Laboratoire de Biochimie Théorique, UPR9080 CNRS, Université Paris Diderot, Sorbonne Paris Cité, Institut de Biologie Physico-Chimique, 13 rue Pierre et Marie Curie, 75005 Paris, France.
J Phys Chem B. 2012 Jul 26;116(29):8412-22. doi: 10.1021/jp2118778. Epub 2012 Feb 10.
The amyloid-β protein (Aβ) oligomers are believed to be the main culprits in the cytoxicity of Alzheimer's disease (AD) and p3 peptides (Aβ17-42 fragments) are present in AD amyloid plaques. Many small-molecule or peptide-based inhibitors are known to slow down Aβ aggregation and reduce the toxicity in vitro, but their exact modes of action remain to be determined since there has been no atomic level of Aβ(p3)-drug oligomers. In this study, we have determined the structure of Aβ17-42 trimers both in aqueous solution and in the presence of five small-molecule inhibitors using a multiscale computational study. These inhibitors include 2002-H20, curcumin, EGCG, Nqtrp, and resveratrol. First, we used replica exchange molecular dynamics simulations coupled to the coarse-grained (CG) OPEP force field. These CG simulations reveal that the conformational ensemble of Aβ17-42 trimer can be described by 14 clusters with each peptide essentially adopting turn/random coil configurations, although the most populated cluster is characterized by one peptide with a β-hairpin at Phe19-Leu31. Second, these 14 dominant clusters and the less-frequent fibril-like state with parallel register of the peptides were subjected to atomistic Autodock simulations. Our analysis reveals that the drugs have multiple binding modes with different binding affinities for trimeric Aβ17-42 although they interact preferentially with the CHC region (residues 17-21). The compounds 2002-H20 and Nqtrp are found to be the worst and best binders, respectively, suggesting that the drugs may interfere at different stages of Aβ oligomerization. Finally, explicit solvent molecular dynamics of two predicted Nqtrp-Aβ17-42 conformations describe at atomic level some possible modes of action for Nqtrp.
淀粉样β蛋白（Aβ）寡聚物被认为是阿尔茨海默病（AD）细胞毒性的主要罪魁祸首，而 p3 肽（Aβ17-42 片段）存在于 AD 淀粉样斑块中。已知许多小分子或肽类抑制剂可以减缓 Aβ聚集并降低体外毒性，但由于没有原子水平的 Aβ（p3）-药物寡聚物，其确切作用机制仍有待确定。在这项研究中，我们使用多尺度计算研究确定了 Aβ17-42 三聚体在水溶液中和存在五种小分子抑制剂时的结构。这些抑制剂包括 2002-H20、姜黄素、EGCG、Nqtrp 和白藜芦醇。首先，我们使用复制交换分子动力学模拟与粗粒度（CG）OPEP 力场相结合。这些 CG 模拟表明，Aβ17-42 三聚体的构象集合可以用 14 个簇来描述，每个肽基本上采用转角/无规卷曲构象，尽管最常见的簇的特征是一个肽在 Phe19-Leu31 处具有β发夹。其次，这些 14 个主要簇和肽的平行登记较少的原纤维样状态被提交给原子 Autodock 模拟。我们的分析表明，尽管这些药物优先与 CHC 区域（残基 17-21）相互作用，但它们对三聚体 Aβ17-42 具有多种结合模式和不同的结合亲和力。化合物 2002-H20 和 Nqtrp 分别被发现是最差和最好的结合剂，这表明这些药物可能在 Aβ 寡聚化的不同阶段发挥作用。最后，两种预测的 Nqtrp-Aβ17-42 构象的显式溶剂分子动力学在原子水平上描述了 Nqtrp 的一些可能作用模式。
