title: Free energy calculations for theophylline binding to an RNA aptamer: Comparison of MM-PBSA and thermodynamic integration methods.
abstract: We have applied the molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) method (J. Srinivasan, T. E. Cheatham, P. Cieplak, P. A. Kollman, and D. A. Case, Journal of the American Chemical Society, 1998, Vol. 120, pp. 9401-9409) to study the interaction of an RNA aptamer with theophylline and its analogs. The MM-PBSA free energy analysis provides a reasonable absolute binding free energy for the RNA aptamer-theophylline complex formation. Energetic analysis reveals that the van der Waals interaction and the nonpolar contribution to solvation provide the basis for the favorable absolute free energy of complex. This trend is similar to other protein-ligand interactions studied previously. The MM-PBSA method also ranks the relative binding energies of five theophylline analogs approximately correctly, but not as well as the more conventional thermodynamic integration calculations, which were carried out to convert theophylline into its analogs. The comparison of MM-PBSA with TI suggests that the MM-PBSA method has some difficulties with the first-solvation-shell energetics.
authors.affiliation: Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94143, USA.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Gouda
authors.forename: Irwin D
authors.initials: ID
authors.lastname: Kuntz
authors.forename: David A
authors.initials: DA
authors.lastname: Case
authors.forename: Peter A
authors.initials: PA
authors.lastname: Kollman
mesh_terms: D001665:Binding Sites; D006860:Hydrogen Bonding; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D009690:Nucleic Acid Conformation; D012313:RNA / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D013806:Theophylline / Q000031:analogs & derivatives / Q000737:chemistry* / Q000378:metabolism*; D013816:Thermodynamics
chemical_list: D012313:RNA; D013806:Theophylline