Conformational entropy of intrinsically disordered proteins bars intruders from biomolecular condensates

It has recently been discovered that eukaryotic cells are host to a multiplicity of non-membrane-bound compartments, which are termed biomolecular condensates. These phase-separated condensates commonly contain protein components with intrinsically disordered regions (IDRs). While many roles of these IDRs have been proposed and demonstrated in the literature, we suggest here an additional underappreciated role of IDRs, which is to exclude large, unwanted "intruders" from condensates. This exclusion effect arises from the large conformational entropy of IDRs, i.e., there is a large free-energy cost to occupying volume that would otherwise be available to the IDRs. We find that at realistic IDR densities, particles as small as the size of a typical protein (5 nm in diameter) can be more than 90% excluded from condensates. Comparison to data on partitioning of particles into natural and engineered condensates suggests that condensate IDRs may play a generic exclusionary role across organisms and types of condensates.