Zhang Tingting, Tian Yuanxin, Li Zhonghuang, Liu Siming, Hu Xiang, Yang Zichao, Ling Xiaotong, Liu Shuwen, Zhang Jiajie
Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University , Guangzhou, 510515, PR China.
J Chem Inf Model. 2017 Sep 25;57(9):2281-2293. doi: 10.1021/acs.jcim.7b00210. Epub 2017 Aug 22.
The mechanisms of dimerization of α-synuclein from full-length monomers and their structural features have been investigated through molecular dynamics simulations in this study. The dimerization of α-syn plays a critical role in the fibrillogenesis mechanism and could initiate and trigger α-syn to aggregate by conformational transforming. According to the alignment between three regions of α-syn monomer, eight diverse starting structures have been constructed. However, only five configurations show the dimeric structures, and the detailed properties of three dimers of them are discussed. During the simulations, both identical α-syn peptides (P1 and P2) of these three dimers reduce the high contents of α-helix from their native folded structures, while the contents of β-sheet increase. Antiparallel β-hairpin motifs within the α-syn peptide are formed by intramolecular interactions. The β-hairpin regions are adjacent to the nonamyloid β component (NAC) of α-syn, and these structural features are consistent with the experimental observation. Moreover, intermolecular β-sheets also are generated between P1 and P2 through hydrogen bonding interactions. The dimers produce both intramolecular β-hairpin and intermolecular β-sheet characters; the former is presented in monomer and oligomer of α-syn, and the latter occurs in the fibril structure. The simulations also show several other interactions such as hydrophobic interactions and salt-bridges, which would contribute to making the α-syn dimers more stable with the aforementioned effects. The results may pave the way to design small molecules to inhibit the dimerization in order to block the aggregation of α-syn in the future.
在本研究中，通过分子动力学模拟研究了全长单体α-突触核蛋白的二聚化机制及其结构特征。α-突触核蛋白的二聚化在纤维形成机制中起着关键作用，可通过构象转变引发并触发α-突触核蛋白聚集。根据α-突触核蛋白单体三个区域之间的比对，构建了八种不同的起始结构。然而，只有五种构型呈现出二聚体结构，并对其中三种二聚体的详细性质进行了讨论。在模拟过程中，这三种二聚体中相同的α-突触核蛋白肽段（P1和P2）均使其天然折叠结构中高含量的α-螺旋减少，而β-折叠的含量增加。α-突触核蛋白肽段内通过分子内相互作用形成了反平行β-发夹基序。β-发夹区域与α-突触核蛋白的非淀粉样β成分（NAC）相邻，这些结构特征与实验观察结果一致。此外，P1和P2之间还通过氢键相互作用产生了分子间β-折叠。这些二聚体兼具分子内β-发夹和分子间β-折叠特征；前者存在于α-突触核蛋白的单体和寡聚体中，后者出现在纤维结构中。模拟还显示了其他几种相互作用，如疏水相互作用和盐桥，这些作用与上述效应共同有助于使α-突触核蛋白二聚体更加稳定。这些结果可能为未来设计小分子抑制二聚化以阻断α-突触核蛋白聚集铺平道路。
