Associative polymers phase separate into a porous phase that mimics the structural features of biomolecular condensates of intrinsically-disordered proteins.

Phase separation of immiscible fluids is a common phenomenon in polymer chemistry, and is recognized as an important mechanism by which cells compartmentalize their biochemical reactions. Biomolecular condensates are condensed fluid droplets in cells that form by liquid-liquid phase separation of intrinsically-disordered proteins. They have a wide range of functions and are associated with chronic neurodegenerative diseases in which they become pathologically rigid. Intrinsically-disordered proteins are conformationally flexible and possess multiple, distributed binding sites for each other or for RNA.However, it remains unclear how their material properties depend on the molecular structure of the proteins. Here we use coarse-grained simulations to explore the phase behavior and structure of a model biomolecular condensate composed of semi-flexible polymers with attractive end-caps in a good solvent.Although highly simplified, the model contains the minimal molecular features that are sufficient to observe liquid-liquid phase separation of soluble polymers.The polymers condense into a porous, three-dimensional network in which their end-caps reversibly bind at junctions. The spatial separation of connected junctions scales with the polymer backbone length as a self-avoiding random walk over a wide range of concentration with a weak affinity-dependent prefactor.By contrast, the average number of polymers that meet at the junctions depends strongly on the end-cap affinity but only weakly on the polymer length. The regularity and porosity of the condensed network suggests a mechanism for cells to regulate biomolecular condensates. Interaction sites along a protein may be turned on or off to modulate the condensate's porosity and tune the diffusion and interaction of additional proteins. ensemble of conformations, 14 and have little conserved sequence similarity. 15Instead of folding into a minimum-energy structure, IDPs sample many almost equi-energy conformational states in aqueous solution. 16,17 As many of these states are extended, their conformational flexibility allows them to bind to multiple proteins via distributed, multivalent, reversible binding sites even at low concentrations. 18 Their ability to explore interaction volumes whose size is comparable to the linear extent of the protein allows IDPs to phase separate from their surroundings into biomolecular condensates.A wide range of experimental techniques have revealed the structure of BCs to resemble a fluid, mesh-like network in which the constituent IDPs transiently bind to each other but are locally disordered. 19 Cryo-electron microscopy has shown that the condensed phase of FUS, an IDP associated with ALS, is amorphous, and lack internal ordered structures. 4 Solution NMR experiments of Burke et al. 20 show that FUS in its condensed phase is locally dynamic, making transient intermolecular contacts that are sufficiently short-lived that the proteins exhibit little or no secondary structure and remain disordered. At the same time, their fluores...