Emulsions ripen with an average droplet size increasing in time. In chemically active emulsions, coarsening can be absent, leading to a non-equilibrium steady state with mono-disperse droplet sizes. By considering a minimal model for phase separation and chemical reactions maintained away from equilibrium, we show that there is a critical transition in the conserved quantity between two classes of chemically active droplets: intensive and extensive ones. Single intensive active droplets reach a stationary size mainly controlled by the reaction-diffusion length scales. Intensive droplets in an emulsion interact only weakly, and the stationary size of a single droplet approximately sets the size of each droplet. On the contrary, the size of a single extensive active droplet scales with the system size, similar to passive phases. In an emulsion of many extensive droplets, their sizes become stationary only due to interactions among them. We discuss how the critical transition between intensive and extensive active droplets affects shape instabilities, including the division of active droplets, paving the way for the observation of successive division events in chemically active emulsions
 

 

 

Formation of biomolecular condensates via phase separation enables compartmentation of many cellular processes. However, how cells can control condensation at specific locations to create complex cellular structures remains poorly understood. Here, we investigated the mechanism of tight junction formation, which involves condensation of scaffold proteins at cell-cell contacts and elongation of the condensates into a belt around the cellular perimeter. Using cell biology, reconstitution, and thermodynamic theory, we discovered that cells use surface phase transitions to control local condensation at the membrane far below bulk saturation. Surface condensation of junctional ZO-scaffold proteins is mediated by receptor binding and regulated by the receptor’s oligomerization state. Functionally, ZO surface condensation is directly coupled to actin polymerization and bundling, which drives elongation of receptor-ZO-actin condensates similar to tight junction belt formation in cells. We conclude that surface phase transitions provide a robust mechanism to control the position and shape of protein condensates.

 

 

Flocks of animals represent a fascinating archetype of collective behavior in the macroscopic classical world, where the constituents, such as birds, concertedly perform motions and actions as if being one single entity. Here, we address the outstanding question of whether flocks can also form in the microscopic world at the quantum level. For that purpose, we introduce the concept of active quantum matter by formulating a class of models of active quantum particles on a one-dimensional lattice. We provide both analytical and large-scale numerical evidence that these systems can give rise to quantum flocks. A key finding is that these flocks, unlike classical ones, exhibit distinct quantum properties by developing strong quantum coherence over long distances. We propose that quantum flocks could be experimentally observed in Rydberg atom arrays. Our work paves the way towards realizing the intriguing collective behaviors of biological active particles in quantum matter systems. We expect that this opens up a path towards a yet totally unexplored class of nonequilibrium quantum many-body systems with unique properties.

 

 

Wetting of liquid droplets on passive surfaces is ubiquitous in our daily lives, and the governing physical laws are well-understood. When surfaces become active, however, the governing laws of wetting remain elusive. Here we propose chemically active wetting as a new class of active systems where the surface is active due to a binding process that is maintained away from equilibrium. We derive the corresponding non-equilibrium thermodynamic theory and show that active binding fundamentally changes the wetting behavior, leading to steady, non-equilibrium states with droplet shapes reminiscent of a pancake or a mushroom. The origin of such anomalous shapes can be explained by mapping to electrostatics, where pairs of binding sinks and sources correspond to electrostatic dipoles along the triple line. This is an example of a more general analogy, where localized chemical activity gives rise to a multipole field of the chemical potential. The underlying physics is relevant for cells, where droplet-forming proteins can bind to membranes accompanied by the turnover of biological fuels.

 

Interactions among proteins in living cells can lead to molecular assemblies of different sizes and large-scale coexisting phases formed via phase separation. Both are essential for the spatial organization of cells and for regulating biological function and dysfunction. A key challenge is understanding the interplay between molecular assembly and phase separation. However, a corresponding theoretical framework that relies on thermodynamic principles is lacking. Here, we present a non-equilibrium thermodynamic theory for a multi-component mixture that contains assemblies of different sizes, which can form, dissolve, and phase-separate from the solvent. We show that the size distributions of assemblies differ between the phases and that the dense phase can gelate. Moreover, we unravel the mechanisms involved in growth and compositional changes of the coexisting phases during assembly kinetics. Our theory can explain how molecular assembly is intertwined with phase separation, and our results are consistent with recent experimental observations on protein phase separation.

 

Phase-separated liquid condensates can spatially organize and thereby regulate chemical processes. However, the physicochemical mechanisms underlying such regulation remain elusive as the intramolecular interactions responsible for phase separation give rise to a coupling between diffusion and chemical reactions at nondilute conditions. Here, we derive a theoretical framework that decouples the phase separation of scaffold molecules from the reaction kinetics of diluted clients. As a result, phase volume and client partitioning coefficients become control parameters, which enables us to dissect the impact of phase-separated condensates on chemical reactions. We apply this framework to two chemical processes and show how condensates affect the yield of reversible chemical reactions and the initial rate of a simple assembly process. In both cases, we find an optimal condensate volume at which the respective chemical reaction property is maximal. Our work can be applied to experimentally quantify how condensed phases alter chemical processes in systems biology and unravel the mechanisms of how biomolecular condensates regulate biochemistry in living cells.

 

Recent experimental studies suggest that wet–dry cycles and coexisting phases can each strongly alter chemical processes. The mechanisms of why and to what degree chemical processes are altered when subjected to evaporation and condensation are unclear. To close this gap, we developed a theoretical framework for nondilute chemical reactions subject to nonequilibrium conditions of evaporation and condensation. We find that such conditions can change the half-time of the product’s yield by more than an order of magnitude, depending on the substrate–solvent interaction. We show that the cycle frequency strongly affects the chemical turnover when the system is maintained out of equilibrium by wet–dry cycles. There exists a resonance behavior in the cycle frequency where the turnover is maximal. This resonance behavior enables wet–dry cycles to select specific chemical reactions, suggesting a potential mechanism for chemical evolution in prebiotic soups at early Earth.

 

Biomolecules, such as proteins and nucleic acids, can phase separate in the cytoplasm of cells to form biomolecular condensates. Such condensates are often liquid-like droplets that can wet biological surfaces such as membranes. Many molecules that participate in phase separation can also reversibly bind to membrane surfaces. When a droplet wets a surface, molecules can diffuse inside and outside of the droplet or in the bound state on the surface. How the interplay between surface binding, diffusion in surface and bulk affects the wetting kinetics is not well understood. Here, we derive the governing equations using non-equilibrium thermodynamics by relating the thermodynamic fluxes and forces at the surface coupled to the bulk. We study the spreading dynamics in the presence of surface binding and find that binding speeds up wetting by nucleating a droplet inside the surface. Our results suggest that the wetting dynamics of droplets can be regulated by two-dimensional surface droplets in the surface-bound layer through changing the binding affinity to the surfaces. These findings are relevant both to engineering life-like systems with condensates and vesicles, and biomolecular condensates in living cells.

 

Biological cells utilize membranes and liquid-like droplets, known as biomolecular condensates, to structure their interior. The interaction of droplets and membranes, despite being involved in several key biological processes, is so far little understood. Here, we present a first numerical method to simulate the continuum dynamics of droplets interacting with deformable membranes via wetting. The method combines the advantages of the phase-field method for multiphase flow simulation and the arbitrary Lagrangian-Eulerian method for an explicit description of the elastic surface. The model is thermodynamically consistent, coupling bulk hydrodynamics with capillary forces, as well as bending, tension, and stretching of a thin membrane. The method is validated by comparing simulations for single droplets to theoretical results of shape equations, and its capabilities are illustrated in two- and three-dimensional axisymmetric scenarios.

 

We present a theory for phase-separated liquid coacervates with salt, taking into account spatial heterogeneities and interfacial profiles. We find that charged layers of alternating sign can form around the interface while the bulk phases remain approximately charge neutral. We show that the salt concentration regulates the number of layers and the amplitude of the layer's charge density and electrostatic potential. Such charged layers can either repel or attract single-charged molecules diffusing across the interface. Our theory could be relevant for artificial systems and biomolecular condensates in cells. Our work suggests that interfaces of biomolecular condensates could mediate charge-specific transport similar to membrane-bound compartments.

 

The emergence of functional oligonucleotides on early Earth required a molecular selection mechanism to screen for specific sequences with prebiotic functions. Cyclic processes such as daily temperature oscillations were ubiquitous in this environment and could trigger oligonucleotide phase separation. Here, we propose sequence selection based on phase separation cycles realized through sedimentation in a system subjected to the feeding of oligonucleotides. Using theory and experiments with DNA, we show sequence-specific enrichment in the sedimented dense phase, in particular of short 22-mer DNA sequences. The underlying mechanism selects for complementarity, as it enriches sequences that tightly interact in the dense phase through base-pairing. Our mechanism also enables initially weakly biased pools to enhance their sequence bias or to replace the previously most abundant sequences as the cycles progress. Our findings provide an example of a selection mechanism that may have eased screening for auto-catalytic self-replicating oligonucleotides.

 

Liquid-liquid phase separation yields spherical droplets that eventually coarsen to one large, stable droplet governed by the principle of minimal free energy. In chemically fueled phase separation, the formation of phase-separating molecules is coupled to a fuel-driven, non-equilibrium reaction cycle. It thus yields dissipative structures sustained by a continuous fuel conversion. Such dissipative structures are ubiquitous in biology but are poorly understood as they are governed by non-equilibrium thermodynamics. Here, we bridge the gap between passive, close-to-equilibrium, and active, dissipative structures with chemically fueled phase separation. We observe that spherical, active droplets can undergo a morphological transition into a liquid, spherical shell. We demonstrate that the mechanism is related to gradients of short-lived droplet material. We characterize how far out of equilibrium the spherical shell state is and the chemical power necessary to sustain it. Our work suggests alternative avenues for assembling complex stable morphologies, which might already be exploited to form membraneless organelles by cells.

 

We study a chemically active binary mixture undergoing phase separation and show that under nonequilibrium conditions, stable liquid spherical shells can form via a spinodal instability in the droplet center. A single liquid shell tends to grow until it undergoes a shape instability beyond a critical size. In an active emulsion, many stable and stationary liquid shells can coexist. We discuss conditions under which liquid shells are stable and dominant as compared to regimes where droplets undergo shape instabilities and divide.

 

Living cells are spatially organized by compartments that can nucleate, grow, and dissolve. Compartmentalization can emerge by phase separation, leading to the formation of droplets in the cell's nucleo- or cytoplasm, also called biomolecular condensates. Such droplets can organize the biochemistry of the cell by providing specific chemical environments in space and time. These compartments provide transient environments, suggesting the relevance of nonequilibrium physics of droplets as a key to unraveling the underlying physicochemical principles of biological functions in living cells. In this review, we highlight coarse-grained approaches that capture the physics of chemically active emulsions as a model for condensates orchestrating chemical processes. We also discuss the dynamics of single molecules in condensates and the material properties of biological condensates and their relevance for the cell. Finally, we propose wetting, prewetting, and surface phase transitions as a possibility for intracellular surfaces to control biological condensates, spatially organize membranes, and exert mechanical forces.

 

The kinetics of chemical reactions are determined by the law of mass action, which has been successfully applied to homogeneous, dilute mixtures. At non-dilute conditions, interactions among the components can give rise to coexisting phases, which can significantly alter the kinetics of chemical reactions. Here, we derive a theory for chemical reactions in coexisting phases at phase equilibrium. We show that phase equilibrium couples the rates of chemical reactions of components with their diffusive exchanges between the phases. Strikingly, the chemical relaxation kinetics can be represented as a flow along the phase equilibrium line in the phase diagram. A key finding of our theory is that differences in reaction rates between coexisting phases stem solely from phase- dependent reaction rate coefficients. Our theory is key to interpret how concentration levels of reactive components in condensed phases control chemical reaction rates in synthetic and biological systems.

 

 

Liquid condensates are membraneless organelles that form via phase separation in living cells. These condensates provide unique heterogeneous environments that have much potential in regulating a range of biochemical processes from gene expression to filamentous protein aggregation—a process linked to Alzheimer's and Parkinson's diseases. Here we theoretically study the physical interplay between protein aggregation, its inhibition, and liquid-liquid phase separation. Our key finding is that the action of protein aggregation inhibitors can be strongly enhanced by liquid condensates. The physical mechanism of this enhancement relies on the partitioning and colocalization of inhibitors with their targets inside the liquid condensate. Our theory uncovers how the physicochemical properties of condensates can be used to modulate inhibitor potency, and we provide experimentally testable conditions under which drug potency is maximal. Our findings suggest design principles for protein aggregation inhibitors with respect to their phase-separation properties.

 

 

Biomolecular condensates in living cells can exhibit a complex rheology, including viscoelastic and glassy behavior. This rheological behavior of condensates was suggested to regulate polymerization of cytoskeletal filaments and aggregation of amyloid fibrils. Here, we theoretically investigate how the rheological properties of condensates can control the formation of linear aggregates. To this end, we propose a kinetic theory for linear aggregation in coexisting phases, which accounts for the aggregate size distribution and the exchange of aggregates between inside and outside of condensates. The rheology of condensates is accounted in our model via aggregate mobilities that depend on aggregate size. We show that condensate rheology determines whether aggregates of all sizes or dominantly small aggregates are exchanged between condensate inside and outside on the timescale of aggregation. As a result, the ratio of aggregate numbers inside to outside of condensates differs significantly. Strikingly, we also find that weak variations in the rheological properties of condensates can lead to a switch-like change of the number of aggregates. These results suggest a possible physical mechanism for how living cells could control linear aggregation in a switch-like fashion through variations in condensate rheology.

 

 

Chemically active droplets provide simple models for cell-like systems that can grow and divide. Such active droplet systems are driven away from thermodynamic equilibrium and turn over chemically, which corresponds to a simple metabolism. Two scenarios of nonequilibrium driving are considered. First, droplets are driven via the system boundaries by external reservoirs that supply nutrient and remove waste (boundary-driven). Second, droplets are driven by a chemical energy provided by a fuel in the bulk (bulk-driven). For both scenarios, the conservation of energy and matter as well as the balance of entropy are discussed. Conserved and nonconserved fields are used to analyse the nonequilibrium steady states of active droplets. Using an effective droplet model, droplet stability and instabilities leading to droplet division are explored. This work reveals that droplet division occurs quite generally in active droplet systems. The results suggest that life-like processes such as metabolism and division can emerge in simple nonequilibrium systems that combine the physics of phase separation and chemical reactions.

 

 

Recent studies have shown that the interactions between condensates and biological membranes are of functional importance. Here, we study how the interaction between complex coacervates and liposomes as model systems can lead to wetting, membrane deformation, and endocytosis. Depending on the interaction strength between coacervates and liposomes, the wetting behavior ranged from nonwetting to engulfment (endocytosis) and complete wetting. Endocytosis of coacervates was found to be a general phenomenon: coacervates made from a wide range of components could be taken up by liposomes. A simple theory taking into account surface energies and coacervate sizes can explain the observed morphologies. Our findings can help to better understand condensate–membrane interactions in cellular systems and provide new avenues for intracellular delivery using coacervates.

 

 

In living cells, protein-rich condensates can wet the cell membrane and surfaces of membrane-bound organelles. Interestingly, many phase-separating proteins also bind to membranes leading to a molecular layer of bound molecules. Here we investigate how binding to membranes affects wetting, prewetting and surface phase transitions. We derive a thermodynamic theory for a three-dimensional bulk in the presence of a two-dimensional, flat membrane. At phase coexistence, we find that membrane binding facilitates complete wetting and thus lowers the wetting angle. Moreover, below the saturation concentration, binding facilitates the formation of a thick layer at the membrane and thereby shifts the prewetting phase transition far below the saturation concentration. The distinction between bound and unbound molecules near the surface leads to a large variety of surface states and complex surface phase diagrams with a rich topology of phase transitions. Our work suggests that surface phase transitions combined with molecular binding represent a versatile mechanism to control the formation of protein-rich domains at intra-cellular surfaces.

 

 

We discuss the stochastic trajectories of single molecules in a phase-separated liquid, when a dense and a dilute phase coexist. Starting from a continuum theory of macroscopic phase separation we derive a stochastic Langevin equation for molecular trajectories that takes into account thermal fluctuations. We find that molecular trajectories can be described as diffusion with drift in an effective potential, which has a steep gradient at phase boundaries. We discuss how the physics of phase coexistence affects the statistics of molecular trajectories and in particular the statistics of displacements of molecules crossing a phase boundary. At thermodynamic equilibrium detailed balance imposes that the distributions of displacements crossing the phase boundary from the dense or from the dilute phase are the same. Our theory can be used to infer key phase separation parameters from the statistics of single-molecule trajectories. For simple Brownian motion, there is no drift in the presence of a concentration gradient. We show that interactions in the fluid give rise to an average drift velocity in concentration gradients. Interestingly, under non-equilibrium conditions, single molecules tend to drift uphill the concentration gradient. Thus, our work bridges between single-molecule dynamics and collective dynamics at macroscopic scales and provides a framework to study single-molecule dynamics in phase-separating systems.

 

 

Phase separation and transitions among different molecular states are ubiquitous in living cells. Such transitions can be governed by local equilibrium thermodynamics or by active processes controlled by biological fuel. It remains largely unexplored how the behavior of phase-separating systems with molecular transitions differs between thermodynamic equilibrium and cases in which the detailed balance of the molecular transition rates is broken because of the presence of fuel. Here, we present a model of a phase-separating ternary mixture in which two components can convert into each other. At thermodynamic equilibrium, we find that molecular transitions can give rise to a lower dissolution temperature and thus reentrant phase behavior. Moreover, we find a discontinuous thermodynamic phase transition in the composition of the droplet phase if both converting molecules attract themselves with similar interaction strength. Breaking the detailed balance of the molecular transition leads to quasi-discontinuous changes in droplet composition by varying the fuel amount for a larger range of intermolecular interactions. Our findings showcase that phase separation with molecular transitions provides a versatile mechanism to control properties of intracellular and synthetic condensates via discontinuous switches in droplet composition.

 

 

Key processes of biological condensates are diffusion and material exchange with their environment. Experimentally, diffusive dynamics are typically probed via fluorescent labels. However, to date, a physics-based, quantitative framework for the dynamics of labeled condensate components is lacking. Here, we derive the corresponding dynamic equations, building on the physics of phase separation, and quantitatively validate the related framework via experiments. We show that by using our framework, we can precisely determine diffusion coefficients inside liquid condensates via a spatio-temporal analysis of fluorescence recovery after photobleaching (FRAP) experiments. We showcase the accuracy and precision of our approach by considering space- and time-resolved data of protein condensates and two different polyelectrolyte-coacervate systems. Interestingly, our theory can also be used to determine a relationship between the diffusion coefficient in the dilute phase and the partition coefficient, without relying on fluorescence measurements in the dilute phase. This enables us to investigate the effect of salt addition on partitioning and bypasses recently described quenching artifacts in the dense phase. Our approach opens new avenues for theoretically describing molecule dynamics in condensates, measuring concentrations based on the dynamics of fluorescence intensities, and quantifying rates of biochemical reactions in liquid condensates.

 

 

Membraneless compartments, also known as condensates, provide chemically distinct environments and thus spatially organize the cell. A well-studied example of condensates is P granules in the roundworm Caenorhabditis elegans that play an important role in the development of the germline. P granules are RNA-rich protein condensates that share the key properties of liquid droplets such as a spherical shape, the ability to fuse, and fast diffusion of their molecular components. An outstanding question is to what extent phase separation at thermodynamic equilibrium is appropriate to describe the formation of condensates in an active cellular environment. To address this question, we investigate the response of P granule condensates in living cells to temperature changes. We observe that P granules dissolve upon increasing the temperature and recondense upon lowering the temperature in a reversible manner. Strikingly, this temperature response can be captured by in vivo phase diagrams that are well described by a Flory–Huggins model at thermodynamic equilibrium. This finding is surprising due to active processes in a living cell. To address the impact of such active processes on intracellular phase separation, we discuss temperature heterogeneities. We show that, for typical estimates of the density of active processes, temperature represents a well-defined variable and that mesoscopic volume elements are at local thermodynamic equilibrium. Our findings provide strong evidence that P granule assembly and disassembly are governed by phase separation based on local thermal equilibria where the nonequilibrium nature of the cytoplasm is manifested on larger scales.

 

 

Non-equilibrium, fuel-driven reaction cycles serve as model systems of the intricate reaction networks of life. Rich and dynamic behavior is observed when reaction cycles regulate assembly processes, such as phase separation. However, it remains unclear how the interplay between multiple reaction cycles affects the success of emergent assemblies. To tackle this question, we created a library of molecules that compete for a common fuel that transiently activates products. Often, the competition for fuel implies that a competitor decreases the lifetime of these products. However, in cases where the transient competitor product can phase-separate, such a competitor can increase the survival time of one product. Moreover, in the presence of oscillatory fueling, the same mechanism reduces variations in the product concentration while the concentration variations of the competitor product are enhanced. Like a parasite, the product benefits from the protection of the host against deactivation and increases its robustness against fuel variations at the expense of the robustness of the host. Such a parasitic behavior in multiple fuel-driven reaction cycles represents a lifelike trait, paving the way for the bottom-up design of synthetic life.

 

 

A major challenge in cell biology remains unraveling how cells control their biochemical reaction cycles. For instance, how do they regulate gene expression in response to stress? How does their metabolism change when resources are scarce? Control theory has proven useful in understanding how networks of chemical reactions can robustly tackle those and other tasks.1 The essential ingredients in such approaches are chemical feedback loops that create control mechanisms similar to the circuits that regulate, for example, the temperature of a heating system, the humidity of an archive, or the pH of a fermentation tank.

 

 

Zellen führen biochemische Prozesse aus, um zentrale Abläufe wie die Zellteilung zu realisieren. Bei der dafür erforderlichen raumzeitlichen Organisation der zellulären Prozesse kommt den Organellen eine wichtige Rolle zu. Organellen wie die Mitochondrien oder der Zellkern sind durch Membranen von ihrer Umgebung getrennt. Diese ermöglichen es ihnen, in ihrem Inneren geeignete biochemische Bedingungen für biologische Prozesse zu erzeugen. Doch es gibt auch membranlose Organellen. Wie bewahren diese ihre chemische Identität? Hierbei kommt die Koexistenz proteinreicher, flüssiger Phasen ins Spiel. Ausgehend von der Physikder Phasenseparation ist ein tieferes Verständnis der Dynamik und raumzeitlichen Organisation biochemischer Prozesse möglich.

 

 

We present a minimal model to study the effects of pH on liquid phase separation of macromolecules. Our model describes a mixture composed of water and macromolecules that exist in three different charge states and have a tendency to phase separate. This phase separation is affected by pH via a set of chemical reactions describing protonation and deprotonation of macromolecules, as well as self-ionization of water. We consider the simple case in which interactions are captured by Flory-Huggins interaction parameters corresponding to Debye screening lengths shorter than a nanometer, which is relevant to proteins inside biological cells under physiological conditions. We identify the conjugate thermodynamic variables at chemical equilibrium and discuss the effective free energy at fixed pH. First, we study phase diagrams as a function of macromolecule concentration and temperature at the isoelectric point of the macromolecules. We find a rich variety of phase diagram topologies, including multiple critical points, triple points, and first-order transition points. Second, we change the pH relative to the isoelectric point of the macromolecules and study how phase diagrams depend on pH. We find that these phase diagrams as a function of pH strongly depend on whether oppositely charged macromolecules or neutral macromolecules have a stronger tendency to phase separate. One key finding is that we predict the existence of a reentrant behavior as a function of pH. In addition, our model predicts that the region of phase separation is typically broader at the isoelectric point. This model could account for both in vitro phase separation of proteins as a function of pH and protein phase separation in yeast cells for pH values close to the isoelectric point of many cytosolic proteins.

 

 

Chemically fueled emulsions are solutions with droplets made of phase-separated molecules that are activated and deactivated by a chemical reaction cycle. These emulsions play a crucial role in biology as a class of membrane-less organelles. Moreover, theoretical studies show that droplets in these emulsions can evolve to the same size or spontaneously self-divide when fuel is abundant. All of these exciting properties, i. e., emergence, decay, collective behavior, and self-division, are pivotal to the functioning of life. However, these theoretical predictions lack experimental systems to test them quantitively. Here, we describe the synthesis of synthetic emulsions formed by a fuel-driven chemical cycle, and we find a surprising new behavior, i. e., the dynamics of droplet growth is regulated by the kinetics of the fuel-driven reaction cycle. Consequently, the average volume of these droplets grows orders of magnitude faster compared to Ostwald ripening. Combining experiments and theory, we elucidate the underlying mechanism.

 

 

Channel formation and branching is widely seen in physical systems where movement of fluid through a porous structure causes the spatiotemporal evolution of the medium. We provide a simple theoretical framework that embodies this feedback mechanism in a multiphase model for flow through a frangible porous medium with a dynamic permeability. Numerical simulations of the model show the emergence of branched networks whose topology is determined by the geometry of external flow forcing. This allows us to delineate the conditions under which splitting and/or coalescing branched network formation is favored, with potential implications for both understanding and controlling branching in soft frangible media.

 

 

Protein aggregation has been implicated in many medical disorders, including Alzheimer’s and Parkinson’s diseases. Potential therapeutic strategies for these diseases propose the use of drugs to inhibit specific molecular events during the aggregation process. However, viable treatment protocols require balancing the efficacy of the drug with its toxicity, while accounting for the underlying events of aggregation and inhibition at the molecular level. To address this key problem, we combine here protein aggregation kinetics and control theory to determine optimal protocols that prevent protein aggregation via specific reaction pathways. We find that the optimal inhibition of primary and fibril-dependent secondary nucleation require fundamentally different drug administration protocols. We test the efficacy of our approach on experimental data for the aggregation of the amyloid-β(1-42) peptide of Alzheimer’s disease in the model organism Caenorhabditis elegans. Our results pose and answer the question of the link between the molecular basis of protein aggregation and optimal strategies for inhibiting it, opening up avenues for the design of rational therapies to control pathological protein aggregation.

 

 

Phase separating systems that are maintained away from thermodynamic equilibrium via molecular processes represent a class of active systems, which we call active emulsions. These systems are driven by external energy input, for example provided by an external fuel reservoir. The external energy input gives rise to novel phenomena that are not present in passive systems. For instance, concentration gradients can spatially organise emulsions and cause novel droplet size distributions. Another example are active droplets that are subject to chemical reactions such that their nucleation and size can be controlled, and they can divide spontaneously. In this review, we discuss the physics of phase separation and emulsions and show how the concepts that govern such phenomena can be extended to capture the physics of active emulsions. This physics is relevant to the spatial organisation of the biochemistry in living cells, for the development of novel applications in chemical engineering and models for the origin of life.

 

 

Liquid cellular compartments form in the cyto- or nucleoplasm and can regulate aberrant protein aggregation. Yet, the mechanisms by which these compartments affect protein aggregation remain unknown. Here, we combine kinetic theory of protein aggregation and liquid-liquid phase separation to study the spatial control of irreversible protein aggregation in the presence of liquid compartments. We find that even for weak interactions aggregates strongly partition into the liquid compartment. Aggregate partitioning is caused by a positive feedback mechanism of aggregate nucleation and growth driven by a flux maintaining the phase equilibrium between the compartment and its surrounding. Our model establishes a link between specific aggregating systems and the physical conditions maximizing aggregate partitioning into the compartment. The underlying mechanism of aggregate partitioning could be used to confine cytotoxic protein aggregates inside droplet-like compartments but may also represent a common mechanism to spatially control irreversible chemical reactions in general.

 

 

Many bacteria rely on active cell appendages, such as type IV pili, to move over substrates and interact with neighboring cells. Here, we study the motion of individual cells and bacterial colonies, mediated by the collective interactions of multiple pili. It was shown experimentally that the substrate motility of Neisseria gonorrhoeae cells can be described as a persistent random walk with a persistence length that exceeds the mean pili length. Moreover, the persistence length increases for a higher number of pili per cell. With the help of a simple, tractable stochastic model, we test whether a tug of war without directional memory can explain the persistent motion of single Neisseria gonorrhoeae cells. While persistent motion of single cells indeed emerges naturally in the model, a tug of war alone is not capable of explaining the motility of microcolonies, which becomes weaker with increasing colony size. We suggest sliding friction between the microcolonies and the substrate as the missing ingredient. While such friction almost does not affect the general mechanism of single cell motility, it has a strong effect on colony motility. We validate the theoretical predictions by using a three-dimensional computational model that includes explicit details of the pili dynamics, force generation, and geometry of cells.