Mesoscopic heterogeneity in biomolecular condensates from sequence patterning

TL;DR

This study uses minimal physical modeling to reveal how sequence patterning in intrinsically disordered proteins influences nano-scale heterogeneities and organization within biomolecular condensates, advancing understanding of their physical mechanisms.

Contribution

It introduces a coarse-grained molecular-dynamics model that links sequence patterning to emergent mesoscale heterogeneity in condensates, providing a new conceptual framework.

Findings

Sequence patterning affects nano-scale heterogeneity.

Local coil-to-globule transitions promote cluster formation.

Different sequence patterns lead to distinct morphological phases.

Abstract

Biomolecular condensates composed of intrinsically disordered proteins (IDPs) are vital for proper cellular function, and their dysfunction is associated with diseases including neurodegeneration and cancer. Despite their biological importance, the precise physical mechanisms underlying condensate (dys)function are unclear, in part owing to the difficulties in understanding how biomolecular sequence patterns influence emergent condensate behaviours across relevant length and timescales. Here, through minimal physical modelling, we explain how IDP sequence patterning gives rise to nano-scale organisational heterogeneities in condensates. By applying 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 of sequence patterns. We demonstrate how sequences that enable local coil-to-globule transitions within regions of single polymers - driven by a competition between the preferred crowding densities of different regions in the sequence - also exhibit cluster formation in condensates. Overall, our work provides a conceptual framework to understand how sequence properties determine mesoscopic organisation within biomolecular condensates.