Ginell Garrett M, Emenecker Ryan J, Lotthammer Jeffrey M, Keeley Alex T, Plassmeyer Stephen P, Razo Nicholas, Usher Emery T, Pelham Jaqueline F, Holehouse Alex S
Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO, USA.
Center for Biomolecular Condensates (CBC), Washington University in St. Louis, St. Louis, MO, USA.
Science. 2025 May 22;388(6749):eadq8381. doi: 10.1126/science.adq8381.
Intrinsically disordered regions (IDRs) in proteins play essential roles in cellular function. A growing body of work has shown that IDRs often interact with partners in a manner that does not depend on the precise order of amino acids but is instead driven by complementary chemical interactions, leading to disordered bound-state complexes. However, these chemically specific dynamic interactions are difficult to predict. In this study, we repurposed the chemical physics developed originally for molecular simulations to predict this chemical specificity between IDRs and partner proteins using protein sequence as the only input. Our approach-FINCHES-enables the direct prediction of phase diagrams, the identification of chemically specific interaction hotspots on IDRs, the decomposition of chemically distinct domains in IDRs, and a route to develop and test mechanistic hypotheses regarding IDR function in molecular recognition.
蛋白质中的内在无序区域（IDR）在细胞功能中发挥着重要作用。越来越多的研究表明，IDR通常以一种不依赖于氨基酸精确顺序的方式与伙伴相互作用，而是由互补的化学相互作用驱动，从而形成无序的结合态复合物。然而，这些化学特异性的动态相互作用很难预测。在本研究中，我们重新利用最初为分子模拟开发的化学物理学，以蛋白质序列作为唯一输入来预测IDR与伙伴蛋白之间的这种化学特异性。我们的方法——FINCHES——能够直接预测相图，识别IDR上化学特异性的相互作用热点，分解IDR中化学性质不同的结构域，并为制定和测试关于IDR在分子识别中功能的机制假说提供一条途径。
