CMOD-RNA · Coarse-grained modelling of RNA phase transitions in multicomponent biomolecular condensates

Biomolecular condensates of proteins and nucleic acids are crucial for cellular organization, enabling adaptable compartmentalization without a membrane. Liquid-like condensates allow dynamic molecular exchange, whereas pathological solidification disrupts their function, leading to kinetically trapped states linked to neurodegenerative diseases. Although protein condensation has been extensively studied, how RNA sequence, structure, and concentration govern condensate stability and drive pathological solidification remains as a key open question. My project aims to advance the state-of-the-art by designing the first residue-level coarse-grained RNA model to explore RNA and RNA–protein condensates integrated with established protein models. By including canonical and non-canonical base-pairing as well as key tertiary interactions such as G-quadruplexes, my model will enable simulations of RNA–protein condensates with unprecedented resolution and physicochemical realism. The project will achieve three key goals: (1) identify the molecular grammar of RNA–RNA and RNA–protein condensates by mapping the nucleotide and nucleotide–amino acid interactions behind phase-separation via all-atom simulations; (2) develop a sequence-resolved RNA model compatible with residue-resolution protein models to describe RNA-driven phase behaviour of multicomponent condensates as well as their potential aberrant liquid-to-solid transitions; and (3) perform the first high-resolution simulation of stress granules containing multiple proteins and RNAs to resolve their complex interaction motifs, multivalent binding networks, and spatial organization controlling their stability and molecular architecture. By providing a predictive framework for multicomponent condensates, this work will lay the foundation for understanding the sequence-encoded principles of RNA–protein assemblies and their dysfunction in disease, advancing fundamental biological knowledge and informing therapeutic innovation.