MCSS-based predictions of RNA binding sites |
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Authors: | Fabrice Leclerc Martin Karplus |
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Institution: | (1) Harvard University, Department of Chemistry and Chemical Biology, 12 Oxford Street, Cambridge, MA 02138, USA, US;(2) Université de Strasbourg I, Institut le Bel, Laboratoire de Chimie Biophysique, F-67000 Strasbourg, France, FR |
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Abstract: | The diversity of RNA tertiary structures provides the basis for specific recognition by proteins or small molecules. To investigate
the structural basis and the energetics which control RNA-ligand interactions, favorable RNA binding sites are identified
using the MCSS method, which has been employed previously only for protein receptors. Two different RNAs for which the structures
have been determined by NMR spectroscopy were examined: two structures of the TAR RNA which contains an arginine binding site,
and the structure of the 16S rRNA which contains an aminoglycoside binding site (paromomycin). In accord with the MCSS methodology,
the functional groups representing the entire ligand or only part of it (one residue in the case of the aminoglycosides) are
first replicated and distributed with random positions and orientations around the target and then energy minimized in the
force field of the target RNA. The Coulombic term and the dielectric constant of the force field are adjusted to approximate
the effects of solvent-screening and counterions. Optimal force field parameters are determined to reproduce the binding mode
of arginine to the TAR RNA. The more favorable binding sites for each residue of the aminoglycoside ligands are then calculated
and compared with the binding sites observed experimentally. The predictability of the method is evaluated and refinements
are proposed to improve its accuracy.
Received: 24 April 1998 / Accepted: 4 August 1998 / Published online: 7 December 1998 |
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Keywords: | : MCSS Ligand Design RNA Binding |
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