Frictional Effects on RNA Folding: Speed Limit and Kramers Turnover

Area of Science:

• Biophysics
• Computational Biology
• Molecular Biology

Background:

• RNA folding is crucial for biological function.
• Understanding the kinetics of RNA folding, particularly the influence of environmental factors like solvent viscosity, is essential.
• The human telomerase hairpin (hTR HP) and Beet Western Yellow Virus pseudoknot (BWYV PK) are model systems for studying RNA folding.

Purpose of the Study:

• To investigate the frictional effects of solvent viscosity on the folding rates of hTR HP and BWYV PK.
• To quantitatively fit folding rate data using Kramers's theory and identify the Kramers turnover point.
• To determine the theoretical speed limit for RNA folding in water.

Main Methods:

• Simulations using the Three Interaction Site (TIS) model for RNA.
• Temperature replica exchange simulations to calculate heat capacity.
• Analysis of over 100 folding trajectories for each solvent viscosity value.
• Application of one-dimensional Kramers's theory to folding rate data.

Main Results:

• TIS model heat capacity accurately reproduces experimental data for hTR HP.
• Folding rates (kF) exhibit a Kramers turnover, with a maximum rate at moderate viscosity (∼10^-6 Pa·s).
• In high friction, kF decreases as 1/η; in low friction, kF increases with η.
• The speed limit for RNA folding in water is estimated to be between 1 and 4 μs.
• Solvent viscosity can alter the flux through parallel folding pathways.

Conclusions:

• Solvent viscosity plays a critical role in modulating RNA folding kinetics.
• The study provides quantitative predictions for BWYV PK folding rates.
• The findings align with experimental observations and theoretical predictions for RNA folding speed limits.
• Altering pathway flux via viscosity offers a testable prediction for RNA folding mechanisms.