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Interactions of 2’-O-methyl oligoribonucleotides with the RNA models of the 30S subunit A-site

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dc.abstract.enSynthetic oligonucleotides targeting functional regions of the prokaryotic rRNA could be promising antimicrobial agents. Indeed, such oligonucleotides were proven to inhibit bacterial growth. 2’-O-methylated (2’-O-Me) oligoribonucleotides with a sequence complementary to the decoding site in 16S rRNA were reported as inhibitors of bacterial translation. However, the binding mode and structures of the formed complexes, as well as the level of selectivity of the oligonucleotides between the prokaryotic and eukaryotic target, were not determined. We have analyzed three 2’-O-Me oligoribonucleotides designed to hybridize with the models of the prokaryotic rRNA containing two neighboring aminoglycoside binding pockets. One pocket is the paromomycin/kanamycin binding site corresponding to the decoding site in the small ribosomal subunit and the other one is the close-by hygromycin B binding site whose dynamics has not been previously reported. Molecular dynamics (MD) simulations, as well as isothermal titration calorimetry, gel electrophoresis and spectroscopic studies have shown that the eukaryotic rRNA model is less conformationally stable (in terms of hydrogen bonds and stacking interactions) than the corresponding prokaryotic one. In MD simulations of the eukaryotic construct, the nucleotide U1498, which plays an important role in correct positioning of mRNA during translation, is flexible and spontaneously flips out into the solvent. In solution studies, the 2’-O-Me oligoribonucleotides did not interact with the double stranded rRNA models but all formed stable complexes with the single-stranded prokaryotic target. 2’-O-Me oligoribonucleotides with one and two mismatches bound less tightly to the eukaryotic target. This shows that at least three mismatches between the 2’-O-Me oligoribonucleotide and eukaryotic rRNA are required to ensure target selectivity. The results also suggest that, in the ribosome environment, the strand invasion is the preferred binding mode of 2’-O-Me oligoribonucleotides targeting the aminoglycoside binding sites in 16S rRNA.
dc.affiliationUniwersytet Warszawski
dc.contributor.authorTrylska, Joanna
dc.contributor.authorStolarski, Ryszard
dc.contributor.authorWojciechowska, Monika
dc.contributor.authorKulik, Marta
dc.contributor.authorJasiński, Maciej
dc.date.accessioned2024-01-25T04:21:17Z
dc.date.available2024-01-25T04:21:17Z
dc.date.issued2018
dc.description.financeNie dotyczy
dc.identifier.doi10.1371/JOURNAL.PONE.0191138
dc.identifier.issn1932-6203
dc.identifier.urihttps://repozytorium.uw.edu.pl//handle/item/109458
dc.languageeng
dc.pbn.affiliationphysical sciences
dc.relation.ispartofPLoS ONE
dc.rightsClosedAccess
dc.sciencecloudnosend
dc.titleInteractions of 2’-O-methyl oligoribonucleotides with the RNA models of the 30S subunit A-site
dc.typeJournalArticle
dspace.entity.typePublication