Deciphering the origins of observed heat capacity changes for aminoglycoside binding to prokaryotic and eukaryotic ribosomal RNA a-sites: a calorimetric, computational, and osmotic stress study.
Isothermal titration calorimetry (ITC), computational, and osmotic stress techniques have been used to characterize the changes in heat capacity, solvent-accessible surface, and hydration that accompany the binding of the aminoglycoside paromomycin to both prokaryotic and eukaryotic rRNA A-site model oligonucleotides. Regarded as a whole, the results of these studies suggest that the intrinsic heat capacity change (DeltaC(p)) for the binding of paromomycin to each rRNA A-site is near zero, with the negative DeltaC(p) observed for the binding of the drug to the prokaryotic rRNA A-site being dictated by the coupled destacking of the adenine residues at positions 1492 and 1493. In this connection, DeltaC(p) provides a useful calorimetric signature for assessing the relative impacts of novel and existing A-site targeting ligands on rRNA conformation, which, in turn, should provide a useful analytical tool for facilitating the drug design process, since aminoglycoside-induced destacking of A1492 and A1493 is thought to be a determining factor in the mistranslational and antimicrobial activities of the drugs.
Barbieri
Christopher M
CM
Department of Pharmacology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, 675 Hoes Lane, Piscataway, New Jersey 08854-5635, USA.
Srinivasan
Annankoil R
AR
Pilch
Daniel S
DS
D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000378:metabolism; D002151:Calorimetry / Q000379:methods; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008958:Models, Molecular; D009690:Nucleic Acid Conformation; D009994:Osmolar Concentration; D009997:Osmotic Pressure; D010303:Paromomycin / Q000737:chemistry* / Q000378:metabolism; D012335:RNA, Ribosomal / Q000737:chemistry* / Q000378:metabolism; D013696:Temperature; D013816:Thermodynamics; D017186:Titrimetry; D014867:Water / Q000737:chemistry
D000900:Anti-Bacterial Agents; D012335:RNA, Ribosomal; D014867:Water; D010303:Paromomycin