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Chemical Reactions as Control Mechanisms for Biomolecular Condensates

dc.contributor.advisorZwicker, David Dr.
dc.contributor.authorKirschbaum, Jan
dc.titleChemical Reactions as Control Mechanisms for Biomolecular Condensatesde
dc.contributor.refereeZwicker, David Dr.
dc.subject.gokPhysik (PPN621336750)de
dc.description.abstractengBiological cells need to structure their interior in space and time. One way this is done are containers enclosed by a membrane as a physical barrier that can control which molecules enter and leave the container. Another, recently discovered, class are biomolecular condensates. These are liquid like droplets that form via liquid liquid phase separation. Although they have no membrane, they do have distinctly different composition from the surrounding. Weak attractive interactions between the molecules in the condensate prevent them from diffusing out of the condensate. To control the formation and dissolution of these condensates, the cell can change the attractive interaction between molecules via chemical reactions. In this thesis, we develop a theory of phase separation with chemical reactions based on thermodynamic arguments. The chemical reactions switch between two states of a protein, one state phase separates and forms droplets, while the other state is soluble in the solvent. The aim of this thesis was to analyze how such simple reactions can control the phase separation process, for example, the formation, dissolution, and size control of droplets. In the first part of the thesis, we investigate equilibrium reactions. In this case, the system relaxes to thermodynamic equilibrium. Unlike two component fluids, fluids consisting of multiple components with equilibrium reactions can form droplets, depending on the system parameters. We find that equilibrium reactions introduce a new parameter to control phase separation, the internal energy difference between the two protein states. This internal energy difference can control how much protein is in the phase separating state and thereby, if droplets form or not. We show that the droplet size is very sensitive to changes in the internal energy difference. However, the parameter range for control of droplets is narrow. In addition, the internal energy difference is an equilibrium property of the proteins, thus, it can not be changed fast or in a specific manner. In the second part of the thesis, we extend our model to non-equilibrium reactions. In this case, the reaction is coupled to fuel molecules, which introduce external energy into the system and drive the reaction away from thermodynamic equilibrium. The external driving strength is a new parameter, which describes how strong the system is driven from equilibrium. We find, that driven reactions alone can be mapped onto an effective equilibrium system with rescaled internal energy difference that depends on the driving strength. This is different if both reaction pathways, the driven and equilibrium reaction, are present. In this case, the total amount of phase separating proteins depends on the reaction kinetics, i.e. on the relative reaction rates of the two pathways. We show that this allows precise, fast and specific control over droplet formation and dissolution. The reason is, that the kinetic parameters can be tuned by enzymes that act only on specific reactions. Finally, motivated by experimental observations, we investigate what happens if enzymes that catalyze the driven reaction are enriched in the droplet phase. We find that the enzymatic enrichment can control individual droplet size and stabilize multiple droplets of the same size against their thermodynamic tendency to form one big droplet. We show that size control of droplets by reactions is based on three specific features of the reactions. (i) A protein exists in a soluble and a phase separating state and the transition between the two states can be described as a chemical reaction. (ii) There are at least two reaction pathways for the transition and at least one has to be driven out of equilibrium. (iii) The reaction rates in droplet and solvent phase need to be different, for example, due to enrichment of enzymes in the droplet. More generally, our results highlight that chemical reactions in phase separating environments can not be described by standard mass action kinetics. The reason is that phase separating systems are inherently non-ideal and mass action kinetics are only valid in ideal, dilute solutions. Instead, a thermodynamic treatment of reactions is necessary, which takes into account that droplets formed by phase separation are chemically different from the solvent phase due to enthalpic
dc.contributor.coRefereeMüller, Marcus Prof. Dr.
dc.contributor.thirdRefereeAlim, Karen Prof. Dr.
dc.subject.engBiomolecular Condensatesde
dc.subject.engReaction-Diffusion Equationde
dc.subject.engPhase Separationde
dc.affiliation.instituteFakultät für Physikde

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