Physical laws to control and regulate composition of multi-component biomolecular condensates

控制和调节多组分生物分子凝聚物成分的物理定律

• 批准号: 10713887
• 负责人: Gregory Dignon
• 金额: $ 35.94万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-22 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10713887
• 关键词: Binding; Biological; Biological Process; Biology; Cells; Communities; Computing Methodologies; Development; Disease; Dissociation; Environment; Laws; Life; Membrane; Modeling; Molecular Computations; Nucleic Acids; Organelles; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Physical condensation; Physics; Process; Proteins; Research; Research Personnel; Sodium Chloride; Stimulus; System; Temperature; Theoretical model; Work; design; new therapeutic target; programs; small molecule

Abstract Biomolecular phase separation is a fundamental process in biology which facilitates many biological functions. Through the process of phase separation, cells can compartmentalize certain molecules into a highly- concentrated condensed phase – commonly termed a condensate, or membraneless organelle (MLO) – that is distinct from the surrounding environment. These MLOs are important to biology because they are functionally distinct from their membrane-bound counterparts, and can be regulated by external stimuli, sometimes forming or dissociating spontaneously upon a change in conditions in the surroundings. Usually, MLOs are stabilized by a small subset of molecules, such as multivalent proteins containing intrinsically disordered regions, but contain dozens to hundreds of other proteins, nucleic acids, and other molecules. It is important to understand the physics and molecular interactions that determine the relative composition, and how this relates to the function and efficiency of an MLO. This is especially important for development of novel drugs that target proteins and nucleic acids within disease-causing condensates in biology. I plan to develop my research program to tackle important problems in this field by developing theoretical models to describe interactions and phase separation of multi-component mixtures of proteins and other biomolecules. Successful completion of this work will enable researchers to make predictions of how biomolecules contribute to phase separation in a multi-component system. We will also work to understand how MLOs are regulated by cellular conditions such as temperature, pH, or concentration of salt and other small molecules. We particularly wish to focus on the question of how phase separation is controlled by the presence of small molecules, such as metabolites, or pharmaceutical drugs. By working with theoretical and computational methods, we can consistently model the interactions of small molecules with MLO constituents, and how they partition inside a condensate. Successful completion of this work will contribute greatly to the community's understanding of how condensates are regulated and provide important design principles for small molecule, and biologic drugs developed specifically to target MLOs.

摘要 生物分子相分离是生物学中的一个基本过程，它促进了许多生物功能。 通过相分离过程，细胞可以将某些分子分隔成高度- 浓缩的凝聚相-通常称为凝聚物，或无膜细胞器（MLO）-即 与周围环境不同。这些MLO对生物学很重要，因为它们在功能上 与它们的膜结合对应物不同，并且可以由外部刺激调节，有时形成 或在环境条件变化时自发解离。通常，MLO通过以下方式稳定 分子的一小部分，如含有内在无序区域的多价蛋白质，但含有 几十到几百种其他蛋白质、核酸和其他分子。重要的是要了解 决定相对组成的物理和分子相互作用，以及这与功能的关系 和效率。这对于开发靶向蛋白质的新药尤其重要， 在生物学中致病浓缩物中的核酸。我计划发展我的研究项目， 通过发展理论模型来描述相互作用和相分离， 蛋白质和其他生物分子的多组分混合物。这项工作的顺利完成将使 研究人员预测生物分子如何在多组分体系中促进相分离 系统我们还将努力了解MLO如何受到细胞条件（如温度）的调节， pH值或盐和其他小分子的浓度。我们特别希望集中讨论如何 相分离由小分子如代谢物或药物的存在控制 毒品通过使用理论和计算方法，我们可以一致地模拟 具有MLO成分的小分子，以及它们如何在冷凝物内分配。成功完成 这项工作将大大有助于社会的理解如何冷凝调节，并提供 小分子的重要设计原则和专门针对MLO开发的生物药物。