Inside Condensates: Bridging molecular structure and condensate material properties through simulation

PROJECT SUMMARY Proteins and nucleic acids within cells assemble into membraneless compartments referred to as biomolecular condensates. Condensates display a range of material properties, which have implications for health and disease. To better understand the origins of condensate properties, it is necessary to first elucidate the molecular structures and interactions that sustain them. Experimental advances are enhancing the detail with which we can characterize molecules within condensates. However, many of these approaches require significant time and resources, impeding the systematic evaluation of condensates. The aim of this research is to address this technical challenge and push the limits of our ability to resolve molecules inside condensates. Biomolecules that form condensates have complex structures that feature both disordered and well-folded regions. While extensive research has clarified the roles of disordered regions in shaping condensate properties, our understanding of how well-folded regions influence condensates lags considerably. In previous work, we demonstrated how data integration can create computer models that achieve quantitative agreement with experimental results for disordered proteins in condensates. Here, we propose three synergistic research themes that will develop accurate and efficient simulation models to characterize molecules within condensates. We will focus on stress granules, which are cytoplasmic condensates that are primarily composed of RNA-binding proteins and mRNA. Importantly, stress granules have been implicated in neurodegenerative diseases, infectious diseases, and cancers, making them potential drug targets. Yet, the biophysical rules governing their properties and malfunctions are unclear, complicating therapeutic design. To gain mechanistic insight into stress granule biophysics, we will develop state-of-the-art computational models to: (1) map the structures of RNA-binding proteins to stress granule properties; (2) elucidate the role of mRNA sequences in regulating stress granule dynamics; (3) investigate interactions between small molecules (drugs, metabolites) and stress granules. All approaches developed in this work will be validated against experimental data supplied by our collaborators. By examining the intricate molecular interactions within stress granules, this research will offer mechanistic insights into their functions and disease implications. Furthermore, the findings from this research will aid in the design of drugs targeting dysfunctional stress granules.