Molecular Modulation of the SAM-I Riboswitch Drives Global Dynamical Shifts

Abstract

A surge in antimicrobial resistance in recent years has made protein-targeting antibiotics less effective against key pathogens. It is possible to expand the range of therapeutic targets by using RNA-based therapies, but it remains necessary to improve the molecular-level understanding of interactions between RNA and known and potential binders. The SAM-I riboswitch, which controls the transcriptional termination of gene expression involved in sulfur metabolism in most bacteria, is an excellent ligand target. Thus, understanding its behavior with and without ligand complexes would be helpful for drug design. Here, we studied the interactions between the SAM-I riboswitch and its natural ligand, SAM, which controls riboswitch function, and compared those to its interactions with the similar small molecule SAH, which does not control riboswitch function, and to its interactions with a potential binder JS4, identified via virtual screening. From our simulations, we deepen understanding of small molecule interactions with the SAM-I riboswitch on both a local and a distal level. The results reveal how differently ligands (SAM, SAH and JS4) can bind to and potentially induce conformational changes in the riboswitch. Our findings offer valuable insight into the molecular mechanisms underlying riboswitch RNA-ligand interactions for the design of more effective RNA-targeting therapeutics.