Coarse-Grained Modeling of Stress Granule Structure and Dissolution with Small-Molecule Compounds

Abstract

Stress granules, which are principally comprised of ribonucleic acids and proteins, belong to specific class of biomolecular condensates that form in the cytoplasm upon exposure to environmental stressors to enhance cell survival. Because aberrant formation of stress granules is implicated in a range of devastating pathologies, they are promising therapeutic targets. In particular, small-molecule compounds of specific chemistry can modulate stress-granule stability, providing a novel route for treating neurodegenerative diseases. Nevertheless, the mechanisms underlying stress-granule dissolution remain unclear. Here, we utilize coarse-grained molecular dynamics simulations to understand the structure and stability of stress-granule systems, including in the presence of small-molecule compounds. We find that small molecule drugs disrupt specific stress granule protein-protein, protein-RNA, and RNA-RNA interactions which induces dissolution of the condensate. This in turn results in changes in the condensate properties. Furthermore, these properties can be used to predict the effect of a small molecule species on stress granule stability. Importantly, these predictions are in good agreement with experimental data. This work thus provides new insights regarding the important interactions that dictate stress-granule properties and crucially illustrates the viability of coarse-grained modeling in screening small-molecule compounds with therapeutic potential.