CAREER: Programmable control of biomolecular condensate self-assembly

职业：生物分子凝聚体自组装的可编程控制

• 批准号: 2143670
• 负责人: William Jacobs
• 金额: $ 60.06万
• 依托单位: Princeton University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2143670&HistoricalAwards=false
• 关键词: CAREER; Programmable; control; biomolecular; condensate

NONTECHNICAL SUMMARYThe cytoplasm within a living cell consists of thousands of different types of molecules, including proteins and nucleic acids such as RNA. In order for many biological functions to occur, this complex mixture must be organized, with specific types of biomolecules either colocalizing or assembling into larger structures. This spatial organization is often dynamic, in the sense that many structures assemble, disassemble, or rearrange themselves in response to external stimuli. This CAREER award focuses on a particular class of structures known as biomolecular condensates, which are liquid-like structures composed of proteins and RNA. Using theoretical models and computer simulations, the PI aims to understand the mechanisms by which biomolecular condensates assemble and interface with one another, as well as how these processes can be controlled. These theories will not only improve our understanding of how biomolecules are organized inside of living cells, but also help to guide the development of biomimetic "living materials" that can similarly respond dynamically to specific stimuli.This project includes an integrated education plan that will train future scientists working at the interface of computational materials research and theoretical biophysics. This plan is motivated by the need to teach aspiring theorists both fundamental concepts and state-of-the-art methods for performing practical calculations. To unify the presentation of these topics, the PI will develop a pair of graduate-level courses that cover modern theories of complex fluids in parallel with related computer simulation techniques. These courses will emphasize applications relevant to the research activities of this award, as well as to current research at the interface of biology and soft condensed matter physics more broadly.TECHNICAL SUMMARYThis CAREER award supports theoretical and computational research to elucidate the self-assembly dynamics of intracellular biomolecular condensates, a recently discovered class of liquid-like protein and RNA-rich structures. Although many condensates assemble spontaneously, the dynamics of these intracellular self-assembly processes appear to be tightly controlled both spatially and temporally. This project will establish the physical principles underlying the assembly dynamics of multicomponent condensates by probing the mechanisms that allow condensates to assemble rapidly and in response to specific stimuli. Building on recent advances in the theory of multicomponent phase behavior, this research will use coarse-grained molecular simulations and rare-event sampling techniques to: 1) derive design rules for selectively seeding the assembly of one condensate out of a large number of competing structures, 2) investigate the relationship between the structure of protein/RNA interaction networks and the emergent condensate morphology, and 3) develop a molecular-level theory to describe how chemical reactions affect the nucleation dynamics of self-assembled condensates. The results of these studies will be used to guide future experimental efforts to manipulate biomolecular condensates in vivo, construct synthetic biomimetic condensates, and engineer stimulus-responsive soft materials.The integrated education plan addresses the need to unify the presentation of theoretical concepts, molecular-scale simulations, and continuum-level numerical methods in modern graduate-level coursework. The PI will develop a pair of graduate-level courses that cover topics from equilibrium and non-equilibrium statistical mechanics in parallel with techniques for performing practical calculations. The first of these courses will introduce students to modern molecular-level theories of complex fluids and non-equilibrium systems alongside closely related computational tools. The second course will cover the kinetics of phase transformations, with a focus on numerical methods spanning both molecular simulation and continuum-level approaches. Both courses will emphasize applications relevant to current research at the interface of biology and soft condensed matter physics by incorporating case studies from the current literature.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

活细胞内的细胞质由数千种不同类型的分子组成，包括蛋白质和核酸（如RNA）。 为了使许多生物功能发生，这种复杂的混合物必须被组织起来，特定类型的生物分子要么共定位，要么组装成更大的结构。 这种空间组织往往是动态的，在这个意义上，许多结构组装，拆卸，或重新安排自己响应外部刺激。 这个职业奖专注于一类特殊的结构，称为生物分子缩合物，这是由蛋白质和RNA组成的液体状结构。 使用理论模型和计算机模拟，PI旨在了解生物分子凝聚物组装和相互作用的机制，以及如何控制这些过程。 这些理论不仅有助于提高我们对生物分子在活细胞内如何组织的理解，而且有助于指导仿生“活材料”的开发，这种仿生“活材料”可以对特定刺激做出类似的动态响应。该项目包括一个综合教育计划，将培养未来从事计算材料研究和理论生物物理学接口的科学家。 这个计划的动机是需要教有抱负的理论家的基本概念和国家的最先进的方法进行实际计算。 为了统一这些主题的介绍，PI将开发一对研究生课程，涵盖复杂流体的现代理论与相关的计算机模拟技术。 这些课程将强调与该奖项的研究活动相关的应用，以及与更广泛的生物学和软凝聚态物理学接口的当前研究相关的应用。技术总结该职业奖项支持理论和计算研究，以阐明细胞内生物分子凝聚物的自组装动力学，这是最近发现的一类液体样蛋白质和富含RNA的结构。 虽然许多凝聚体组装自发，这些细胞内的自组装过程的动力学似乎是严格控制的空间和时间。 该项目将通过探索允许凝聚物快速组装和响应特定刺激的机制，建立多组分凝聚物组装动力学的物理原理。 基于多组分相行为理论的最新进展，本研究将使用粗粒度分子模拟和稀有事件采样技术：1）推导出用于从大量竞争结构中选择性地播种一种缩合物的组装的设计规则，2）研究蛋白质/RNA相互作用网络的结构与涌现的缩合物形态之间的关系，3）发展分子水平理论来描述化学反应如何影响自组装冷凝物的成核动力学。 这些研究的结果将被用来指导未来的实验工作，以操纵生物分子凝聚体在体内，构建合成仿生凝聚体，和工程师刺激响应softmaterials.The集成的教育计划解决了需要统一的理论概念，分子尺度模拟和连续水平的数值方法在现代研究生水平的课程介绍。 PI将开发一对研究生水平的课程，涵盖平衡和非平衡统计力学的主题，并与执行实际计算的技术并行。 这些课程的第一个将向学生介绍复杂流体和非平衡系统的现代分子水平理论以及密切相关的计算工具。 第二门课程将涵盖相变的动力学，重点是跨越分子模拟和连续水平方法的数值方法。 这两门课程都将通过结合当前文献中的案例研究来强调与当前生物学和软凝聚态物理学接口研究相关的应用。该奖项反映了NSF的法定使命，并被认为值得通过使用基金会的智力价值和更广泛的影响审查标准进行评估来支持。

项目成果

Programmable phase behavior in fluids with designable interactions

具有可设计相互作用的流体中的可编程相行为

• DOI: 10.1063/5.0147211
• 发表时间: 2023
• 期刊: The Journal of Chemical Physics
• 作者: Chen, Fan;Jacobs, William M.
• 通讯作者: Jacobs, William M.

Tuning Nucleation Kinetics via Nonequilibrium Chemical Reactions

通过非平衡化学反应调节成核动力学

• DOI: 10.1103/physrevlett.130.128203
• 发表时间: 2023
• 期刊: Physical Review Letters
• 影响因子: 8.6
• 作者: Cho, Yongick;Jacobs, William M.
• 通讯作者: Jacobs, William M.

Nonequilibrium interfacial properties of chemically driven fluids

化学驱动流体的非平衡界面特性

• DOI: 10.1063/5.0166824
• 发表时间: 2023
• 期刊: The Journal of Chemical Physics
• 作者: Cho, Yongick;Jacobs, William M.
• 通讯作者: Jacobs, William M.

Interplay between self-assembly and phase separation in a polymer-complex model

聚合物复合物模型中自组装和相分离之间的相互作用

• DOI: 10.1103/physreve.108.064501
• 发表时间: 2023
• 期刊: Physical Review E
• 影响因子: 2.4
• 作者: Li, Tianhao;Rogers, W. Benjamin;Jacobs, William M.
• 通讯作者: Jacobs, William M.

Theory and Simulation of Multiphase Coexistence in Biomolecular Mixtures

生物分子混合物中多相共存的理论与模拟

• DOI: 10.1021/acs.jctc.3c00198
• 发表时间: 2023
• 期刊: Journal of Chemical Theory and Computation
• 影响因子: 5.5
• 作者: Jacobs, William M.