Condensates of disordered proteins have small-world network structures and interfaces defined by expanded conformations

Abstract

The formation of membraneless biomolecular condensates is driven by macromolecules with sticker-and-spacer architectures that undergo phase separation coupled to percolation (PSCP). Driving forces for PSCP are governed by the interplay between reversible inter-sticker crosslinks and solvation preferences of spacers. Here, we introduce molecular and mesoscale descriptions of structures within, outside, and at the interfaces of condensates that are formed by prion-like low complexity domains (PLCDs), which are exemplars of intrinsically disordered, linear multivalent proteins. Our studies are based on simulations that accurately describe sequence-specific phase behaviors of PLCDs. We find that networks of reversible, intermolecular, inter-sticker crosslinks organize PLCDs into small-world topologies within condensates. These topologies result from distinct conformational preferences within dense, dilute, and interfacial regions. Specifically, the degree of conformational expansion varies non-monotonically, being most expanded at the interface and most compact in the dilute phase with molecules preferring to be oriented perpendicular to condensate interfaces. This contrasts with dense and dilute phases where molecules are randomly oriented relative to one another. Our results demonstrate that even simple condensates, with only one type of macromolecule, feature inhomogeneous spatial organizations of molecules and interfacial features that likely prime them for being locations of biochemical activity.