title: Electrostatic interactions in aminoglycoside-RNA complexes.
abstract: Electrostatic interactions often play key roles in the recognition of small molecules by nucleic acids. An example is aminoglycoside antibiotics, which by binding to ribosomal RNA (rRNA) affect bacterial protein synthesis. These antibiotics remain one of the few valid treatments against hospital-acquired infections by Gram-negative bacteria. It is necessary to understand the amplitude of electrostatic interactions between aminoglycosides and their rRNA targets to introduce aminoglycoside modifications that would enhance their binding or to design new scaffolds. Here, we calculated the electrostatic energy of interactions and its per-ring contributions between aminoglycosides and their primary rRNA binding site. We applied either the methodology based on the exact potential multipole moment (EPMM) or classical molecular mechanics force field single-point partial charges with Coulomb formula. For EPMM, we first reconstructed the aspherical electron density of 12 aminoglycoside-RNA complexes from the atomic parameters deposited in the University at Buffalo Databank. The University at Buffalo Databank concept assumes transferability of electron density between atoms in chemically equivalent vicinities and allows reconstruction of the electron densities from experimental structural data. From the electron density, we then calculated the electrostatic energy of interaction using EPMM. Finally, we compared the two approaches. The calculated electrostatic interaction energies between various aminoglycosides and their binding sites correlate with experimentally obtained binding free energies. Based on the calculated energetic contributions of water molecules mediating the interactions between the antibiotic and rRNA, we suggest possible modifications that could enhance aminoglycoside binding affinity.
authors: Department of Chemistry, University of Warsaw, Warsaw, Poland; Centre of New Technologies, University of Warsaw, Warsaw, Poland.
authors: Marta
authors: M
authors: Kulik
authors: Department of Chemistry, University of Warsaw, Warsaw, Poland; College of Inter-Faculty Individual Studies in Mathematics and Natural Sciences, University of Warsaw, Warsaw, Poland.
authors: Anna M
authors: AM
authors: Goral
authors: Centre of New Technologies, University of Warsaw, Warsaw, Poland; College of Inter-Faculty Individual Studies in Mathematics and Natural Sciences, University of Warsaw, Warsaw, Poland.
authors: Maciej
authors: M
authors: Jasiński
authors: Department of Chemistry, University of Warsaw, Warsaw, Poland.
authors: Paulina M
authors: PM
authors: Dominiak
authors: Centre of New Technologies, University of Warsaw, Warsaw, Poland. Electronic address: joanna@cent.uw.edu.pl.
authors: Joanna
authors: J
authors: Trylska
mesh_terms: D000617:Aminoglycosides / Q000737:chemistry*; D001483:Base Sequence; D001665:Binding Sites; D006860:Hydrogen Bonding; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation; D012313:RNA / Q000737:chemistry*; D055672:Static Electricity; D013816:Thermodynamics; D014867:Water / Q000737:chemistry
chemical_list: D000617:Aminoglycosides; D014867:Water; D012313:RNA
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