Temperature-dependent ion migration underlies sequence-specific collapse of unstructured RNA

Area of Science:

• Biophysics
• Computational Biology
• RNA Biology

Background:

• Ions and temperature critically influence RNA structure, dynamics, and phase behavior.
• The molecular-level interplay of these factors, especially for flexible single-stranded RNA (ssRNA), is not fully understood.
• ssRNA's sensitivity to ionic and thermal changes poses challenges for studying its behavior.

Purpose of the Study:

• To investigate how electrostatics, stacking, and hydration collectively dictate ssRNA behavior under varying ionic and temperature conditions.
• To extend a validated coarse-grained RNA model with temperature-dependent ion-phosphate interactions and revised stacking potentials.
• To elucidate the molecular mechanisms governing RNA conformational transitions in response to environmental changes.

Main Methods:

• Utilized a coarse-grained RNA model incorporating temperature-dependent divalent ion-phosphate potentials.
• Introduced revised stacking interactions to capture electrostatic, stacking, and hydration effects.
• Performed simulations to analyze RNA compaction, ion-RNA interactions, and ion dehydration across different ionic strengths and temperatures.

Main Results:

• Simulations accurately reproduced experimental small-angle X-ray scattering (SAXS) profiles across diverse ionic conditions.
• Observed a non-monotonic temperature dependence of RNA compaction: expansion upon heating followed by collapse.
• Demonstrated that rising temperatures strengthen ion-RNA interactions, leading to ion dehydration and RNA collapse.

Conclusions:

• The ion atmosphere acts as a dynamic, sequence-dependent extension of RNA structure.
• Provides molecular insights into how temperature and ions regulate RNA conformational changes.
• Offers a microscopic basis for RNA thermoadaptation, cold-induced misfolding, and RNA phase transitions.