Conformational entropy of intrinsically disordered proteins bars intruders from biomolecular condensates

Abstract

It has recently been discovered that eukaryotic cells are host to a multiplicity of biomolecular condensates. These condensates typically contain protein components with intrinsically disordered regions (IDRs). While IDRs have been proposed and demonstrated to play many roles in the literature, we suggest here an additional crucial role of IDRs, which is to exclude 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 an average protein (4 nm in diameter) can be more than 98% excluded from condensates. Application of the developed size-exclusion theory to biological condensates suggests that condensate IDRs may play a generic exclusionary role across organisms and types of condensates.