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Comparing aminoglycoside binding sites in bacterial ribosomal RNA and aminoglycoside modifying enzymes

Authors

  • Julia Romanowska,

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    1. Department of Biophysics, Faculty of Physics, University of Warsaw, Hoża 69, 00-681 Warsaw, Poland
    2. Interdisciplinary Centre for Mathematical and Computational Modelling, University of Warsaw, Pawińskiego 5a, 02-106 Warsaw, Poland
    • Department of Biophysics, Faculty of Physics, University of Warsaw, Hoz?a 69, 00-681 Warsaw, Poland
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  • Nathalie Reuter,

    1. Computational Biology Unit, Bergen Center for Computational Science, University of Bergen, Thormohlensgt. 55, N-5008 Bergen, Norway
    2. Department of Molecular Biology, University of Bergen, Thormohlensgt. 55, N-5008 Bergen, Norway
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  • Joanna Trylska

    1. Centre of New Technologies, University of Warsaw, Żwirki i Wigury 93, 02-089 Warsaw, Poland
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Abstract

Aminoglycoside antibiotics are used against severe bacterial infections. They bind to the bacterial ribosomal RNA and interfere with the translation process. However, bacteria produce aminoglycoside modifying enzymes (AME) to resist aminoglycoside actions. AMEs form a variable group and yet they specifically recognize and efficiently bind aminoglycosides, which are also diverse in terms of total net charge and the number of pseudo-sugar rings. Here, we present the results of 25 molecular dynamics simulations of three AME representatives and aminoglycoside ribosomal RNA binding site, unliganded and complexed with an aminoglycoside, kanamycin A. A comparison of the aminoglycoside binding sites in these different receptors revealed that the enzymes efficiently mimic the nucleic acid environment of the ribosomal RNA binding cleft. Although internal dynamics of AMEs and their interaction patterns with aminoglycosides differ, the energetical analysis showed that the most favorable sites are virtually the same in the enzymes and RNA. The most copied interactions were of electrostatic nature, but stacking was also replicated in one AME:kanamycin complex. In addition, we found that some water-mediated interactions were very stable in the simulations of the complexes. We show that our simulations reproduce well findings from NMR or X-ray structural studies, as well as results from directed mutagenesis. The outcomes of our analyses provide new insight into aminoglycoside resistance mechanism that is related to the enzymatic modification of these drugs. Proteins 2013. © 2012 Wiley Periodicals, Inc.

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