Abstract
Riboswitches sense cellular concentrations of small molecules and use this information to adjust synthesis rates of related metabolites. Riboswitches include an aptamer domain to detect the ligand and an expression platform to control gene expression. Previous structural studies of riboswitches largely focused on aptamers, truncating the expression domain to suppress conformational switching. To link ligand/aptamer binding to conformational switching, we constructed models of an S-adenosyl methionine (SAM)-I riboswitch RNA segment incorporating elements of the expression platform, allowing formation of an antiterminator (AT) helix. Using Anton, a computer specially developed for long timescale Molecular Dynamics (MD), we simulated an extended (three microseconds) MD trajectory with SAM bound to a modeled riboswitch RNA segment. Remarkably, we observed a strand migration, converting three base pairs from an antiterminator (AT) helix, characteristic of the transcription ON state, to a P1 helix, characteristic of the OFF state. This conformational switching towards the OFF state is observed only in the presence of SAM. Among seven extended trajectories with three starting structures, the presence of SAM enhances the trend towards the OFF state for two out of three starting structures tested. Our simulation provides a visual demonstration of how a small molecule (<500 MW) binding to a limited surface can trigger a large scale conformational rearrangement in a 40 kDa RNA by perturbing the Free Energy Landscape. Such a mechanism can explain minimal requirements for SAM binding and transcription termination for SAM-I riboswitches previously reported experimentally.
Highlights
Riboswitches reveal the versatility of Ribonucleic Acid (RNA) folding, and its remarkable biological impact
Folding dynamics is crucial for RNA function
A new computer specialized for long timescale molecular dynamics (MD) simulations, called Anton, helps us to extend the simulation timescale
Summary
Riboswitches reveal the versatility of Ribonucleic Acid (RNA) folding, and its remarkable biological impact. They are folded mRNAs that sense cellular metabolite levels and control expression of downstream genes [1,2,3,4]. Riboswitches contain an aptamer, which recognizes and binds the metabolite. This binding triggers conformational rearrangement of the expression platform, which controls gene expression. The P1 and terminator (T) helices form in the ligand-bound state (Figure 1). This bound state is called the transcription OFF state since the terminator stops transcription. Without ligand the antiterminator (AT) helix forms, preventing formation of P1 and T helices, and allowing transcription (the transcription ON state)
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