Phosphorylation is one of the most common post-translational modifications. The phosphorylation of the kinase-inducible domain (KID), which is an intrinsically disordered protein (IDP), promotes the folding of KID and binding with the KID-interacting domain (KIX). However, the regulation mechanism of the phosphorylation on KID is still elusive. In this study, the structural ensembles and binding process of pKID and KIX are studied by all-atom enhanced sampling technologies. The results show that more hydrophobic interactions are formed in pKID, which promote the formation of the special hydrophobic residue cluster (HRC). The pre-formed HRC promotes binding to the correct sites of KIX and further lead the folding of pKID. Consequently, a flexible conformational selection model is proposed to describe the binding and folding process of intrinsically disordered proteins. The binding mechanism revealed in this work provides new insights into the dynamic interactions and phosphorylation regulation of proteins.

磷酸化是最常见的翻译后修饰之一。激酶诱导结构域 (KID) 的磷酸化是一种本质上无序的蛋白质 (IDP)，可促进 KID 的折叠并与 KID 相互作用结构域 (KIX) 结合。然而，磷酸化对 KID 的调控机制仍不清楚。在这项研究中，pKID 和 KIX 的结构整体和结合过程通过全原子增强采样技术进行了研究。结果表明，pKID 中形成了更多的疏水相互作用，促进了特殊疏水残基簇 (HRC) 的形成。预先形成的 HRC 促进与 KIX 正确位点的结合，并进一步引导 pKID 的折叠。最后，提出了一种灵活的构象选择模型来描述本质上无序蛋白质的结合和折叠过程。这项工作中揭示的结合机制为蛋白质的动态相互作用和磷酸化调控提供了新的见解。