Fox Stephen John, Kannan Srinivasaraghavan
Bioinformatics Institute (A*STAR), 30 Biopolis Street, #07-01 Matrix, 138671, Singapore.
Prog Biophys Mol Biol. 2017 Sep;128:57-62. doi: 10.1016/j.pbiomolbio.2017.05.008. Epub 2017 May 26.
Intrinsically disordered proteins (IDPs) play an important role in many diseases. IDPs are a large and important class of proteins; estimated to represent a significant fraction of many genomes. In contrast to protein-protein interactions between well-folded proteins, IDPs typically bind to targets using short consecutive stretches of amino acids. Structures of IDPs complexed with a target have shown great diversity in binding modes. However, how this binding diversity is achieved at the molecular level is not well understood. Unfortunately, the prediction and detailed characterization of IDPs experimentally is still a very challenging task; however molecular mechanics based molecular dynamics simulation are well suited for studying the dynamic behavior of IDPs. We look into the current state for force fields for simulating IDPs and an example of how these methods have been applied to the p53 protein. p53 is one of the most extensively studied IDPs, with multiple intrinsically disordered regulatory domains that mediate its interactions with many other proteins engaged in multiple biological pathways. We show how molecular dynamics simulations can be used to elucidate on the mechanisms involved in selection of the different binding partners.
内在无序蛋白（IDP）在许多疾病中起着重要作用。IDP是一大类重要的蛋白质；据估计，它们在许多基因组中占相当大的比例。与折叠良好的蛋白质之间的蛋白质-蛋白质相互作用不同，IDP通常利用短的连续氨基酸片段与靶标结合。与靶标复合的IDP结构在结合模式上表现出极大的多样性。然而，在分子水平上这种结合多样性是如何实现的，目前还不太清楚。不幸的是，通过实验对IDP进行预测和详细表征仍然是一项非常具有挑战性的任务；然而，基于分子力学的分子动力学模拟非常适合研究IDP的动态行为。我们研究了用于模拟IDP的力场的当前状态，以及这些方法如何应用于p53蛋白的一个例子。p53是研究最广泛的IDP之一，它有多个内在无序的调节结构域，介导其与参与多种生物途径的许多其他蛋白质的相互作用。我们展示了分子动力学模拟如何用于阐明选择不同结合伙伴所涉及的机制。
