Publications

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.

arxiv.org/pdf/2112.07576.pdf

Condensates in living cells can exhibit a complex rheology including viscoelastic and glassy behaviour. This rheological behavior of condensates was suggested to regulate polymerisation 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 the aggregate size distribution and the exchange of aggregates between inside and outside of condensates. The rheology of condensates is accounted for by aggregate mobilities that depend on aggregate size. We show that condensate rheology can control whether either aggregates of all sizes or dominantly small aggregates are exchanged between condensate inside and outside on the time-scale 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.

doi.org/10.1101/2021.11.05.467474

In living cells, liquid condensates form in the cytoplasm and nucleoplasm via phase separation and regulate physiological processes. They also regulate aberrant aggregation of amyloid fibrils, a process linked to Alzheimer's and Parkinson's diseases. In the absence of condensates it has been shown that amyloid aggregation can be inhibited by molecular chaperones and rationally designed drugs. However it remains unknown how this drug- or chaperone-mediated inhibition of amyloid fibril aggregation is affected by phase-separated condensates. Here we study the interplay between protein aggregation, its inhibition and liquid-liquid phase separation. Our key finding is that the potency of inhibitors of amyloid formation can be strongly enhanced. We show that the corresponding mechanism relies on the colocalization of inhibitors and aggregates inside the liquid condensate. We provide experimentally testable physicochemical conditions under which the increase of inhibitor potency is most pronounced. Our work highlights the role of spatio-temporal heterogeneity in curtailing aberrant protein aggregation and suggests design principles for amyloid inhibitors accounting for partitioning of drugs into liquid condensates.

www.biorxiv.org/content/10.1101/2020.10.29.360206v1

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.

https://doi.org/10.1088/1367-2630/ac320b

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.

doi.org/10.1103/PhysRevResearch.3.043150

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.

https://doi.org/10.1016/j.bpj.2021.09.036

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.

elifesciences.org/articles/68620

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.

https://doi.org/10.1073/pnas.2102772118

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.

pubs.rsc.org/en/content/articlelanding/2021/SC/D1SC01106E

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.

physicstoday.scitation.org/doi/10.1063/PT.3.4771

The physics of phase separation and the formation of protein-rich droplets play an important role for biochemical processes in living cells. The shape, size and composition of such droplets can change with time and thereby affect biochemical reactions. Such reactions also affect the dynamics of droplets. Obtaining insights into this interplay is key to better understand the mechanisms underlying the spatio-temporal organization of biological cells.

www.mpg.de/16067567/pks_jb_2020

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.

Physik Journal der deutschen physikalischen Gesellschaft, Dec 2020

We present a minimal model to study liquid phase separation in a fixed pH ensemble. The model describes a mixture composed of macromolecules that exist in three different charge states and have a tendency to phase separate. We introduce the pH dependence of phase separation by means of a set of reactions describing the protonation and deprotonation of macromolecules, as well as the self-ionisation of water. We use conservation laws to identify the conjugate thermodynamic variables at chemical equilibrium. Using this thermodynamic conjugate variables we perform a Legendre transform which defines the corresponding free energy at fixed pH. We first study the possible phase diagram topologies at the isoelectric point of the macromolecules. We then show how the phase behavior depends on pH by moving away from the isoelectric point. We find that phase diagrams as a function of pH strongly depend on whether oppositely charged macromolecules or neutral macromolecules have a stronger tendency to phase separate. We predict the existence of reentrant behavior as a function of pH. In addition, our model also predicts that the region of phase separation is typically broader at the isoelectric point. This model could account for both, the protein separation observed in yeast cells for pH values close to the isoelectric point of many cytosolic proteins and also for the in vitro experiments of single proteins exhibiting phase separation as a function of pH.

Biophys. J www.sciencedirect.com/science/article/abs/pii/S0006349520307165

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 in response to the flow, in turn causing flow pathways to evolve. We provide a simple theoretical framework that embodies this feedback mechanism in a multi-phase model for flow through a fragile 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.

arxiv.org/abs/2007.02997

Phys. Rev. Lett. 125, 158002 (2020)

A range of medical conditions, such as Alzheimer’s disease, Parkinson’s disease, and type II diabetes, are linked to protein aggregation. Thus, it is imperative to develop effective therapeutic strategies to combat protein aggregation. Here, we lay out a general approach for optimizing inhibition strategies based on small molecules that suppress nucleation or growth of aggregates. Our model reveals that the optimal timing of drug administration crucially depends on whether the compound inhibits primary nucleation, secondary nucleation, or the growth of aggregates. This approach could guide the rational design of therapeutic strategies to target protein aggregation diseases.

PNAS: doi.org/10.1073/pnas.1904090116

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.

Reports on Progress in Physics, Volume 82, Number 6

Liquid cellular compartments spatially segregate from the cytoplasm and can regulate aberrant protein aggregation, a process linked to several medical conditions, including Alzheimer's and Parkinson's diseases. Yet the mechanisms by which these droplet-like 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 between the compartment constituents and the aggregating monomers, aggregates are strongly enriched inside the liquid compartment relative to the surrounding cytoplasm. We show that this enrichment is caused by a positive feedback mechanism of aggregate nucleation and growth which is mediated by a flux maintaining the phase equilibrium between the compartment and the cytoplasm. Our model predicts that the compartment volume that maximizes aggregate enrichment in the compartment is determined by the reaction orders of aggregate nucleation. The underlying mechanism of aggregate enrichment could be used to confine cytotoxic protein aggregates inside droplet-like compartments suggesting potential new avenues against aberrant protein aggregation. Our findings could also represent a common mechanism for the spatial control of irreversible chemical reactions in general.

eLife 2019;8:e42315 DOI: 10.7554/eLife.42315

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 the 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.

Phys. Rev. E 99, 042419 

Microcolonies are aggregates of a few dozen to a few thousand cells exhibited by many bacteria. The formation of microcolonies is a crucial step towards the formation of more mature bacterial communities known as biofilms, but also marks a significant change in bacterial physiology. Within a microcolony, bacteria forgo a single cell lifestyle for a communal lifestyle hallmarked by high cell density and physical interactions between cells potentially leading to differentiation. It is thus crucial to understand how initially identical single cells start to behave differently while assembling in these tight communities. Here we show that cells in the microcolonies formed by the human pathogen Neisseria gonorrhoeae (Ng) present differential motility behaviors within an hour upon colony formation. Observation of merging microcolonies and tracking of single cells within microcolonies reveal a heterogeneous motility behavior: cells close to the surface of the microcolony exhibit a much higher motility compared to cells towards the center. Numerical simulations of a biophysical model for the microcolonies at the single cell level of detail suggest that mechanical forces exerted by the bacterial cells are sufficient to generate the observed heterogeneous motility. Further corroborating this idea, bacteria lacking the ability to exert forces on their surroundings segregate on the outside of microcolonies as predicted by the model. This emergence of differential behavior within a multicellular microcolony of otherwise identical cells is thus mainly of mechanical origin and is likely the first step toward further bacterial differentiation and ultimately mature biofilms.

Scientific Reportsvolume 8, Article number: 16567 (2018) 

Here we investigate how droplet position can be controlled using concentration profiles of a regulator that influences phase separation. We consider a mean field model of a ternary mixture where a concentration gradient of a regulator is imposed by an external potential. We show that novel first order phase transition exists that controls droplet position in a discontinuous manner. Such a droplet switch in concentration gradients could be relevant for the spatial organization of biological cells and provides a control mechanism for droplets in microfluidic systems.

New Journal of Physics, 20, 2018.

Active stresses can cause instabilities in contractile gels and living tissues. Here we provide a generic hydrodynamic theory that treats these systems as a mixture of two phases of varying activity and different mechanical properties. We find that differential activity between the phases causes a uniform mixture to undergo a demixing instability. We follow the nonlinear evolution of the instability and characterize a phase diagram of the resulting patterns. Our study complements other instability mechanisms in mixtures driven by differential adhesion, differential diffusion, differential growth, and differential motion.

Phys. Rev. Lett. 120, 248003 (2018).

Living cells use phase separation and concentration gradients to organize chemical compartments in space. Here, we present a theoretical study of droplet dynamics in gradient systems. We derive the corresponding growth law of droplets and find that droplets exhibit a drift velocity and position dependent growth. As a consequence, the dissolution boundary moves through the system, thereby segregating droplets to one end. We show that for steep enough gradients, the ripening leads to a transient arrest of droplet growth that is induced by a narrowing of the droplet size distribution.

New Journal of Physics, 19, 5, Pp. 053021 (2017).

The influence of size differences, shape, mass, and persistent motion on phase separation in binary mixtures has been intensively studied. Here we focus on the exclusive role of diffusivity differences in binary mixtures of equal-sized particles. We find an effective attraction between the less diffusive particles, which are essentially caged in the surrounding species with the higher diffusion constant. This effect leads to phase separation for systems above a critical size: A single close-packed cluster made up of the less diffusive species emerges. Experiments for testing our predictions are outlined.

Phys. Rev. Lett., 116, Pp. 058301.

It has been proposed that during the early steps in the origin of life, small droplets could have formed via the segregation of molecules from complex mixtures by phase separation. These droplets could have provided chemical reaction centres. However, whether these droplets could divide and propagate is unclear. Here we examine the behaviour of droplets in systems that are maintained away from thermodynamic equilibrium by an external supply of energy. In these systems, droplets grow by the addition of droplet material generated by chemical reactions. Surprisingly, we find that chemically driven droplet growth can lead to shape instabilities that trigger the division of droplets into two smaller daughters. Therefore, chemically active droplets can exhibit cycles of growth and division that resemble the proliferation of living cells. Dividing active droplets could serve as a model for prebiotic protocells, where chemical reactions in the droplet play the role of a prebiotic metabolism.

 Nature Physics, doi:10.1038/nphys3984, Pp. 1745–2481

Neisseria gonorrhoeae is the causative agent of one of the most common sexually transmitted diseases, gonorrhea. Over the past two decades there has been an alarming increase of reported gonorrhea cases where the bacteria were resistant to the most commonly used antibiotics thus prompting for alternative antimicrobial treatment strategies. The crucial step in this and many other bacterial infections is the formation of microcolonies, agglomerates consisting of up to several thousands of cells. The attachment and motility of cells on solid substrates as well as the cell–cell interactions are primarily mediated by type IV pili, long polymeric filaments protruding from the surface of cells. While the crucial role of pili in the assembly of microcolonies has been well recognized, the exact mechanisms of how they govern the formation and dynamics of microcolonies are still poorly understood. Here, we present a computational model of individual cells with explicit pili dynamics, force generation and pili–pili interactions. We employ the model to study a wide range of biological processes, such as the motility of individual cells on a surface, the heterogeneous cell motility within the large cell aggregates, and the merging dynamics and the self-assembly of microcolonies. The results of numerical simulations highlight the central role of pili generated forces in the formation of bacterial colonies and are in agreement with the available experimental observations. The model can quantify the behavior of multicellular bacterial colonies on biologically relevant temporal and spatial scales and can be easily adjusted to include the geometry and pili characteristics of various bacterial species. Ultimately, the combination of the microbiological experimental approach with the in silico model of bacterial colonies might provide new qualitative and quantitative insights on the development of bacterial infections and thus pave the way to new antimicrobial treatments.

New Journal of Physics, 19, 1, Pp. 015003

P granules are non-membrane-bound RNA-protein compartments that are involved in germline development in C. elegans. They are liquids that condense at one end of the embryo by localized phase separation, driven by gradients of polarity proteins such as the mRNA-binding protein MEX-5. To probe how polarity proteins regulate phase separation, we combined biochemistry and theoretical modeling. We reconstitute P granule-like droplets in vitro using a single protein PGL-3. By combining in vitro reconstitution with measurements of intracellular concentrations, we show that competition between PGL-3 and MEX-5 for mRNA can regulate the formation of PGL-3 droplets. Using theory, we show that, in a MEX-5 gradient, this mRNA competition mechanism can drive a gradient of P granule assembly with similar spatial and temporal characteristics to P granule assembly in vivo. We conclude that gradients of polarity proteins can position RNP granules during development by using RNA competition to regulate local phase separation.

Cell, 166, 6, Pp. 1572–1584

Many organisms form colonies for a transient period of time to withstand environmental pressure. Bacterial biofilms are a prototypical example of such behavior. Despite significant interest across disciplines, physical mechanisms governing the formation and dissolution of bacterial colonies are still poorly understood. Starting from a kinetic description of motile and interacting cells we derive a hydrodynamic equation for their density on a surface, where most of the kinetic coefficients are estimated from experimental data for N. gonorrhoeae bacteria. We use it to describe the formation of multiple colonies with sizes consistent with experimental observations. Finally, we show how the changes in the cell-to-cell interactions lead to the dissolution of the bacterial colonies. The successful application of kinetic theory to a complex far from equilibrium system such as formation and dissolution of living bacterial colonies potentially paves the way for the physical quantification of the initial stages of biofilm formation.

Phys. Rev. E, 92, Pp. 032704.

From the self-organization of the cytoskeleton to the synchronous motion of bird flocks, living matter has the extraordinary ability to behave in a concerted manner. The Boltzmann equation for self-propelled particles is frequently used in silico to link a system's meso- or macroscopic behaviour to the microscopic dynamics of its constituents. But so far such studies have relied on an assumption of simplified binary collisions owing to a lack of experimental data suggesting otherwise. We report here experimentally determined binary-collision statistics by studying a recently introduced molecular system, the high-density actomyosin motility assay. We demonstrate that the alignment induced by binary collisions is too weak to account for the observed ordering transition. The transition density for polar pattern formation decreases quadratically with filament length, indicating that multi-filament collisions drive the observed ordering phenomenon and that a gas-like picture cannot explain the transition of the system to polar order. Our findings demonstrate that the unique properties of biological active-matter systems require a description that goes well beyond that developed in the framework of kinetic theories.

Nature Physics, 11, 10, Pp. 839–843

Constituents of living or synthetic active matter have access to a local energy supply that serves to keep the system out of thermal equilibrium. The statistical properties of such fluctuating active systems differ from those of their equilibrium counterparts. Using the actin filament gliding assay as a model, we studied how nonthermal distributions emerge in active matter. We found that the basic mechanism involves the interplay between local and random injection of energy, acting as an analog of a thermal heat bath, and nonequilibrium energy dissipation processes associated with sudden jump-like changes in the system's dynamic variables. We show here how such a mechanism leads to a nonthermal distribution of filament curvatures with a non-Gaussian shape. The experimental curvature statistics and filament relaxation dynamics are reproduced quantitatively by stochastic computer simulations and a simple kinetic model.

Proceedings of the National Academy of Sciences, 112, 34, Pp. 10703-10707

How do topological defects affect the degree of order in active matter? To answer this question we investigate an agent-based model of self-propelled particles, which accounts for polar alignment and short-ranged repulsive interactions. For strong alignment forces we find collectively moving polycrystalline states with fluctuating networks of grain boundaries. In the regime where repulsive forces dominate, the fluctuations generated by the active system give rise to quasi-long-range transitional order, but unlike the thermal system without creating topological defects.

Phys. Rev. Lett., 112, Pp. 168301

Cells organize many of their biochemical reactions in non-membrane compartments. Recent evidence has shown that many of these compartments are liquids that form by phase separation from the cytoplasm. Here we discuss the basic physical concepts necessary to understand the consequences of liquid-like states for biological functions.

Annual review of cell and developmental biology, 30, Pp. 39–58

Kinetic theories constitute one of the most promising tools to decipher the characteristic spatiotemporal dynamics in systems of actively propelled particles. In this context, the Boltzmann equation plays a pivotal role, since it provides a natural translation between a particle-level description of the system's dynamics and the corresponding hydrodynamic fields. Yet, the intricate mathematical structure of the Boltzmann equation substantially limits the progress toward a full understanding of this equation by solely analytical means. Here, we propose a general framework to numerically solve the Boltzmann equation for self-propelled particle systems in two spatial dimensions and with arbitrary boundary conditions. We discuss potential applications of this numerical framework to active matter systems and use the algorithm to give a detailed analysis to a model system of self-propelled particles with polar interactions. In accordance with previous studies, we find that spatially homogeneous isotropic and broken-symmetry states populate two distinct regions in parameter space, which are separated by a narrow region of spatially inhomogeneous, density-segregated moving patterns. We find clear evidence that these three regions in parameter space are connected by first-order phase transitions and that the transition between the spatially homogeneous isotropic and polar ordered phases bears striking similarities to liquid-gas phase transitions in equilibrium systems. Within the density-segregated parameter regime, we find a novel stable limit-cycle solution of the Boltzmann equation, which consists of parallel lanes of polar clusters moving in opposite directions, so as to render the overall symmetry of the system's ordered state nematic, despite purely polar interactions on the level of single particles.

Phys. Rev. X, 4, Pp. 041030

Generic models of propelled particle systems posit that the emergence of polar order is driven by the competition between local alignment and noise. Although this notion has been confirmed employing the Boltzmann equation, the range of applicability of this equation remains elusive. We introduce a broad class of mesoscopic collision rules and analyze the prerequisites for the emergence of polar order in the framework of kinetic theory. Our findings suggest that a Boltzmann approach is appropriate for weakly aligning systems but is incompatible with experiments on cluster forming systems.

Phys. Rev. Lett., 111, Pp. 190601

Vibrated polar disks have been used experimentally to investigate collective motion of driven particles, where fully ordered asymptotic regimes could not be reached. Here we present a model reproducing quantitatively the single, binary, and collective properties of this granular system. Using system sizes not accessible in the laboratory, we show in silico that true long-range order is possible in the experimental system. Exploring the model?s parameter space, we find a phase diagram qualitatively different from that of dilute or pointlike particle systems.

Phys. Rev. Lett., 110, Pp. 208001

Actively propelled particles undergoing dissipative collisions are known to develop a state of spatially distributed coherently moving clusters. For densities larger than a characteristic value, clusters grow in time and form a stationary well-ordered state of coherent macroscopic motion. In this work we address two questions. (i) What is the role of the particles' aspect ratio in the context of cluster formation, and does the particle shape affect the system's behavior on hydrodynamic scales? (ii) To what extent does particle conservation influence pattern formation? To answer these questions we suggest a simple kinetic model permitting us to depict some of the interaction properties between freely moving particles and particles integrated in clusters. To this end, we introduce two particle species: single and cluster particles. Specifically, we account for coalescence of clusters from single particles, assembly of single particles on existing clusters, collisions between clusters and cluster disassembly. Coarse graining our kinetic model, (i) we demonstrate that particle shape (i.e. aspect ratio) shifts the scale of the transition density, but does not impact the instabilities at the ordering threshold and (ii) we show that the validity of particle conservation determines the existence of a longitudinal instability, which tends to amplify density heterogeneities locally, and in turn triggers a wave pattern with wave vectors parallel to the axis of macroscopic order. If the system is in contact with a particle reservoir, this instability vanishes due to a compensation of density heterogeneities.

New Journal of Physics, 15, 4, Pp. 045014

Collective motion in actively propelled particle systems is triggered on the very local scale by nucleation of coherently moving units consisting of just a handful of particles. These units grow and merge over time, ending up in a long-range ordered, coherently moving state. So far, there exists no bottom-up understanding of how the microscopic dynamics and interactions between the constituents are related to the system's ordering instability. In this paper, we study a class of models for propelled colloids allowing an explicit treatment of the microscopic details of the collision process. Specifically, the model equations are Newtonian equations of motion with separate force terms for particles' driving, dissipation, and interaction forces. Focusing on dilute particle systems, we analyze the binary scattering behavior for these models and determine, based on the microscopic dynamics, the corresponding collision rule, i.e., the mapping of precollisional velocities and impact parameter on postcollisional velocities. By studying binary scattering we also find that the considered models for active colloids share the same principle for parallel alignment: The first incoming particle (with respect to the center of collision) is aligned to the second particle as a result of the encounter. This behavior distinctively differs from alignment in nondriven dissipative gases. Moreover, the obtained collision rule lends itself as a starting point to apply kinetic theory for propelled particle systems in order to determine the phase boundary to a long-range ordered, coherently moving state. The microscopic origin of the collision rule offers the opportunity to quantitatively scrutinize the predictions of kinetic theory for propelled particle systems through direct comparison with multiparticle simulations. We identify local precursor correlations at the onset of collective motion to constitute the essential determinant for a qualitative and quantitative validity of kinetic theory. In conclusion, our "renormalized" approach clearly indicates that the framework of kinetic theory is flexible enough to accommodate the complex behavior of soft active colloids and allows a bottom-up understanding of how the microscopic dynamics of binary collisions relates to the system's behavior on large length and time scales.

Phys. Rev. E, 88, Pp. 052309

While the existence of polar ordered states in active systems is well established, the dynamics of the self-assembly processes are still elusive. We study a lattice gas model of self-propelled elongated particles interacting through excluded volume and alignment interactions, which shows a phase transition from an isotropic to a polar ordered state. By analyzing the ordering process we find that the transition is driven by the formation of a critical nucleation cluster and a subsequent coarsening process. Moreover, the time to establish a polar ordered state shows a power-law divergence.

Phys. Rev. E, 86, Pp. 030901

Directed cell migration toward spatio-temporally varying chemotactic stimuli requires rapid cytoskeletal reorganization. Numerous studies provide evidence that actin reorganization is controlled by intracellular redistribution of signaling molecules, such as the PI4,5P2/PI3,4,5P3 gradient. However, exploring underlying mechanisms is difficult and requires careful spatio-temporal control of external chemotactic stimuli. We designed a microfluidic setup to generate alternating chemotactic gradient fields for simultaneous multicell exposure, greatly facilitating statistical analysis. For a quantitative description of intracellular response dynamics, we apply alternating time sequences of spatially homogeneous concentration gradients, reorienting on timescales down to a few seconds. Dictyostelium discoideum amoebae respond to gradient switching rates below 0.02 Hz by readapting their migration direction. For faster switching, cellular repolarization ceases and is completely stalled at 0.1 Hz. In this chemotactically trapped cell state, external stimuli alternate faster than intracellular feedback is capable to respond by onset of directed migration. To investigate intracellular actin cortex rearrangement during gradient switching, we correlate migratory cell response with actin repolymerization dynamics, quantified by a fluorescence distribution moment of the GFP fusion protein LimEcc. We find two fundamentally different cell polarization types and we could reveal the role of PI3-Kinase for cellular repolarization. In the early aggregation phase, PI3-Kinase enhances the capability of D. discoideum cells to readjust their polarity in response to spatially alternating gradient fields, whereas in aggregation competent cells the effect of PI3-Kinase perturbation becomes less relevant.

Proceedings of the National Academy of Sciences, 108, 28, Pp. 11417-11422

Even simple active systems can show a plethora of intriguing phenomena and often we find complexity where we would have expected simplicity. One striking example is the occurrence of a quiescent or absorbing state with frozen fluctuations that at first sight seems to be impossible for active matter driven by the incessant input of energy. While such states were reported for externally driven systems through macroscopic shear or agitation, the investigation of frozen active states in inherently active systems like cytoskeletal suspensions or active gels is still at large. Using high-density motility assay experiments, we demonstrate that frozen steady states can arise in active systems if active transport is coupled to growth processes. The experiments are complemented by agent-based simulations which identify the coupling between self-organization, growth, and mechanical properties to be responsible for the pattern formation process.

Proceedings of the National Academy of Sciences, 108, 48, Pp. 19183-19188

How order can emerge spontaneously from a disordered system has always fascinated scientists from numerous disciplines. Especially in active systems like flocks animals, self-propelled microorganisms or the cytoskeleton, a unifying understanding of the pattern formation remains elusive. This is attributed to the inherent complexity of most model systems that prevents a thorough identification of the fundamental mechanisms that are responsible for the intriguing self-organizing phenomena in active systems. Here we show that long ranged hydrodynamic interactions play a crucial role in the pattern forming mechanisms in the high density motility assay, a precisely controllable minimal model system consisting of highly concentrated filaments that are driven on the nanoscale. Stability and size of the patterns depend on long ranged hydrodynamic interactions that are self-induced by the coherently moving filaments. The hydrodynamic interactions not only influence the spatial and temporal scale of the patterns but also affect the dynamics of a particular cluster in close proximity to confining boundaries or other surrounding clusters.

Soft Matter, 7, Pp. 3213–3218

The emergence of collective motion exhibited by systems ranging from flocks of animals to self-propelled microorganisms to the cytoskeleton is a ubiquitous and fascinating self-organization phenomenon. Similarities between these systems, such as the inherent polarity of the constituents, a density-dependent transition to ordered phases or the existence of very large density fluctuations suggest universal principles underlying pattern formation. This idea is followed by theoretical models at all levels of description: micro- or mesoscopic models directly map local forces and interactions using only a few, preferably simple, interaction rules, and more macroscopic approaches in the hydrodynamic limit rely on the systems' generic symmetries. All these models characteristically have a broad parameter space with a manifold of possible patterns, most of which have not yet been experimentally verified. The complexity of interactions and the limited parameter control of existing experimental systems are major obstacles to our understanding of the underlying ordering principles. Here we demonstrate the emergence of collective motion in a high-density motility assay that consists of highly concentrated actin filaments propelled by immobilized molecular motors in a planar geometry. Above a critical density, the filaments self-organize to form coherently moving structures with persistent density modulations, such as clusters, swirls and interconnected bands. These polar nematic structures are long lived and can span length scales orders of magnitudes larger than their constituents. Our experimental approach, which offers control of all relevant system parameters, complemented by agent-based simulations, allows backtracking of the assembly and disassembly pathways to the underlying local interactions. We identify weak and local alignment interactions to be essential for the observed formation of patterns and their dynamics. The presented minimal polar-pattern-forming system may thus provide new insight into emerging order in the broad class of active fluids and self-propelled particles.

Nature, 467, 7311, Pp. 73–77