title: Differences between cotranscriptional and free riboswitch folding.
abstract: Riboswitches are part of noncoding regions of messenger RNA (mRNA) that act as RNA sensors regulating gene expression of the downstream gene. Typically, one out of two distinct conformations is formed depending on ligand binding when the transcript leaves RNA polymerase (RNAP). Elongation of the RNA chain by RNAP, folding and binding all occurs simultaneously and interdependently on the seconds' timescale. To investigate the effect of transcript elongation velocity on folding for the S-adenosylmethionine (SAM)-I and adenine riboswitches we employ two complementary coarse-grained in silico techniques. Native structure-based molecular dynamics simulations provide a 3D, atomically resolved model of folding with homogenous energetics. Energetically more detailed kinetic Monte Carlo simulations give access to longer timescale by describing folding on the secondary structure level and feature the incorporation of competing aptamer conformations and a ligand-binding model. Depending on the extrusion scenarios, we observe and quantify different pathways in structure formation with robust agreements between the two techniques. In these scenarios, free-folding riboswitches exhibit different folding characteristics compared with transcription-rate limited folding. The critical transcription rate distinguishing these cases is higher than physiologically relevant rates. This result suggests that in vivo folding of the analyzed SAM-I and adenine riboswitches is transcription-rate limited.
authors.affiliation: Steinbuch Centre for Computing, Karlsruhe Institute of Technology, 76344 Karlsruhe, Germany Department of Physics, Karlsruhe Institute of Technology, 76149 Karlsruhe, Germany and Max Planck Institute of Colloids and Interfaces, 14424 Potsdam, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Lutz
authors.forename: Michael
authors.initials: M
authors.lastname: Faber
authors.forename: Abhinav
authors.initials: A
authors.lastname: Verma
authors.forename: Stefan
authors.initials: S
authors.lastname: Klumpp
authors.forename: Alexander
authors.initials: A
authors.lastname: Schug
mesh_terms: D056004:Molecular Dynamics Simulation; D009010:Monte Carlo Method; D059370:RNA Folding; D058928:Riboswitch; D014158:Transcription, Genetic
chemical_list: D058928:Riboswitch