Résumé
SignificanceThe complex and crowded cellular environment profoundly influences the structural properties and functions of biomolecules, including RNAs. In particular, biomolecular condensates represent an emerging principle for the compartmentalization of RNA and its regulation. Despite their significance, our understanding of their molecular-scale organization and effects on RNA structure remains limited. In this study, we employ atomistic simulations to investigate RNA properties in a crowded peptide environment resembling biomolecular condensates. Our findings reveal that this environment destabilizes RNA secondary structures and promotes extended nonnative conformations. Notably, the composition of peptides—specifically arginine-rich versus lysine-rich—modulates RNA behavior, suggesting that variations in condensate composition can fine-tune RNA activity in health and disease.
Biomolecular condensates are currently recognized to play a key role in organizing cellular space and in orchestrating biochemical processes. Despite an increasing interest in characterizing their internal organization at the molecular scale, not much is known about how the densely crowded environment within these condensates affects the structural properties of recruited macromolecules. Here, we adopted explicit-solvent all-atom simulations based on a combination of enhanced sampling approaches to investigate how the conformational ensemble of an RNA hairpin is reshaped in a highly concentrated peptide solution that mimics the interior of a biomolecular condensate. Our simulations indicate that RNA structure is greatly perturbed by this distinctive physico-chemical environment, which weakens RNA secondary structure and promotes extended nonnative conformations. The resulting high-resolution picture reveals that RNA unfolding is driven by the effective solvation of nucleobases through hydrogen bonding and stacking interactions with surrounding peptides. This solvent effect can be modulated by the amino acid composition of the model condensate as proven by the differential RNA behavior observed in the case of arginine-rich and lysine-rich peptides.