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The physicochemical driving forces of protein-free, RNA-driven phase transitions were previously unclear, but it is now shown that RNAs undergo entropically driven liquid–liquid phase separation upon heating in the presence of magnesium ions. In the condensed phase, RNAs can undergo an enthalpically favourable percolation transition that leads to arrested condensates.

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.

The authors provide a physical description for condensates as complex fluids defined by small-world network structures for their interiors, and of interfaces featuring a preference of locally and globally expanded conformations.

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.

Mixtures of prion-like low complexity domains (PLCDs) are found in condensates such as stress granules. In this work, the authors report how the interplay between homotypic and heterotypic interactions contributes to condensate formation by mixtures of PLCDs.

The time-dependent viscoelastic moduli of biomolecular condensates are connected to the functions that the condensates influence in cells. Now sticker and spacer residues in proteins are shown to regulate condensate viscoelasticity and ageing dynamics.

Here, the authors use small angle neutron scattering and coarse-grained molecular dynamics simulations to demonstrate that condensates based on the granular components of nucleoli are network fluids.

In this work, the authors report that protein-RNA condensates with shared proteins and distinct RNAs can form and persist in vitro and in cells as distinct entities if the nonshared RNA molecules are dynamically arrested, but the shared protein components are dynamically exchangeable.

Experiments confirm the prediction that fluid-like biomolecular condensates are defined by spatially inhomogeneous organization of the underlying molecules.

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.

The complex link between protein sequence and phase behaviour for a family of prion-like low-complexity domains (PLCDs) has now been revealed. The results have uncovered a set of rules—which are interpreted using a stickers-and-spacers model—that govern the sequence-encoded phase behaviour of such PLCDs and enable physicochemical rationalizations that are connected to the underlying sequence composition.

Intrinsically disordered protein polymers can be designed to encode tunable lower or upper critical solution temperatures in physiological solutions.

Biomolecular condensates formed by intrinsically disordered protein condensates are known to be semidilute solutions, however, the molecular interactions in the dilute versus dense phases remain underexplored. Here, the authors use all-atom simulations based on a polarizable forcefield to understand the difference between protein sidechain interactions in dilute versus dense phases of protein-based condensates, revealing that strong inter-sidechain interactions are attenuated by backbone-mediated effects.

Foutel et. al. identify conformational buffering as a mechanism for functional selection in intrinsically disordered protein regions that allows robust encoding of a tethering function by a hypervariable disordered linker through compensatory changes in sequence length and composition.

Ultrafast-scanning fluorescence correlation spectroscopy has now been used to measure the molecular interactions underlying the phase behaviour of disordered proteins. Sequence-encoded conformational fluctuations of these proteins are shown to give rise to phase-separated droplets of surprisingly low concentrations. These results provide insight into how the structural features of the droplets affect the properties of liquid-phase intracellular organelles.

De novo protein nanostructures are typically assembled via top-down approaches. Here, the authors developed a bottom-up approach, using split inteins to ligate multiple copies of a three-helix bundle to create 2D triangular and square-shaped structures with high stability.

Dai et al. present a streamlined approach for the design and engineering of synthetic biomolecular condensates for controlling different cellular processes, such as gene flow, transcriptional regulation and modulation of protein circuits.

A protein-based material with temperature-modulated mechanical properties and function is achieved by the rational incorporation of structural ordering and disordering elements into its polypeptide sequence.

The internal structure of cells is organized into compartments, many of which lack a confining membrane and instead resemble viscous liquid droplets. Evidence is mounting that these compartments form via spontaneous phase transitions.

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.

Nuclear magnetic resonance spectroscopy is transforming our views of proteins by revealing how their structures and dynamics are closely intertwined to underlie their functions and interactions. Compelling representations of proteins as statistical ensembles are uncovering the presence and biological relevance of conformationally heterogeneous states, thus gradually making it possible to go beyond the dichotomy between order and disorder through more quantitative descriptions that span the continuum between them.

This study reports the structure of hRSV NS1, identifying unique regions that modulate host gene expression and contribute to inhibition of the IFN-I pathway and of dendritic cell maturation, pointing to new avenues of hRSV attenuation.