Disordered Binding of Small Molecules to Aβ(12-28)
Disordered Binding of Small Molecules to Aβ(12-28)
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DOI：
10.1074/jbc.m111.285957
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发表时间：
2011-12-02
影响因子：
4.8
通讯作者：
Caflisch, Amedeo
中科院分区：
文献类型：
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作者：
Convertino, Marino;Vitalis, Andreas;Caflisch, Amedeo
近年来，越来越多的小分子和短肽已被鉴定为干扰阿尔茨海默病β-淀粉样肽（A β）的聚集和/或寡聚化。他们中的许多人拥有芳香族部分，这表明在与A β相互作用的主导作用，沿着沿着的各个阶段的聚集过程。在这项研究中，我们试图阐明这种芳香族抑制剂与单体A β（12-28）的相互作用是否指向一个共同的作用机制，通过在平衡状态下进行原子分子动力学模拟。我们的研究结果表明，独立的抑制剂的存在下，单体A β（12-28）填充的部分塌陷的合奏，在300 K和中性pH值下，在很大程度上是缺乏典型的二级结构。小分子具有不同的亲和力A β（12-28），可以部分合理化的芳香族和带电部分构成的分子的平衡。没有主要的结合模式，尽管聚集抑制剂优先与片段的N-末端部分（残基13-20）相互作用。A β（12-28）的自由能图谱分析揭示了抑制剂存在下环状构象异构体的改变群体所突出的差异。我们的结论是AB的内在障碍持续在结合小分子的水平，抑制剂可以显着改变通过多种途径的不同特异性的单体AB的属性。
In recent years, an increasing number of small molecules and short peptides have been identified that interfere with aggregation and/or oligomerization of the Alzheimer beta-amyloid peptide (A beta). Many of them possess aromatic moieties, suggesting a dominant role for those in interacting with A beta along various stages of the aggregation process. In this study, we attempt to elucidate whether interactions of such aromatic inhibitors with monomeric A beta(12-28) point to a common mechanism of action by performing atomistic molecular dynamics simulations at equilibrium. Our results suggest that, independently of the presence of inhibitors, monomeric A beta(12-28) populates a partially collapsed ensemble that is largely devoid of canonical secondary structure at 300 K and neutral pH. The small molecules have different affinities for A beta(12-28) that can be partially rationalized by the balance of aromatic and charged moieties constituting the molecules. There are no predominant binding modes, although aggregation inhibitors preferentially interact with the N-terminal portion of the fragment (residues 13-20). Analysis of the free energy landscape of A beta(12-28) reveals differences highlighted by altered populations of a looplike conformer in the presence of inhibitors. We conclude that intrinsic disorder of AB persists at the level of binding small molecules and that inhibitors can significantly alter properties of monomeric AB via multiple routes of differing specificity.