Modeling Conformational Ensembles of the Disordered Proteins

无序蛋白质的构象整体建模

基本信息

批准号：
10034318
负责人：
Kingshuk Ghosh
金额：
$ 23万
依托单位：
UNIVERSITY OF DENVER (COLORADO SEMINARY)
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10034318
关键词：
Alternative Splicing Amino Acid Sequence Amino Acids Benchmarking Biological Biological Process Biology Cell Differentiation process Cells Charge Chemicals Collaborations Communities Coupling DNA Data Disease Disease model Explosion Face Gaussian model Goals Grain Homology Modeling Hot Spot Human In Vitro Inosine Diphosphate Ionic Strengths Knowledge Link Liquid substance Location Maps Measures Minor Modeling Modification Molecular Conformation Mutation Organelles Pattern Phase Phase Transition Phosphorylation Physical condensation Physics Polymers Positioning Attribute Post-Translational Protein Processing Predisposition Property Proteins Proteome Publishing RNA Splicing Radial Regulation Research Role Saline Science Sequence Alignment Shapes Site Source Structure Temperature Therapeutic Transcriptional Regulation Variant Work base combinatorial computer framework cost design environmental change exhaustion experimental study functional gain high throughput analysis in vivo insight mathematical model multi-scale modeling novel protein folding protein function simulation single-molecule FRET success theories tool trend

项目摘要

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.

抽象的本质上无序的蛋白质和无序区域（统称为IDP）执行重要的生物学转录调控，细胞分化和DNA缩合的功能。 IDP迅速互连在不同的构象，赋予可塑性，形成瞬态接触和促进变构之间。 IDP 还参与相变，形成液滴。液滴促进了多种生物学过程这需要在细胞中的不同区域进行定位。但是，了解蛋白质的原则序列塑造其无序构象的合奏以执行其功能并促进相位仍然缺乏分离。氨基酸组成的简单度量解释了广泛的构象特征（半径，缩放指数）和趋势，序列的较小变化，由翻译后引起修改（PTM）/突变会大大改变无序的构象及其功能。 IDP也是如此避免传统的序列比对工具，以对各种物种的功能上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型计算框架，以描述具有任意序列的IDP的无序构象的合奏。了解PTM/突变如何夫妇患有不同的解决方案条件，以改变IDP构象和IDP倾向分开，我们需要计算高效的模型。模型必须能够处理组合由于优先突变/修改，分析多个序列及其变体的挑战，在不同条件下的替代剪接。寻求进化签名时面临同样的挑战跨不同物种的多个序列。结合聚合物物理学，全原子的综合方法模拟和多个实验将建立粗粒模型，以进行此类高通量分析。提出的理论方法i）提供指导以确定IDP构象在体外如何不同 ii）ii）线束有限的数据（特定探针之间的SMFRET），以对距离进行预测在任意残留对和iii之间）建立一个严格的框架，用于比较残留物特异性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。计算高效的形式主义将大规模应用，以提供详细的描述构象合奏，包括残留对特定距离图（超越简单的可观察到回旋的半径，端到端距离，缩放指数）用于理解无序蛋白功能相似性/差异性，仅通过序列比对就不可能。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）改变 IDP解决方案中的构象，功能和促进或抑制相分离倾向。