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.

Disruption of Bcr-Abl Coiled Coil Oligomerization by Design

“…To estimate the relative binding free energies of the coils in the dimers, MM-PBSA as implemented in AMBER (40) and described by Gohlke and Case (41) was applied to independent MD trajectories for the dimer and individual monomers. In addition to the postprocessing of MD results, calculations of the relative free energy of binding with respect to the wild-type dimer (⌬⌬G binding ) were completed using more detailed thermodynamic integration methods for the CCmut2 dimers (42). On the basis of a thermodynamic cycle (see supplemental Fig.…”

Recent Advances in Free Energy Calculations with a Combination of Molecular Mechanics and Continuum Models

“…Gouda et al applied MM-PBSA to study the interaction of theophylline and its derivatives with an RNA aptamer [91]. Although the rank of the relative binding free energies of the five theophylline analogs was the same as that of experiment with one exception, no good correlation between the calculated and the experimental binding free energies could be found.…”

Electrostatics in Proteins and Protein–Ligand Complexes

“…However, sometimes water molecules are not 'average' and their effect is consequently reproduced inaccurately by a continuum model. This is the case for conserved water molecules in protein-ligand complexes that bridge interactions between ligand and protein [116], tightly bound water molecules in active sites and other cavities, and in these cases it is therefore important to treat the water molecules explicitly. Warshel and co-workers proposed a thermodynamic cycle which accounts for "water penetration" effect in the binding process by mutating the ligand to water molecules in both the protein binding site and in solution (see Figure 15.8 in [27]).…”