The flavin mononucleotide (FMN)-dependent riboswitch is an RNA element that controls the biosynthesis of FMN in bacteria. In this talk, I will describe our application of the <b><i>selectively scaled molecular dynamics (ssMD)</i></b> simulation method to carry out a comparative study of the unbinding of WG-3 and ribocil-B from the aptamer domain of the FMN-dependent riboswitch. Our simulations, coupled with kinetic modeling, predict that compared to ribocil-B, WG-3 rapidly unbinds from the aptamer of the riboswitch. The latter suggests that on the transcriptional time scale, WG-3 is unable to lock the FMN-dependent riboswitch into the conformational state needed to terminate transcription, providing a possible explanation of why WG-3 is unable to inhibit bacterial replication.

Pre-equilibrium kinetics may underlie the differential activity of selective binders of the FMN-dependent riboswitch

ACS Spring Meeting 2021

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