Periodic Reporting for period 1 - EmulSim (Integrated simulations of active emulsions in complex environments)
Reporting period: 2022-10-01 to 2025-03-31
Biological cells consist of a myriad of interacting biomolecules that collectively arrange in stable structures. Understanding the physical principles of such spatiotemporal control is crucial for curing diseases and leveraging similar principles for designing synthetic systems. The project EmulSim focus on the physical process of phase separation, which describes how molecular interactions lead to the spontaneous formation of droplets, known as biomolecular condensates, in cells. We now know that malfunctioning condensates can cause diseases like Alzheimer’s, Parkinson’s, and cancer. Yet, we do not understand how condensates become malfunctioning and how healthy cells control them. Some challenges in understanding condensate dynamics are that cells are heterogeneous, have complex material properties, and exhibit significant thermal fluctuations. Biological cells are also alive and use fuel molecules to control processes actively. However, it is unclear how such active droplets behave in the complex environments inside cells. The main objective of EmulSim is to study the effect of multiple physical processes onto biomolecular condensates to obtain a clearer picture of how cells control them, what might go wrong during diseases, and how we might be able to fix this.
Specifically, the objective of EmulSim is to provide a novel integrated simulation method incorporating relevant processes on all length scales. On the scale of individual droplets, it will incorporate the influence of driven reactions and elastic material properties of droplets. On the cellular scale, the effect of the elastic cytoskeleton and the presence of multiple compartments will be crucial. For each of these processes, we derive experimentally verified models using examples of relevant biological processes, including cell division, chromatin organization, and signaling. Combining the physical theories for these critical processes will culminate in an agent-based model describing a collection of droplets, ultimately also including thermal fluctuations. This novel simulation framework will model biomolecular condensates in their cellular environment taking key physical processes into account and providing a platform for future research and extensions to include additional processes. Taken together, the objective of EmulSim is to propel our understanding of biomolecular condensates and lay the ground for the development of novel therapies in medicine.
Specifically, the objective of EmulSim is to provide a novel integrated simulation method incorporating relevant processes on all length scales. On the scale of individual droplets, it will incorporate the influence of driven reactions and elastic material properties of droplets. On the cellular scale, the effect of the elastic cytoskeleton and the presence of multiple compartments will be crucial. For each of these processes, we derive experimentally verified models using examples of relevant biological processes, including cell division, chromatin organization, and signaling. Combining the physical theories for these critical processes will culminate in an agent-based model describing a collection of droplets, ultimately also including thermal fluctuations. This novel simulation framework will model biomolecular condensates in their cellular environment taking key physical processes into account and providing a platform for future research and extensions to include additional processes. Taken together, the objective of EmulSim is to propel our understanding of biomolecular condensates and lay the ground for the development of novel therapies in medicine.
In the first period of the project, we started many proposed projects, and brought some to a successful finish, culminating in publications. For instance, we developed a novel numerical method to determine how mixtures of many different components phase separate. Using this method, we found that such systems possess surprisingly many different states that can all be realized. This insight will allow us to assess better how the complex mixture inside cells behave. Along those lines, we also developed a model, which allows us to study the effect of elasticity on droplets that grow by incorporating material using chemical reactions. The physical framework is general, but we tested it on the concrete example of centrosomes, which are crucial during cell division. Together, these steps help us analyze how the complex molecules that make up a cell behave during phase separation.
To understand how droplets interact with the cellular environments, we analyzed a theory that conceptualizes the cell as multiple connected compartments, e.g. formed by lipid membranes. We showed that the interplay between such compartmentalization, multimerization of molecules, and their unspecific interactions can have profound effects on phase separation. After publishing the theory, we are now in the process of validating the theories using the biologically relevant example of membrane patterning. Another example that we analyze in detail concerns droplets embedded in elastic meshes, like that formed by the cytoskeleton. We found that such meshes restrict droplet growth and can lead to a regular arrangement of droplets while also limiting their size.
We also made first steps toward the larger aim of building a flexible simulation framework, where the dynamics of droplets is described explicitly by incorporating the theories described above. We are already using this approach to study the biologically relevant example of crossover interference, which determines how maternal and paternal DNA are mixed during meiosis. We are currently incorporating thermal fluctuations into this framework to account for the small size of natural condensates
To understand how droplets interact with the cellular environments, we analyzed a theory that conceptualizes the cell as multiple connected compartments, e.g. formed by lipid membranes. We showed that the interplay between such compartmentalization, multimerization of molecules, and their unspecific interactions can have profound effects on phase separation. After publishing the theory, we are now in the process of validating the theories using the biologically relevant example of membrane patterning. Another example that we analyze in detail concerns droplets embedded in elastic meshes, like that formed by the cytoskeleton. We found that such meshes restrict droplet growth and can lead to a regular arrangement of droplets while also limiting their size.
We also made first steps toward the larger aim of building a flexible simulation framework, where the dynamics of droplets is described explicitly by incorporating the theories described above. We are already using this approach to study the biologically relevant example of crossover interference, which determines how maternal and paternal DNA are mixed during meiosis. We are currently incorporating thermal fluctuations into this framework to account for the small size of natural condensates
Two aims of the actual proposal led to particularly surprising results, extending the state of the art significantly: First, we developed a new numerical tool to determine coexisting states in multicomponent mixtures, which we can now exploit to study such mixtures in much more detail. This tool is now publicly available as part of our effort to provide computational tools to the community. Second, we discovered that the effect of external meshes on droplets can be best approximated by non-local elasticity theory, which allows us to capture the effect of the mesh even when the mesh size is comparable to the droplet size. This approach extends to many problems in elasticity theory where phenomena take place on the order of the mesh size and is thus also far more general than initially anticipated. In fact, we realized that also other interactions (e.g. chemical reactions and charge) can be conceptualized as nonlocal interactions, which we explorer in ongoing work that goes beyond the aims of the proposal. Beyond these unexpected break-throughs, all finished and ongoing projects improve our understanding of how cells control their condensates and thus push our knowledge beyond the state of the arts. We particularly notice this in our lively discussions with experimentalists and during conferences.