Mesoscopic heterogeneity in biomolecular condensates from sequence patterning Biomolecular condensates formed from intrinsically disordered proteins (IDPs) are vital for proper cellular function. Moreover, the dysregulation of IDP behaviour often results in condensate dysfunction that is implicated in various diseases such as neurodegeneration and cancer. Despite their biological importance, the precise physical mechanisms underlying condensate (dys)function remains largely unresolved, in part due to the difficulties in understanding how the amino acid sequence of IDPs determine the emergent condensate behaviours on different biomolecular length and timescales. Here, through minimal physical modelling we explain how IDP sequence patterning gives rise to various mesoscale organisation in nano-sized condensates. Through our coarse-grained molecular dynamics polymer model, which accounts for steric, attractive, and electrostatic interactions, we systematically quantify and map out the emergent morphological phases resulting from a wide range (253) of unique cohesive-spacer patterning. For the first time, we reveal that optimal crowding of the spacer and cohesive regions is the physical driving force of the mesoscale organization. Overall, we provide a conceptual framework to understand the roles that sequence patterning plays in determining the physics of biomolecular condensates. This article was published on 2025-04-22
