Multiscale Simulations of Droplet-Membrane Mutual Remodelling

在细胞生物学中，细胞内相分离作为一种通过形成液滴状亚室来组织细胞内溶液的方法，最近引起了人们的广泛关注。这种液滴间室的例子包括应力颗粒和p体。这个项目的关键是这些液滴与膜相互作用，因此，液滴和膜可以相互重塑它们的形状和形态。例如，在自噬过程中，膜片重塑成称为自噬体的双膜细胞器。自噬体可以选择性地分离货物以消除，包括有害的细胞质液滴。事实上，许多生理过程已被确定具有类似的膜形态，这表明这些液滴-膜相互作用是一种普遍的细胞机制。这个跨学科项目的目的是发展对这些液滴-膜相互作用的急需的理解，以及它们在液滴分离过程中的相互重塑。在这里，我们将使用多尺度建模方法。在分子水平上，我们将采用分子动力学模拟来研究液滴通过液-液相分离机制的形成以及液滴与膜之间的亲和力。这些结果将为研究液滴和膜的形状提供基于弹性理论的连续体建模方法。学生的理论/计算工作也将提供一个重要的框架来合理化和指导正在进行的体外和体内实验。我们的长期目标是利用这种基于液滴-膜相互作用的新型物理机制，为细胞内的过程提供新的见解。

In cellular biology, intracellular phase separation has garnered much attention recently as a means to organise intracellular solutions through the formation of droplet-like sub-compartments. Examples of such droplet compartments include the stress granules and P-bodies.Key to this project is that these droplets interact with membranes, and as a result, the droplets and the membranes can mutually remodel their shapes and morphologies. For example, during autophagy, membrane sheets remodel into double-membrane organelles called autophagosomes. Autophagosomes can selectively isolate cargoes for elimination, including harmful cytosolic droplets. In fact, numerous physiological processes have been identified with similar membrane morphologies, suggesting that these droplet-membrane interactions are a general cellular mechanism.The aim of this interdisciplinary project is to develop the much-needed understanding of these droplet-membrane interactions, and their mutual remodelling during droplet isolation. Here, we will use a multiscale modelling approach. At the molecular level, we will employ molecular dynamics simulations to study the formation of the droplets via a liquid-liquid phase separation mechanism and the affinity between the droplet and membrane. These results will inform a continuum modelling approach based on elasticity theory for studying the droplet and membrane shapes. The theoretical/computational work by the student will also provide an important framework to rationalise and guide ongoing in vitro and in vivo experiments. Our long-term goal is to provide new insights into processes inside cells exploiting this novel physical mechanism based on droplet-membrane interactions.