Modeling Conformational Ensembles of the Disordered Proteins

摘要 本质上无序的蛋白质和无序区域(统称为IDPs)执行重要的生物学功能 在转录调控、细胞分化和DNA缩合中的作用。国内流离失所者迅速相互转换 在不同构象之间传递可塑性，形成瞬时接触，促进变构。国内流离失所者 也参与相变，形成液滴。水滴促进了不同的生物过程 这需要在细胞的不同区域进行定位。然而，理解蛋白质如何 序列塑造其无序构象的集合，以执行其功能并促进相 分离仍然是缺乏的。而氨基酸组成的简单度量解释了广泛的构象 特征(半径、比例指数)和趋势，顺序上的微小变化，由翻译后引起 修饰(PTM)/突变可以极大地改变无序构象及其功能。国内流离失所者也 避开传统的序列比对工具来对不同物种之间功能相似的蛋白质进行分类。 我们建议建立一个基于物理化学原理的新的计算框架来描述 具有任意序列的国内流离失所者的无序构象系综。要了解PTMS/突变是如何 结合不同的溶液条件来改变国内流离失所者的构象和分阶段分离的倾向， 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/修饰而导致的分析多个序列及其变体的挑战， 在不同条件下的交替拼接。在寻求进化签名时也面临着同样的挑战 不同物种的多个序列。结合聚合物物理、全原子的综合方法 模拟，多个实验将为这种高通量分析建立粗粒度模型。 建议的理论方法将提供指导，以确定IDP在体外的不同构象。 在活体中，ii)利用有限的数据(特定探针之间的smFRET)来预测距离 在任意残基对之间和III)建立用于比较特定残基对的严格框架 不同力场和实验之间的相互作用参数，并提出改进建议，如果需要。 计算效率高的形式主义将被大规模应用，以提供对 构象系综，包括残基对特定距离图(超越简单的可观察性，如 旋转半径、末端到末端距离、标度指数)来理解无序蛋白质组 功能相似/不相似，仅靠序列比对不可能。形式主义也将量化 Idp对化学修饰/突变的敏感性，以及环境变化(pH、盐度)的变化 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.