BPS2026 – Enhancing RNA resolution in coarse-grained protein-RNA condensate simulation

Biomolecular condensates containing a dynamic and heterogeneous mixture of molecular species are increasingly being recognized as mediators of a variety of key cellular processes in health, and as hallmarks of pathology in disease. Among biomolecular condensates, systems comprised of RNA and intrinsically disordered RNA-binding proteins are of particular interest, in which RNA has been shown to promote, dissolve, and modify properties of the condensate. Despite significant interest, molecular details within condensates remain inaccessible to experiment. Computational simulation lends itself as a promising alternative, which has the potential to extract information at a much finer temporal and spatial resolution to unravel the molecular mechanisms behind experimental observations. Single bead coarse-grained simulation models designed to reproduce liquid-liquid phase separation (LLPS)-behavior of biomolecules have seen considerable success. While residue resolution models are attractive on account of improving computational efficiency in large systems, preservation of RNA structure, and specific protein-RNA interactions becomes challenging; as a result, the treatment of RNA within protein-RNA condensates is typically limited to disordered chains. In this work, we present a new simulation model with the goal of providing a framework, which can be used to study protein-RNA interactions in greater detail, and investigate the impact of RNA structure within biomolecular condensates. Building on the well-established three-interaction site (TIS) RNA model, designed to reproduce RNA folding behavior, we have developed interaction parameters representing a combination of hydrophobicity and specific aromatic and cation-π type interactions enabling the use of the TIS model in conjunction with residue resolution protein models.