Dimerization of α-Synuclein Fragments Studied by Isotherma-Isobaric Replica-Permutation Molecular Dynamics Simulation
Dimerization of α-Synuclein Fragments Studied by Isotherma-Isobaric Replica-Permutation Molecular Dynamics Simulation
复制标题
通过等温-等压复制-排列分子动力学模拟研究 α-突触核蛋白片段的二聚化
DOI：
10.1021/acs.jcim.0c01056
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发表时间：
2021
影响因子：
5.6
通讯作者：
Masataka Yamauchi and Hisashi Okumura
中科院分区：
文献类型：
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作者：
高山幸也;草森浩輔;西川元也;Masataka Yamauchi and Hisashi Okumura
本质无序的α-突触核蛋白的聚集体和原纤维与帕金森病相关。在α-突触核蛋白的第61位至第95位残基的非淀粉样蛋白β组分（NAC）中，称为NACore（68 GAVVTGVTAVA 78）的11个残基片段是原纤维形成和细胞毒性的必需区域。尽管已知单独的NAC核心肽形成聚集体和淀粉样原纤维，但聚集和原纤维化的机制仍然未知。本研究探讨了NACore肽的二聚化过程作为聚集和原纤化过程的初始阶段。我们进行了等温等压复制置换分子动力学模拟，这是一种有效的采样方法，在96 μs以上的显式水中的两个NACore肽。该模拟成功地对各种二聚体结构进行了采样。二级结构分析表明，大多数NAC核心二聚体形成分子间β-桥。特别地，观察到比平行β桥更多的反平行β桥。我们还发现，分子内的二级结构，如α-螺旋和反平行β-桥稳定在前二聚体状态。然而，我们发现分子间β-桥倾向于直接在没有特定结构的残基之间形成，而不是通过分子内β-桥形成。这是因为NACore肽仍然具有形成分子内二级结构的低倾向，即使它们稳定在前二聚体状态。
Aggregates and fibrils of intrinsically disordered α-synuclein are associated with Parkinson’s disease. Within a non-amyloid β component (NAC) spanning from the 61st to the 95th residue of α-synuclein, an 11-residue segment called NACore (68GAVVTGVTAVA78) is an essential region for both fibril formation and cytotoxicity. Although NACore peptides alone are known to form aggregates and amyloid fibrils, the mechanisms of aggregation and fibrillation remain unknown. This study investigated the dimerization process of NACore peptides as the initial stage of the aggregation and fibrillation processes. We performed an isothermal–isobaric replica-permutation molecular dynamics simulation, which is one of the efficient sampling methods, for the two NACore peptides in explicit water over 96 μs. The simulation succeeded in sampling a variety of dimer structures. An analysis of secondary structure revealed that most of the NACore dimers form intermolecular β-bridges. In particular, more antiparallel β-bridges were observed than parallel β-bridges. We also found that intramolecular secondary structures such as α-helix and antiparallel β-bridge are stabilized in the pre-dimer state. However, we identified that the intermolecular β-bridges tend to form directly between residues with no specific structure rather than via the intramolecular β-bridges. This is because the NACore peptides still have a low propensity to form the intramolecular secondary structures even though they are stabilized in the pre-dimer state.