Binding free energy empirical approach

Mark, A. E., Xu, Y., Liu, H., van Gunsteren, W. F. Rapid non-empirical approaches for estimating relative binding free energies. Acta Biochim. Polonica 42 (1995) 525-536... 

The more rapid methods for estimation of binding free energies are the empirical or knowledge-based (statistical) scoring approaches, which are based on very simple energy functions75-77 or on the frequency of occurrence of different atom-atom... 

A. E. Mark, Y. Xu, H. Liu, and W. F. van Gunsteren, Acta Biochim. Polon., 42,525 (1995). Rapid Non-Empirical Approaches for Estimating Relative Binding Free Energies. 

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. 

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