Which aminoglycoside ring is most important for binding? A hydropathic analysis of gentamicin, paromomycin, and analogues

The NMR structures of gentamicin and paromomycin in complex with the A-site of Escherichia coli 16S ribosomal RNA were modified with molecular modelin g to 12 analogues. The intermolecular interactions between these molecules and RNA were examined using the HINT (Hydropathic INTeractions) computation al model to obtain interaction scores that have been shown previously to be related to free energy. The calculations correlated well with experimental binding data, and the interaction scores were used to analyze the specific structural features of each aminoglycoside that contribute to the overall binding with the 16S rRNA. Our calculations indicate that, while ring I bin ds to the main binding pocket of the rRNA A-site, ring IV of paromomycin-ba sed aminoglycosides contributes significantly to the overall binding. (C) 2 001 Elsevier Science Ltd. All rights reserved.