Thermodynamic and kinetic folding of riboswitches.
Riboswitches are structured RNA regulatory elements located in the 5'-UTRs of mRNAs. Ligand-binding induces a structural rearrangement in these RNA elements, effecting events in downstream located coding sequences. Since they do not require proteins for their functions, they are ideally suited for computational analysis using the toolbox of RNA structure prediction methods. By their very definition riboswitch function depends on structural change. Methods that consider only the thermodynamic equilibrium of an RNA are therefore of limited use. Instead, one needs to employ computationally more expensive methods that consider the energy landscape and the folding dynamics on that landscape. Moreover, for the important class of kinetic riboswitches, the mechanism of riboswitch function can only be understood in the context of co-transcriptional folding. We present a computational approach to simulate the dynamic behavior of riboswitches during co-transcriptional folding in the presence and absence of a ligand. Our investigations show that the abstraction level of RNA secondary structure in combination with a dynamic folding landscape approach is expressive enough to understand how riboswitches perform their function. We apply our approach to a experimentally validated theophylline-binding riboswitch.
Institute for Theoretical Chemistry, University of Vienna, Vienna, Austria.
Stefan
S
Badelt
Institute for Theoretical Chemistry, University of Vienna, Vienna, Austria; Research Group Bioinformatics and Computational Biology, University of Vienna, Vienna, Austria.
Stefan
S
Hammer
Institute for Theoretical Chemistry, University of Vienna, Vienna, Austria. Electronic address: xtof@tbi.univie.ac.at.
Christoph
C
Flamm
Institute for Theoretical Chemistry, University of Vienna, Vienna, Austria; Research Group Bioinformatics and Computational Biology, University of Vienna, Vienna, Austria.
Ivo L
IL
Hofacker
D000465:Algorithms; D001483:Base Sequence; D019295:Computational Biology / Q000379:methods*; D007700:Kinetics; D008024:Ligands; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation; D059370:RNA Folding; D058928:Riboswitch; D013696:Temperature; D013816:Thermodynamics
D008024:Ligands; D058928:Riboswitch
Co-transcriptional folding; Dynamic landscape; Kinetic folding; RNA secondary structure; Riboswitch; Theophylline aptamer