期刊
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
卷 23, 期 4, 页码 -出版社
MDPI
DOI: 10.3390/ijms23041925
关键词
2 '-deoxyguanosine riboswitch; purine riboswitch; molecular dynamics simulation; network analysis; ligand binding mechanism
资金
- Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior-Brasil (CAPES) [001]
The spread of antibiotic-resistant bacteria poses a significant threat to health, necessitating the search for novel treatment mechanisms. Riboswitches are considered promising targets for antibacterial drugs. Computational biophysics investigations reveal that 2'-dG riboswitches exhibit increased stability and affinity towards nucleoside ligands, with 2'-dG-II riboswitches showing enhanced intramolecular communication and recognition ability for both cognate and noncognate ligands.
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 & PRIME;-dG-I) and class II (2 & PRIME;-dG-II) are two different 2 & PRIME;-deoxyguanosine (2 & PRIME;-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 & PRIME;-dG classes bound to the nucleoside ligands, 2 & PRIME;-deoxyguanosine, and riboguanosine. Our results suggest that the stability and increased interactions in the three-way junction of 2 & PRIME;-dG riboswitches were associated with a higher nucleoside ligand affinity. Also, structural changes in the 2 & PRIME;-dG-II aptamers enable enhanced intramolecular communication. Overall, the 2 & PRIME;-dG-II riboswitch might be a promising drug design target due to its ability to recognize both cognate and noncognate ligands.
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