Metal Binding to Amyloid-ß1-42: A Ligand Field Molecular Dynamics Study.
Metal Binding to Amyloid-ß1-42: A Ligand Field Molecular Dynamics Study.
复制标题
金属与淀粉样蛋白-à1-42 的结合：配体场分子动力学研究。
DOI：
10.1021/acschemneuro.8b00210
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发表时间：
2018
影响因子：
5
通讯作者：
Mutter ST
中科院分区：
文献类型：
--
作者：
Mutter ST
配体场分子力学模拟已用于模拟铜（II）和铂（II）与淀粉样蛋白-β1- 42肽单体的相互作用。两个金属化系统的分子动力学超过几微秒的自由肽的类似结果进行了比较。结构参数的显着差异，观察到，无论是铜和铂结合系统之间，以及之间的自由和金属结合的肽。与未结合的单体相比，这两种金属都能稳定肽中螺旋的形成，并降低β二级结构元件的含量。这与金属减少β-折叠结构的实验报告一致，导致在淀粉样蛋白原纤维上形成无定形聚集体。肽结构的形状和大小也发生了显著的变化，游离肽表现出球状结构，铂（II）系统采用扩展结构，铜（II）系统产生类似于这两种构象的混合物。盐桥网络表现出重大的差异：Asp 23-Lys 28盐桥，已知是重要的原纤维形成，具有不同的距离分布在所有三个系统的研究。在肽的金属结合区域中的盐桥被强烈地改变;特别地，Arg 5-Asp 7盐桥（其在游离肽中的出现率为71%）在两种金属的存在下被减少至零。
Ligand field molecular mechanics simulation has been used to model the interactions of copper(II) and platinum(II) with the amyloid-β1–42peptide monomer. Molecular dynamics over several microseconds for both metalated systems are compared to analogous results for the free peptide. Significant differences in structural parameters are observed, both between Cu and Pt bound systems as well as between free and metal-bound peptide. Both metals stabilize the formation of helices in the peptide as well as reducing the content of β secondary structural elements compared to the unbound monomer. This is in agreement with experimental reports of metals reducing β-sheet structures, leading to formation of amorphous aggregates over amyloid fibrils. The shape and size of the peptide structures also undergo noteworthy change, with the free peptide exhibiting globular-like structure, platinum(II) system adopting extended structures, and copper(II) system resulting in a mixture of conformations similar to both of these. Salt bridge networks exhibit major differences: the Asp23-Lys28 salt bridge, known to be important in fibril formation, has a differing distance profile within all three systems studied. Salt bridges in the metal binding region of the peptide are strongly altered; in particular, the Arg5-Asp7 salt bridge, which has an occurrence of 71% in the free peptide, is reduced to zero in the presence of both metals.