Multiscale Modeling of Phase Transitions Driven by Multivalency and Disordered Proteins

多价和无序蛋白质驱动的相变的多尺度建模

• 批准号: 1614766
• 负责人: Rohit Pappu
• 金额: $ 96.35万
• 依托单位: Washington University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-15 至 2021-06-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1614766&HistoricalAwards=false
• 关键词: Multiscale; Modeling; Phase; Transitions; Driven

This project will uncover how biological matter is organized into tiny functional compartments inside cells. These compartments resemble liquid droplets. They are known as membraneless organelles and they perform different functions in different types of cells. They collect different types of molecules and form in different locations within cells. An example of a specific membraneless organelle is one that collects key protein and RNA molecules to assist in the formation of connections in the brain. This is essential for learning and the development of memories. Distinct protein molecules drive the formation of distinct membraneless organelles. In some cases, the identities of the relevant proteins are known. It is also known that membraneless organelles form by processes known as phase separation, which are similar to processes that lead to the separation of oil from vinegar. Research in this project will uncover the relationships between specific proteins and the physical and chemical interactions that lead to the formation of membraneless organelles via phase separation. This research is important because membraneless organelles control a variety of cellular functions that can go wrong and give rise to diseases. The research will use computations that combine physics and chemistry to answer biologically relevant questions. The research will also fuel the development of specific instruction modules, which will be used in the INSPIRE program at Washington University. The goal is to attract rising high-school freshmen from the St. Louis area and teach them the importance of quantitative sciences for driving discoveries in biology. This will help prepare the next generation of scientists to take on technological challenges at the intersection of physics, chemistry, mathematics and biology.Membrane-less organelles are dense, highly viscous liquids that form via liquid-liquid phase separation. This refers to the separation of polymers into dense, polymer-rich liquids that are in equilibrium with polymer-poor dispersed phases. It is often the case that a single protein is necessary and sufficient to drive the formation of a specific organelle. Multivalent interactions and intrinsic disorder are defining features of proteins that drive phase separation. The project will focus on the specificity of interactions among short linear motifs, their valencies, and the patterning of motifs in archetypal sequences that drive phase separation. The research will also test specific predictions that have been made recently regarding the role of disordered linkers as modulators of the phase behavior of multidomain proteins. A suite of novel multiscale, multiresolution, high-throughput computational methods will drive the project research. These will be combined with experiments in test tubes and in cells. The experiments will be performed in collaboration with accomplished investigators in the field of intracellular phase separation. Polymer physics theories will be adapted to facilitate integration of computational results with experimental data. Integration of the results investigations using polymer physics theories will lead to a comprehensive understanding of how sequence features of low complexity IDPs influence the driving forces for phase separation.This project is jointly funded by the Molecular Biophysics Cluster in the Division of Molecular and Cellular Biosciences and the Physics of Living Systems Program in the Division of Physics.

这个项目将揭示生物物质是如何组织成细胞内微小的功能隔间的。这些隔间类似于液滴。它们被称为无膜细胞器，在不同类型的细胞中发挥不同的功能。它们收集不同类型的分子，并在细胞内的不同位置形成。一个特定的无膜细胞器的例子是收集关键的蛋白质和RNA分子来帮助大脑中连接的形成。这对于学习和记忆的发展是必不可少的。不同的蛋白质分子驱动形成不同的无膜细胞器。在某些情况下，相关蛋白质的身份是已知的。众所周知，无膜细胞器的形成过程被称为相分离，这类似于从醋中分离油的过程。该项目的研究将揭示特定蛋白质与物理和化学相互作用之间的关系，这些相互作用通过相分离导致无膜细胞器的形成。这项研究很重要，因为无膜细胞器控制着各种细胞功能，这些功能可能会出错并引发疾病。这项研究将使用物理和化学相结合的计算来回答与生物相关的问题。这项研究还将推动特定教学模块的开发，这些模块将用于华盛顿大学的INSPIRE项目。其目标是吸引圣路易斯地区正在崛起的高一新生，并向他们传授定量科学对推动生物学发现的重要性。这将有助于下一代科学家为迎接物理、化学、数学和生物学交叉领域的技术挑战做好准备。无膜细胞器是通过液-液相分离形成的致密、高粘度的液体。这指的是将聚合物分离成致密的富含聚合物的液体，这些液体与贫聚的分散相保持平衡。通常情况下，一种蛋白质是驱动特定细胞器形成所必需的，也是足够的。多价相互作用和内在无序是驱动相分离的蛋白质的定义特征。该项目将专注于短线性基序之间相互作用的特殊性，它们的价态，以及驱动相分离的原型序列中的基序模式。这项研究还将测试最近做出的关于无序连接体作为多结构域蛋白质相行为调节器的作用的具体预测。一套新颖的多尺度、多分辨率、高通量计算方法将推动该项目的研究。这些将与试管和细胞中的实验相结合。这些实验将与细胞内相分离领域的资深研究人员合作进行。聚合物物理理论将被调整，以促进计算结果与实验数据的整合。综合使用聚合物物理理论的研究结果，将导致对低复杂性IDPs的序列特征如何影响相分离的驱动力的全面理解。该项目由分子和细胞生物科学部的分子生物物理学集群和物理系的生命系统物理计划联合资助。