ArticlePLoS computational biology2011
Understanding the origins of bacterial resistance to aminoglycosides through molecular dynamics mutational study of the ribosomal A-site.
Article in PLoS computational biology, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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Who cites it
6 citing papers in PubMed, 30 citations in OpenAlex.
- Machines on Genes through the Computational Microscope.Journal of chemical theory and computation · 2023Review
- RNA Structural Dynamics As Captured by Molecular Simulations: A Comprehensive Overview.Chemical reviews · 2018Review
- Flipping of the ribosomal A-site adenines provides a basis for tRNA selection.Journal of molecular biology · 2014Article
- Interplay of the bacterial ribosomal A-site, S12 protein mutations and paromomycin binding: a molecular dynamics study.PloS one · 2014Article
- Isosteric and nonisosteric base pairs in RNA motifs: molecular dynamics and bioinformatics study of the sarcin-ricin internal loop.The journal of physical chemistry. B · 2013Article
- Novel insights of structure-based modeling for RNA-targeted drug discovery.Journal of chemical information and modeling · 2012Article
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Authors and funding
3 authors at 2 institutions in 2 countries.
Funding
Abstract
Paromomycin is an aminoglycosidic antibiotic that targets the RNA of the bacterial small ribosomal subunit. It binds in the A-site, which is one of the three tRNA binding sites, and affects translational fidelity by stabilizing two adenines (A1492 and A1493) in the flipped-out state. Experiments have shown that various mutations in the A-site result in bacterial resistance to aminoglycosides. In this study, we performed multiple molecular dynamics simulations of the mutated A-site RNA fragment in explicit solvent to analyze changes in the physicochemical features of the A-site that were introduced by substitutions of specific bases. The simulations were conducted for free RNA and in complex with paromomycin. We found that the specific mutations affect the shape and dynamics of the binding cleft as well as significantly alter its electrostatic properties. The most pronounced changes were observed in the U1406C∶U1495A mutant, where important hydrogen bonds between the RNA and paromomycin were disrupted. The present study aims to clarify the underlying physicochemical mechanisms of bacterial resistance to aminoglycosides due to target mutations.
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Registered trials
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