RNA-RNA interactions drive the formation of biomolecular condensates via liquid-liquid phase separation (LLPS), but their underlying molecular mechanisms remain poorly understood. Here, we employ Martini 3 coarse-grained molecular simulations to investigate phase transitions of G4C2 RNA repeats─sequences implicated in neurodegenerative disorders such as ALS and FTD─across varying salt concentrations. The model captures salt-dependent transitions from dispersed to condensed-like states and suggests that dominant interaction patterns, including Watson-Crick-like and G-G contacts, shift with ionic strength. Notably, longer RNA sequences maintain phase-separated states at salt concentrations that dissolve shorter ones, in line with experimental observations. Our findings demonstrate the ability of the Martini coarse-grained model to reproduce key biophysical features of RNA LLPS, including sequence-length dependence and interaction specificity. This work provides molecular-level insight into RNA-driven phase separation and reveals how sequence composition and ionic strength govern the emergence and stability of RNA-rich assemblies.
Zhang et al. (2026) studied this question.