Dimerization Process of Amyloid-β(29-42) Studied by the Hamiltonian Replica-Permutation Molecular Dynamics Simulations
Dimerization Process of Amyloid-β(29-42) Studied by the Hamiltonian Replica-Permutation Molecular Dynamics Simulations
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DOI：
10.1021/jp505984e
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发表时间：
2014-10-02
影响因子：
3.3
通讯作者：
Okumura, Hisashi
中科院分区：
文献类型：
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作者：
Itoh, Satoru G.;Okumura, Hisashi
淀粉样β肽形成与阿尔茨海默病相关的淀粉样纤维。淀粉样蛋白-β（29-42）是其C-末端片段，并且是淀粉样蛋白形成速率的关键决定因素。该片段本身形成淀粉样纤维。然而，原纤维中的片段构象尚未确定。包括二聚过程的低聚过程也仍然是未知的。二聚化过程对应于淀粉样蛋白生成的早期过程。为了研究二聚化过程和构象，我们应用了哈密顿复制置换方法，这是一个更好的替代哈密顿复制交换方法，两个淀粉样蛋白-β（29-42）分子在明确的水溶剂。在二聚化过程的第一步，两个淀粉样蛋白-β（29-42）分子彼此靠近并具有分子间侧链接触。当两个分子间存在侧链接触时，淀粉样蛋白β（29-42）尤其倾向于具有分子内二级结构。β-发夹结构这两个分子在二聚化过程的第二步更接近，从而具有分子间β-桥结构。这些分子间β-桥结构的形成由β-发夹结构诱导。分子间β-折叠结构在最后一步被拉长。淀粉样蛋白-β（29-42）在单体和二聚体状态下的结构也显示为自由能景观，这是通过在我们的模拟中在构象空间中进行有效采样而获得的。
The amyloid-beta peptides fom amyloid fibrils which are associated with Alzheimers's disease. Amyloid-beta(29-42) is it C-terminal fragment and a critical determinant of the amyloid formation rate. This fragment forms the amyloid fibril by itself. However, the fragment conformation in the fibril has yet to be determined. The oligomerization process including the dimerization process is also still unknown. The dimerization process corresponds to an early process of the amyloidogenesis. In order to investigate the dimerization process and conformations we applied the Hamiltonian replica permutation method which is a better alternative to the Hamiltonian replica-exchange method to two amyloid-beta(29-42) molecules in explicit water solvent. At the first step of the dimerization process two amyloid-beta(29-42) molecules came close to each other and had intermolecular side chain contacts. When two molecules had the intermolecules side chain contacts, the amyloid-beta(29-42) tended to have intramolecular secondary structures espically. beta-hairpin structures The two molecules had intermolecular beta-bridge structures by coming much closer at the sencond step of the dimerization process. Formation of these intermolecular beta-bridge structures was induced by the beta-hairpin structures. The intermolecular beta-sheet structures elongated at the final step. Structures of the amyloid-beta(29-42) in the monomer and dimer states are also shown with the free energy landscapes, which were obatined by performing efficient sampling in the conformational space in our simulations.