Effects of Ions and Small Compounds on the Structure of Aβ 42 Monomers
Effects of Ions and Small Compounds on the Structure of Aβ 42 Monomers
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离子和小化合物对 Aβ 42 单体结构的影响
DOI：
10.1021/acs.jpcb.0c09617
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发表时间：
2021
期刊：
影响因子：
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通讯作者：
Dias, Cristiano L.
中科院分区：
文献类型：
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作者：
Mahmoudinobar, Farbod;Nilsson, Bradley L.;Dias, Cristiano L.
淀粉样蛋白-β（Aβ）蛋白在脑中的聚集是阿尔茨海默病的标志。向Aβ包埋的溶液中加入小分子可以促进或抑制这种现象。这些分子甚至在聚集开始之前就影响Aβ单体采样的构象系综。在这里，我们进行了广泛的全原子复制交换分子动力学（REMD）模拟，以提供Aβ 42单体在溶液中采样的构象系综的比较研究，含有NaCl的水溶液）和抑制（即，含有肌醇或4-氨基苯酚的水溶液）聚集。在纯水中进行的模拟用作我们的参考。我们发现，二级结构的内容只影响在C-末端和中央亲水核心的启动子和抑制剂的拮抗方式。在NaCl溶液中，C端末端与Aβ 42疏水核心区的结合更为有利，呈链-环-链结构，而抑制剂不支持这种结构。形成较大Aβ42聚集体干核的非极性残基（例如，PDB ID 2BEG）在这些链-环-链结构中非常接近，表明它们的形成在引发成核中起重要作用。在抑制剂的存在下，C-末端结合中央亲水核心的概率比我们的参考模拟更高。这种敏感性的C-末端，这是一个拮抗剂和促进剂的方式影响，提供了证据，其关键作用，占聚集。
Aggregation of amyloid-β (Aβ) proteins in the brain is a hallmark of Alzheimer’s disease. This phenomenon can be promoted or inhibited by adding small molecules to the solution where Aβ is embedded. These molecules affect the ensemble of conformations sampled by Aβ monomers even before aggregation starts. Here, we perform extensive all-atom replica exchange molecular dynamics (REMD) simulations to provide a comparative study of the ensemble of conformations sampled by Aβ42monomers in solutions that promote (i.e., aqueous solution containing NaCl) and inhibit (i.e., aqueous solutions containingscyllo-inositol or 4-aminophenol) aggregation. Simulations performed in pure water are used as our reference. We find that secondary-structure content is only affected in an antagonistic manner by promoters and inhibitors at the C-terminus and the central hydrophilic core. Moreover, the end of the C-terminus binds more favorably to the central hydrophobic core region of Aβ42in NaCl adopting a type of strand–loop–strand structure that is disfavored by inhibitors. Nonpolar residues that form the dry core of larger aggregates of Aβ42(e.g., PDB ID 2BEG) are found at close proximity in these strand–loop–strand structures, suggesting that their formation could play an important role in initiating nucleation. In the presence of inhibitors, the C-terminus binds the central hydrophilic core with a higher probability than in our reference simulation. This sensitivity of the C-terminus, which is affected in an antagonistic manner by inhibitors and promoters, provides evidence for its critical role in accounting for aggregation.