MM-PBSA

Swanson, J. M. J. Henchman, R. H. McCammon, J. A., Revisiting free energy calculations a theoretical connection to MM/PBSA and direct calculation of the association free energy, Biophys. J. 2004, 86, 67-74... 

Free Energy Methods Using an Implicit Solvent PBFE, MM/PBSA, and Other Acronyms... 

Other Free Energy Components MM/PBSA Methods... 

The most important model parameter in PBFE and MM/PBSA is the dielectric constant used for the solutes. Most studies have taken an empirical approach, viewing the dielectric constant as an adjustable parameter. While this seems plausible, it is prudent to analyze the physical problem in more detail, because, in some cases, the experimental data can be fit by models that are distinctly unphysical, despite some plausible features. We therefore come back to the simplest possible PBFE calculation the important problem of proton binding, or pKa shifts. We discuss a nonem-pirical model that attempts to avoid parameter fitting and that gives insights into the limitations of simplified continuum electrostatic free energy methods. 

Gouda, H. Kuntz, I.D. Case, D.A. Kollman, P.A., Free energy calculations for theophylline binding to an RNA aptamer Comparison of MM-PBSA and thermodynamic integration methods, Biopolymers 2003, 68,16-34. 

B. Kuhn, O. Donini, S. Huo, J. Wang, and P. A. Kollman, MM-PBSA applied to computer-assisted ligand design, in Free Energy Calculations in Rational Drug Design, M. R. Reddy and M. D. Erion, eds., Kluwer/Plenum Press, New York (2001), pp. 243-251. 

MM-PBSA Applied to Computer-Assisted Ligand Design... 

The MM-PBSA approach assumes that the free energy of a macromolecular system in solution can be adequately approximated by Equation 1... 

In the following, we give a brief description on how to evaluate the various terms in Equation 1. A more extensive summary of the computational details typically used in our studies as well as the CPU requirements of the MM/PBSA approach can be found elsewhere.11 simply evaluates the average potential energy of the system using the same force field (e.g. Equation 3 of Cornell et al.)12 as used to propagate the molecular dynamics trajectory. 

We summarize the results from the various MM-PBSA studies comparing the free energy of binding of different ligands to protein targets. The full details and results can be found in the original papers and in a recently published review of the MM-PBSA approach.17... 

Overall, the initial applications of MM-PBSA suggest that the method can effectively calculate the relative binding free energies in a number of protein-ligand complexes. However, there are a number of issues involving limitations or potential improvements in this methodology which we now discuss. 

Massova I, KoUman PA. 2000. Combined molecular mechanical and continuum solvent approach (MM-PBSA/GBSA) to predict ligand binding. Perspect Drug Discov Des... 

---