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

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的发挥。 通过相分离的过程，细胞可以将某些分子分割成高度... 浓缩凝聚相--通常称为凝聚态，或无膜细胞器(MLO)--即 与周围环境截然不同。这些MLO对生物学很重要，因为它们在功能上 与膜结合的同类不同，可以受到外部刺激的调节，有时形成 或在周围条件发生变化时自发地解离。通常，MLO通过以下方式稳定下来 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 几十到数百种其他蛋白质、核酸和其他分子。重要的是要了解 确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MLO的效率。这对于靶向蛋白质和蛋白质的新药的开发尤为重要 生物学中致病凝集物中的核酸。我计划开发我的研究项目来解决 通过开发描述相互作用和相分离的理论模型来解决该领域中的重要问题 蛋白质和其他生物分子的多组分混合物。这项工作的成功完成将使 研究人员预测生物分子如何促进多组分的相分离 系统。我们还将努力了解MLO是如何受到温度等细胞条件的调节的， PH值，即盐和其他小分子的浓度。我们特别希望集中讨论如何 相分离是由小分子的存在控制的，如代谢物或药物 毒品。通过使用理论和计算方法，我们可以一致地对 含有MLO成分的小分子，以及它们如何在凝析油中分配。成功完成 这项工作将极大地有助于社区了解凝析油是如何受到监管的，并提供 小分子的重要设计原则，以及专门针对MLO开发的生物药物。

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.