Exploring RNA destabilization mechanisms in biomolecular condensates through atomistic simulations

Area of Science:

• Biochemistry
• Molecular Biology
• Biophysics

Background:

• Biomolecular condensates organize cellular functions and space.
• The internal molecular organization of condensates and their effect on macromolecules is poorly understood.

Purpose of the Study:

• To investigate how the crowded interior of biomolecular condensates affects the structural properties of RNA hairpins.
• To elucidate the molecular mechanisms driving RNA structural changes within condensates.

Main Methods:

• Explicit-solvent all-atom simulations.
• Enhanced sampling techniques to model RNA behavior in concentrated peptide solutions mimicking condensate interiors.

Main Results:

• RNA structure is significantly perturbed within the simulated condensate environment.
• Weakened RNA secondary structure and promotion of extended, nonnative conformations were observed.
• RNA unfolding is driven by hydrogen bonding and stacking interactions between nucleobases and surrounding peptides.

Conclusions:

• The crowded, peptide-rich environment within biomolecular condensates alters macromolecular structure.
• RNA structural changes are modulated by the specific amino acid composition of the condensate peptides (e.g., arginine-rich vs. lysine-rich).
• This study provides high-resolution insights into the physical chemistry governing RNA behavior in cellular condensates.