The spread of antibiotic-resistant bacteria represents a substantial health threat. Current antibiotics act on a few metabolic pathways, facilitating resistance. Consequently, novel regulatory inhibition mechanisms are necessary. Riboswitches represent promising targets for antibacterial drugs. Purine riboswitches are interesting, since they play essential roles in the genetic regulation of bacterial metabolism. Among these, class I (2'-dG-I) and class II (2'-dG-II) are two different 2'-deoxyguanosine (2'-dG) riboswitches involved in the control of deoxyguanosine metabolism. However, high affinity for nucleosides involves local or distal modifications around the ligand-binding pocket, depending on the class. Therefore, it is crucial to understand these riboswitches' recognition mechanisms as antibiotic targets. In this work, we used a combination of computational biophysics approaches to investigate the structure, dynamics, and energy landscape of both 2'-dG classes bound to the nucleoside ligands, 2'-deoxyguanosine, and riboguanosine. Our results suggest that the stability and increased interactions in the three-way junction of 2'-dG riboswitches were associated with a higher nucleoside ligand affinity. Also, structural changes in the 2'-dG-II aptamers enable enhanced intramolecular communication. Overall, the 2'-dG-II riboswitch might be a promising drug design target due to its ability to recognize both cognate and noncognate ligands.
Keywords: 2′-deoxyguanosine riboswitch; ligand binding mechanism; molecular dynamics simulation; network analysis; purine riboswitch.