Computational Science Laboratory, Universitat Pompeu Fabra, 08003 Barcelona, Spain.
Acellera Ltd., 08005 Barcelona, Spain.
J Chem Inf Model. 2020 Oct 26;60(10):5003-5010. doi: 10.1021/acs.jcim.0c00381. Epub 2020 Aug 15.
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 and the small molecule . 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 . 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.
无规蛋白的极端动力学行为阻碍了能够调节它们的类药化合物的发展。有几个小分子的例子可以与无规肽特异性相互作用。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结合自适应采样算法，在无规蛋白的背景下进行游离配体结合研究。我们在由无序蛋白的 D2 亚结构域和小分子组成的系统中测试了这种方法。结果表明，有几种蛋白-配体结合状态，其特征是通过配体与关键残基之间的有限数量的接触建立松散的定向相互作用。最后，孤立的蛋白也可能探索结合状态下的蛋白构象，从而支持这样一种模型，即小分子的加入限制了可用的构象空间。
