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Biomolecular phase separation arises from collective molecular interactions and is emerging as a key theme for biological function. Here the authors propose a broadly applicable method to quantify these interactions based on compositional and energetic parameters.

Using RFdiffusion, a general method for targeting intrinsically disordered proteins and regions for protein design has been developed.

The organization of supramolecular peptide polymers determines their properties; however, controlling their dimensions still remains a problem. Here, Gazitet al. show the spontaneous elongation and shortening of these polymers at an individual nano-assembly level by using a microfluidic platform.

Nixon-Abell et al. show that ANXA11 condensation on lysosomal membranes causes a coupled phase transition of the underlying lipids and mechanical stiffening of the overall ensemble involved in RNP granule-lysosome tethering and co-trafficking.

The cytoskeleton, a network of fibrils, controls how cells divide. Here, the authors show that synthetic protein fibrils added to an emulsion can control the division of droplets and that this method can be used to control the morphology of microparticles during biomaterial preparation.

Experiments and computations show that the organization and dynamics of molecules within and at interfaces of biomolecular condensates are governed by differential interaction strengths leading to the classification of adsorbents versus scaffolds.

Molecular chaperones from the Hsp70 family can break up protein aggregates, including amyloids. Here, the authors utilize microfluidic diffusional sizing to assess the mechanism of α-synuclein (αS) disaggregation by the Hsc70–DnaJB1–Apg2 system, and show that single αS molecules are removed directly from the fibril ends.

Physical characterisation of proteins is challenging. Here the authors report single-molecule microfluidic diffusional sizing (smMDS) to enable calibration-free single-molecule diffusional-sizing based monitoring of protein hydrodynamic radii even within heterogenous multicomponent mixtures.

The formation of protein aggregates is a hallmark of Parkinson’s disease, with small oligomeric species implicated as a major source of toxicity. In this work, Xu et al. determine their mechanism of formation and role in aggregation.

Protein condensates exhibit diverse material properties linked to cellular functions, yet characterizing these properties remains challenging. Here, the authors employ a microfluidic sample deposition and nanometre-resolution mapping technique to characterize the time-dependent material properties in FUS protein condensates, revealing two distinct phase transitions within FUS condensates.

Protein aggregation and amyloid deposition are associated with a wide range of medical disorders, including Alzheimer's disease and type II diabetes. Studies into the amyloid state are revealing fundamental principles that underlie the maintenance of protein homeostasis, and the origins of aberrant protein behaviour and disease.

Small unilamellar vesicles composed of the negatively charged lipid DMPS enhance the aggregation of the Lewy Body disease protein α-synuclein by increasing the rate of primary nucleation by a thousandfold.

Biological photovoltaic devices (BPVs) use photosynthetic microorganisms to generate electricity, but their efficiency is low. Here the authors report power densities of over 0.5 W per m² for a flow-based BPV system, by decoupling the charging and the power delivery units.

Biomolecular condensates with internal structure allow cells to further organise their processes. In this work the authors investigate how condensates can obtain an internal structure with droplets of dilute phase inside via kinetic, rather than purely thermodynamic driving forces.

Suparmolecular polymers are built by monomers via non-covalent bonds, whilst the pathway of their nucleation processes is not yet clear. Here, Levin et al.show that the self-assembly of monomers proceeds through a series of metastable states, which are energetically governed by Ostwald’s rule of stages.

The elastic energy built up during peptide self-assembly is exploited in the realization of a microactuator. The energy stored is released on millisecond timescales via a buckling instability controlled with droplet microfluidics.

Biomolecular condensates help cells organise their content in space and time. Here the authors report a machine learning driven methodology to predict the composition of biomolecular condensates and they then validate their predictions against the composition of known biomolecular condensates.

Biomolecular condensates can contain multiple phases. The number of droplets of each phase and their location give the condensate a certain architecture. Here the authors present a method to create a range of transient architectures in biomolecular condensates, making the architecture or interfacial area controllable design variables in experiments.

A central concept for characterising phase-separating systems is the phase diagram but generation of such diagrams for biomolecular systems is typically slow and low-throughput. Here the authors describe PhaseScan, a combinatorial droplet microfluidic platform for high-resolution acquisition of multidimensional biomolecular phase diagrams.

There are limitations with current protein sensing methods. Here the authors report DigitISA, a digital immunosensor assay based on microchip electrophoretic separation and single-molecule detection that enables quantitation of protein biomarkers in a single, solution-phase step.

Well-ordered and highly rigid macroscopic films can be self-assembled from amyloid protein fibrils.

In this work the authors describe antimicrobial peptides (AMPs)-driven phase transitions of intracellular nucleic acids, whereby AMPs induce compaction and phase separation of nucleic acids, resulting in their sequestration and eventual cell death.

A dissipative self-assembly system was developed by re-engineering a naturally hexameric adenosine 5′-triphosphatase (ATPase) enzyme (filamentous temperature-sensitive protease H) to form transient one-dimensional tubular structures in an ATP-dependent fashion. These tubular structures in turn exert negative feedback on the ATP-dependent activation of the protein building blocks.

Molecular chaperones are recognized to interfere with protein aggregation, yet the underlying mechanisms are largely unknown. Here, the authors develop a kinetic model that reveals the variety of distinct microscopic mechanisms through which molecular chaperones act to suppress amyloid formation.

All-aqueous emulsions are useful for delivering and processing biomolecules, but their stability is constrained by low interfacial adsorption energy. Song et al. solve this problem using protein nanofibrils that form a crosslinked network, whose stability is superior to conventional colloidal capsules.

Fluorescence microscopy and kinetics analyses reveal that Aβ42 oligomers generated through secondary nucleation are responsible for membrane disruption.

Elucidating the molecular driving forces underlying liquid–liquid phase separation is a key objective for understanding biological function and malfunction. Here the authors show that a wide range of cellular proteins, including FUS, TDP-43, Brd4, Sox2, and Annexin A11, which form condensates at low salt concentrations, can reenter a phase-separated regime at high salt concentrations.

Developing disease-modifying drugs for neurodegenerative diseases has been very challenging. Now a machine learning approach has been used to identify small molecule inhibitors of α-synuclein aggregation, a process implicated in Parkinson’s disease and other synucleinopathies. Compounds that bind to the catalytic sites on the surface of the aggregates were identified and then progressively optimized into secondary nucleation inhibitors.

Cholesterol embedded in lipid membranes strongly promotes the aggregation of Aβ42 that is associated with Alzheimer's disease. Now, a kinetic analysis has shown that the mechanism of action responsible for this effect involves the introduction of a heterogeneous nucleation pathway that enhances the primary nucleation rate of Aβ42 aggregation by up to 20-fold.

Labelling biomolecules to improve the sensitivity of analysis can perturb their interactions. Now, microfluidic and chemical tools have been used to allow simple, sensitive detection of a labelled system to reveal the behaviour of the native and physiologically relevant unlabelled system. The system was used to characterize the solution-phase behaviour of a clinically relevant protein–protein interaction.

Short peptides derived from the HIV-1 glycoprotein form nanofibrils that can be used to improve viral gene delivery and concentrate viruses without the need for ultracentrifugation.

Green use of plant derived proteins in functional materials has been limited by inefficient methods to control micro and nanoscale structure. Here, the authors use nanoscale assembly of water-insoluble plant proteins to make meter scale films with comparable properties to conventional plastics.

The kinetics of prion aggregation are now dissected in mice, revealing slower PrP^Sc replication in vivo than in vitro and the contribution of aggregate fragmentation.

The effects of four antibodies on the aggregation pathway of Aβ are examined via an in-depth kinetics approach, revealing the specific molecular steps affected by each antibody.

The realization that the cell is abundantly compartmentalized into biomolecular condensates has opened new opportunities for understanding the physics and chemistry underlying many cellular processes¹, fundamentally changing the study of biology². The term biomolecular condensate refers to non-stoichiometric assemblies that are composed of multiple types of macromolecules in cells, occur through phase transitions, and can be investigated by using concepts from soft matter physics³. As such, they are intimately related to aqueous two-phase systems⁴ and water-in-water emulsions⁵. Condensates possess tunable emergent properties such as interfaces, interfacial tension, viscoelasticity, network structure, dielectric permittivity, and sometimes interphase pH gradients and electric potentials^6–14. They can form spontaneously in response to specific cellular conditions or to active processes, and cells appear to have mechanisms to control their size and location^15–17. Importantly, in contrast to membrane-enclosed organelles such as mitochondria or peroxisomes, condensates do not require the presence of a surrounding membrane.

Extrusion bioprinting can be used to produce living materials but controlling cell microenvironments is challenging. Here, the authors use a type of core-shell microgel ink that decouples cell culture from material processing to produce functional materials with a range of potential applications.

Aβ42 oligomers are key toxic species associated with protein aggregation; however, the molecular pathways determining the dynamics of oligomer populations have remained unknown. Now, direct measurements of oligomer populations, coupled to theory and computer simulations, define and quantify the dynamics of Aβ42 oligomers formed during amyloid aggregation.

Biomolecular condensates form via phase separation of multivalent macromolecules. Phase separation is governed by solubility whereas multivalence drives percolation, also known as gelation. The authors in this work identify the distinct energy and length scales that influence phase separation versus percolation.

An approach to design proteins that can capture amyloidogenic protein regions present in, for example, tau and Aβ42 has now been developed. These designer proteins can inhibit the formation of pathogenic amyloid fibrils and protect cells from toxic species.

Cecilia Lindgren and colleagues report results of a large-scale genome-wide association study for waist-to-hip ratio, a measure of body fat distribution. They identify 13 new loci associated with this trait, several of which show stronger effects in women than in men.

Certain proteins are capable of self-replicating, including those associated with Alzheimer’s disease. Simulations now pinpoint the adsorption of monomeric proteins onto protein fibril surfaces as the mechanism responsible for self-replication.

Aβ peptide aggregation is associated with Alzheimer's disease, and Aβ fibrils can catalyze formation of toxic oligomers. Molecular chaperone Brichos binds to the fibril surface, inhibiting the catalytic cycle in vitro, and limits Aβ toxicity.

Aggregated forms of α-synuclein are characteristic of Parkinson’s disease. Here the authors show that the condensation-driven aggregation pathway of α-synuclein can be inhibited using small molecules: the aminosterol claramine stabilizes α-synuclein condensates and inhibits α-synuclein primary nucleation in the aggregation process.

Silk fibres currently used in biotechnology are chemically reconstituted silk fibroins (RSF), which are more stable than native silk fibroin (NSF) but possess different biophysical properties. Here, the authors use microfluidic droplets to encapsulate and store NSF, preserving their native structure.

Mapping energy landscapes has proved to be a powerful approach for studying reaction mechanisms. Now, this strategy has been applied to determine the activation energies and entropies that characterize the molecular steps in the misfolding and aggregation of the amyloid-β peptide, revealing striking differences between the thermodynamic signatures of primary and secondary nucleation.