Ginell Garrett M, Emenecker Ryan J, Lotthammer Jeffrey M, Usher Emery T, Holehouse Alex S
Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO.
Center for Biomolecular Condensates (CBC), Washington University in St. Louis, St. Louis, MO.
bioRxiv. 2024 Jun 3:2024.06.03.597104. doi: 10.1101/2024.06.03.597104.
Intrinsically disordered regions (IDRs) are critical for a wide variety of cellular functions, many of which involve interactions with partner proteins. Molecular recognition is typically considered through the lens of sequence-specific binding events. However, 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 the amino acid order, instead driven by complementary chemical interactions leading to disordered bound-state complexes. Despite this emerging paradigm, we lack tools to describe, quantify, predict, and interpret these types of structurally heterogeneous interactions from the underlying amino acid sequences. Here, we repurpose the chemical physics developed originally for molecular simulations to develop an approach for predicting intermolecular interactions between IDRs and partner proteins. Our approach enables the direct prediction of phase diagrams, the identification of chemically-specific interaction hotspots on IDRs, and a route to develop and test mechanistic hypotheses regarding IDR function in the context of molecular recognition. We use our approach to examine a range of systems and questions to highlight its versatility and applicability.
内在无序区域（IDR）对于多种细胞功能至关重要，其中许多功能涉及与伴侣蛋白的相互作用。分子识别通常是通过序列特异性结合事件来考量的。然而，越来越多的研究表明，IDR 与伴侣的相互作用方式通常并不依赖于氨基酸的精确顺序，而是由互补的化学相互作用驱动，形成无序的结合态复合物。尽管这一新兴范式已出现，但我们仍缺乏从基础氨基酸序列来描述、量化、预测和解释这类结构异质性相互作用的工具。在此，我们重新利用最初为分子模拟而开发的化学物理学方法，来开发一种预测 IDR 与伴侣蛋白之间分子间相互作用的方法。我们的方法能够直接预测相图，识别 IDR 上化学特异性的相互作用热点，并提供一条在分子识别背景下开发和测试关于 IDR 功能的机制假说的途径。我们运用该方法研究了一系列系统和问题，以突出其通用性和适用性。
