Chemical reactions as control mechanisms for biomolecular condensates

Medientyp: E-Book; Hochschulschrift

Titel: Chemical reactions as control mechanisms for biomolecular condensates

Beteiligte: Kirschbaum, Jan [Verfasser:in]; Zwicker, David [Akademische:r Betreuer:in]; Müller, Marcus [Akademische:r Betreuer:in]; Alim, Karen [Akademische:r Betreuer:in]

Erschienen: Göttingen, 2022

Umfang: 1 Online-Ressource; Illustrationen, Diagramme

Sprache: Deutsch

Identifikator:

Schlagwörter: Biomolecular Condensates ; Reaction-Diffusion Equation ; Phase Separation ; Hochschulschrift

Entstehung:

Hochschulschrift: Dissertation, Georg-August-Universität Göttingen, 2022

Anmerkungen:

Beschreibung: Biological 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 forma...

Biological cells need to structure their interior in space and time. One way this is done arecontainers enclosed by a membrane as a physical barrier that can control which molecules enterand leave the container. Another, recently discovered, class are biomolecular condensates.These are liquid like droplets that form via liquid liquid phase separation. Although they haveno membrane, they do have distinctly different composition from the surrounding. Weak attractiveinteractions between the molecules in the condensate prevent them from diffusing outof the condensate. To control the formation and dissolution of these condensates, the cell canchange the attractive interaction between molecules via chemical reactions.In this thesis, we develop a theory of phase separation with chemical reactions based onthermodynamic arguments. The chemical reactions switch between two states of a protein, onestate phase separates and forms droplets, while the other state is soluble in the solvent. Theaim of this thesis was to analyze how such simple reactions can control the phase separationprocess, 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 systemrelaxes to thermodynamic equilibrium. Unlike two component fluids, fluids consisting ofmultiple components with equilibrium reactions can form droplets, depending on the systemparameters. We find that equilibrium reactions introduce a new parameter to control phaseseparation, the internal energy difference between the two protein states. This internal energydifference can control how much protein is in the phase separating state and thereby, if dropletsform or not. We show that the droplet size is very sensitive to changes in the internal energydifference. However, the parameter range for control of droplets is narrow. In addition, theinternal energy difference is an equilibrium property of the proteins, thus, it can not be changedfast or in a specific manner.In the second part of the thesis, we extend our model to non-equilibrium reactions. In thiscase, the reaction is coupled to fuel molecules, which introduce external energy into the systemand drive the reaction away from thermodynamic equilibrium. The external driving strength isa 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 rescaledinternal energy difference that depends on the driving strength. This is different if both reactionpathways, the driven and equilibrium reaction, are present. In this case, the total amountof phase separating proteins depends on the reaction kinetics, i.e. on the relative reaction ratesof the two pathways. We show that this allows precise, fast and specific control over dropletformation and dissolution. The reason is, that the kinetic parameters can be tuned by enzymesthat act only on specific reactions. Finally, motivated by experimental observations, we investigatewhat happens if enzymes that catalyze the driven reaction are enriched in the dropletphase. We find that the enzymatic enrichment can control individual droplet size and stabilizemultiple droplets of the same size against their thermodynamic tendency to form one bigdroplet.We show that size control of droplets by reactions is based on three specific features ofthe reactions. (i) A protein exists in a soluble and a phase separating state and the transitionbetween the two states can be described as a chemical reaction. (ii) There are at least tworeaction pathways for the transition and at least one has to be driven out of equilibrium. (iii) Thereaction rates in droplet and solvent phase need to be different, for example, due to enrichmentof enzymes in the droplet.More generally, our results highlight that chemical reactions in phase separating environmentscan not be described by standard mass action kinetics. The reason is that phase separatingsystems are inherently non-ideal and mass action kinetics are only valid in ideal, dilutesolutions. Instead, a thermodynamic treatment of reactions is necessary, which takes into accountthat droplets formed by phase separation are chemically different from the solvent phasedue to enthalpic interactions.$v2022-07-06$v2022-07-06$xN$4LF

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