Modeling Conformational Ensembles of the Disordered Proteins

摘要 内源性无序蛋白和无序区域（统称为IDP）在细胞内执行重要的生物学功能。 在转录调节、细胞分化和DNA缩合中起作用。国内流离失所者迅速相互转化 在不同的构象之间，赋予可塑性，形成瞬时接触并促进变构。流离失所者 也参与相变，形成液滴。微滴促进了多种生物过程 需要定位在细胞的不同区域。然而，理解蛋白质如何 序列形成其无序构象的集合，以执行其功能并促进相位 分离仍然缺乏。虽然氨基酸组成的简单度量解释了广泛的构象 特征（半径，标度指数）和趋势，序列中的微小变化，由翻译后引起 修饰（PTM）/突变可以显著改变无序构象及其功能。国内流离失所者还 避开了传统的序列比对工具来对跨物种的功能相似的蛋白质进行分类。 我们建议建立一个新的计算框架的基础上物理化学原理来描述 具有任意序列的IDP的无序构象的集合。了解PTM/突变 结合不同的溶液条件以改变IDP构象和IDP相分离的倾向， 我们需要计算效率高的模型模型必须能够处理组合 由于优先突变/修饰，分析多个序列及其变体的挑战， 不同条件下的选择性剪接。在寻找进化特征时也面临着同样的挑战 不同物种的多重序列。一种结合聚合物物理、全原子 模拟和多个实验将为这种高通量分析构建粗粒度模型。 所提出的理论方法将提供指导，以确定如何IDP构象不同，在体外 ii）利用有限的数据（特定探针之间的smFRET）来预测距离 和iii）建立一个严格的框架，用于比较残基对特异性 研究人员将分析不同力场和实验之间的相互作用参数，并在需要时提出改进建议。 计算上有效的形式主义将在大规模应用，以提供详细的描述， 构象集合，包括残基对特定的距离图（除了简单的可观察性， 旋转半径，末端到末端距离，标度指数）的无序蛋白质组，以了解 功能相似性/不相似性，单独通过序列比对是不可能的。形式主义也会量化 IDP对化学修饰/突变的敏感性，以及环境变化（pH值，盐度）改变 构象，功能和促进或抑制IDP溶液中的相分离倾向。

Abstract Intrinsically disordered proteins and disordered regions (collectively termed IDPs) perform vital biological functions in transcriptional regulation, cell differentiation, and DNA condensation. IDPs rapidly interconvert between different conformations, imparting plasticity, forming transient contacts and promoting allostery. IDPs also participate in phase transitions, forming liquid droplets. The droplets facilitate diverse biological processes that require localization in different regions in the cell. Yet, principles for understanding how a protein's sequence shapes its ensemble of disordered conformations to perform its function and to promote phase separation are still lacking. While the simple metric of amino acid composition explains broad conformational features (radius, scaling exponents) and trends, minor variations in sequence, caused by post-translational modifications (PTMs)/mutations can drastically alter disordered conformations and their functions. IDPs also elude traditional sequence alignment tools to classify functionally similar proteins across species. We propose to build a novel computational framework based on physico-chemical principles to describe the ensemble of disordered conformations for IDPs with arbitrary sequence. To understand how PTMs/mutations couple with diverse solution conditions to alter IDP conformation and the propensity of IDPs to phase separate, we need computationally efficient models. The models must be capable of handling the combinatorial challenge of analyzing multiple sequences and their variants due to preferential mutations/modifications, alternate splicing under diverse conditions. The same challenge is faced when seeking evolutionary signatures of multiple sequences across different species. An integrated approach combining polymer physics, all-atom simulation, and multiple experiments will build coarse-grain models for such high-throughput analysis. The proposed theoretical approach will i) provide guidance to determine how IDP conformations differ in vitro and in vivo, ii) harness limited data (smFRET between specific probes) to make predictions for distances between arbitrary residue pairs and iii) build a rigorous framework for comparing residue-pair specific interaction parameters between different force fields and experiments, and suggest improvements, if needed. The computationally efficient formalism will be applied at a large scale to provide a detailed description of conformational ensembles, including residue-pair specific distance maps (beyond simple observables as radius of gyration, end-to-end-distance, scaling exponents) for sets of disordered proteins to understand functional similarities/dissimilarities, not possible by sequence alignment alone. The formalism will also quantify IDP's susceptibility to chemical modifications/mutations, and environmental changes (pH, salinity) to alter conformations, function and promote or suppress phase separation propensities in IDP solutions.