title: Docking of cationic antibiotics to negatively charged pockets in RNA folds.
abstract: The binding of aminoglycosides to RNA provides a paradigm system for the analysis of RNA-drug interactions. The electrostatic field around three-dimensional RNA folds creates localized and defined negatively charged regions which are potential docking sites for the cationic ammonium groups of aminoglycosides. To explore in RNA folds the electronegative pockets suitable for aminoglycoside binding, we used calculations of the electrostatic field and Brownian dynamics simulations of cation diffusion. We applied the technique on those RNA molecules experimentally known to bind aminoglycosides, namely, two tobramycin aptamers (Wang, Y.; Rando, R. R. Chem. Biol. 1995, 2, 281-290): the aminoglycoside-binding region in 16S ribosomal RNA (Moazed, S.; Noller, H. F. Nature 1987, 327, 389-394) and the TAR RNA from human immunodeficiency virus (Mei, H.-Y.; et al. Bioorg. Med. Chem. Lett. 1995, 5, 2755-2760). For the aptamers and ribosomal RNA, for which the binding sites of the aminoglycosides are known, a good agreement between negatively charged pockets and the binding positions of the drugs was found. On the basis of variations between neomycin-like and kanamycin-like aminoglycosides in the interaction with the electrostatic field of ribosomal RNA, we propose a model for the different binding specificities of these two classes of drugs. The spatial congruence between the electronegative pockets in RNA folds and binding positions of aminoglycosides was used to dock aminoglycosides to ribosomal and TAR RNAs. Molecular dynamics simulations were used to analyze possible RNA-drug interactions. Aminoglycosides inhibit the binding of the viral Tat protein to TAR RNA; however, the drug-binding sites are still unknown. Thus, our docking approach provides first structural models for TAR-aminoglycoside complexes. The RNA-drug interactions observed in the modeled complexes support the view that the antibiotics might lock TAR in a conformation with low affinity for the Tat protein, explaining the experimentally found aminoglycoside inhibition of the Tat-TAR interaction (Mei, H.-Y.; et al. Bioorg. Med. Chem. Lett. 1995, 5, 2755-2760).
authors: Institut de Biologie Moléculaire et Cellulaire du CNRS, UPR 9002, 15 rue René Descartes, F-67084 Strasbourg, France.
authors: T
authors: T
authors: Hermann
authors: E
authors: E
authors: Westhof
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry*; D001665:Binding Sites; D015497:HIV-1 / Q000737:chemistry; D007612:Kanamycin / Q000737:chemistry; D008958:Models, Molecular; D009355:Neomycin / Q000737:chemistry; D011487:Protein Conformation; D012313:RNA / Q000737:chemistry*; D012336:RNA, Ribosomal, 16S / Q000737:chemistry; D020218:Response Elements; D014031:Tobramycin / Q000737:chemistry
chemical_list: D000900:Anti-Bacterial Agents; D012336:RNA, Ribosomal, 16S; D007612:Kanamycin; D012313:RNA; D009355:Neomycin; D014031:Tobramycin