Predicting Cotranscriptional Folding Kinetics For Riboswitch

On the basis of a helix-based transition rate model, we developed a new method for sampling cotranscriptional RNA conformational ensemble and the prediction of cotranscriptional folding kinetics. Applications to E. coli. SRP RNA and pbuE riboswitch indicate that the model may provide reliable predictions for the cotranscriptional folding pathways and population kinetics. For E. coli. SRP RNA, the predicted population kinetics and the folding pathway are consistent with the SHAPE profiles in the recent cotranscriptional SHAPE-seq experiments. For the pbuE riboswitch, the model predicts the transcriptional termination efficiency as a function of the force. The theoretical results show (a) a force-induced transition from the aptamer (antiterminator) to the terminator structure and (b) the different folding pathways for the riboswitch with and without the ligand (adenine). More specifically, without adenine, the aptamer structure emerges as a short-lived kinetic transient state instead of a thermodynamically stable intermediate state. Furthermore, from the predicted extension-time curves, the model identifies a series of conformational switches in the pulling process, where the predicted relative residence times for the different structures are in accordance with the experimental data. The model may provide a new tool for quantitative predictions of cotranscriptional folding kinetics, and results can offer useful insights into cotranscriptional folding-related RNA functions such as regulation of gene expression with riboswitches.