们采用粗粒度模型来研究75聚体Aβ寡聚体的聚集以及盐效应，盐效应是纤维形成过程的基石。我们发现，由75个单体生成的寡聚体形态或由50个单体与5个预设五聚体核混合生成的寡聚体形态有所不同（球形与棒状/盘状），其特征分别为富含卷曲结构（前者）和β-转角含量>70%（后者），这表明核在早期聚集阶段发挥了新的作用。前者寡聚体的聚集采用主核机制，而后者单体与五聚体的组合则呈现多核机制。随着聚集过程的发展，随机的盐离子会在聚集体周围分布形成几个离子壳层。在含有100 mm NaCl的系统中，观察到壳层之间存在独特的两倍间距，这赋予了生理盐浓度特殊的意义。同时，预测了一个精确的离子-溶质截止距离（0.66 nm），并建议将其应用于许多其他聚集的生物分子系统。尽管离子的当前分布情况严格依赖于特定聚集体的特性，如电荷和组成，但这种分布情况可以推广到其他聚集系统。
