Intramolecular and intermolecular effects of aromatic sticker residue strength on intrinsically disordered protein regions

The formation of biomolecular condensates plays critical roles in cellular life and is implicated in various diseases. Condensate formation is often driven by multivalent interactions between aromatic “sticker” residues embedded between non-interacting “spacers” in intrinsically disordered protein regions (IDRs). One underappreciated factor, however, is that homotypic stickers such as aromatic residues can interact not only intermolecularly but also intramolecularly. This is especially important when considering the high “effective concentration” of intrachain stickers. How and under what conditions can intermolecular sticker-sticker interactions outcompete intramolecular sticker-sticker interactions? To investigate these questions, we examine minimal IDR constructs containing Gly-Ser repeat spacers and aromatic stickers of varying strengths. We combine atomistic and coarse-grained simulations with ensemble FRET and small-angle X-ray scattering data to compare the monomeric ensembles of these constructs against their tendency to form intermolecular interactions. We further show how this competition is modulated by changes in solution composition. Our experiments reveal how sticker strength, spacer length, and the chemical environment work together to determine the winner of the competition between inter- and intramolecular interactions.