Biomolecular condensates: insight or illusion into cellular compartmentalisation?

Julian Shillcock, Laboratory for Biomolecular modelling, Ecole polytechnique fédérale de Lausanne, Switzerland

Biomolecular condensates are believed to provide cells with reversible compartmentalisation, which enables the sequestration and concentration of selected proteins, and other molecules, while excluding others. Condensates are formed from intrinsically disordered proteins (IDP), with little or no secondary structure, and, often, RNA. Biochemical and biophysical interactions within condensates are likely to be influenced by the spatial structure of the constituent molecules. In vitro experiments show that a single species of IDP is capable of phase separating in solvent, and forms a useful model system for exploring their phase behaviour. RNA is incorporated into specific biomolecular condensates, such as stress granules, which raises the question of how the presence of flexible, RNA-like molecules may modify, or disrupt the structure of the host condensate.

We have previously used coarse grained simulations to show that polymeric IDPs with weakly-attractive, punctate interactions phase separate into a dense phase with heterogeneous spatial structure. Here we explore the consequences for this structural of the addition of short or long RNA-like homopolymers. We find that the presence of the homopolymeric RNA shifts the phase boundary to higher IDP concentration in an RNA-dependent manner, but leaves its internal spatial structure unmodified. Our results predict that RNA-like homopolymers of widely-ranging molecular weights contribute an effective long-range attraction that spontaneously drives them to sequester themselves within a reversible, dense phase of IDPs without perturbing its internal biochemically-relevant spatial organisation.