Small Molecule Modulation of Intrinsically Disordered Proteins Using Molecular Dynamics Simulations
Small Molecule Modulation of Intrinsically Disordered Proteins Using Molecular Dynamics Simulations
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DOI：
10.1021/acs.jcim.0c00381
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发表时间：
2020-10-26
影响因子：
5.6
通讯作者：
De Fabritiis, Gianni
中科院分区：
文献类型：
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作者：
Herrera-Nieto, Pablo;Perez, Adria;De Fabritiis, Gianni
本质上无序的蛋白质的极端动态行为阻碍了能够调节它们的类药物化合物的开发。有几个小分子与无序肽特异性相互作用的例子。然而，它们的作用机制仍不清楚。在这里，我们使用广泛的分子动力学模拟与自适应采样算法相结合，在本质上无序的蛋白质背景下进行自由配体结合研究。我们在由无序蛋白 p27 的 D2 子结构域和小分子 SJ403 组成的系统中测试了这种方法。结果显示了几种蛋白质-配体结合状态，其特征是通过配体和 p27 关键残基之间有限数量的接触介导的松散定向相互作用的建立。最后，分离的蛋白质也可能探索结合状态下的蛋白质构象，因此支持添加小分子限制可用构象空间的模型。
The extreme dynamic behavior of intrinsically disordered proteins hinders the development of drug-like compounds capable of modulating them. There are several examples of small molecules that specifically interact with disordered peptides. However, their mechanisms of action are still not well understood. Here, we use extensive molecular dynamics simulations combined with adaptive sampling algorithms to perform free ligand binding studies in the context of intrinsically disordered proteins. We tested this approach in the system composed by the D2 sub-domain of the disordered protein p27 and the small molecule SJ403. The results show several protein-ligand bound states characterized by the establishment of a loosely oriented interaction mediated by a limited number of contacts between the ligand and critical residues of p27. Finally, protein conformations in the bound state are likely to be explored by the isolated protein too, therefore supporting a model where the addition of the small molecule restricts the available conformational space.