Free Energy Calculations and Ligand Binding

Abstract

This chapter gives an overview of some different methods for calculating ligand binding free energies that are all based on force fields and conformational sampling. Many of these studies of protein–ligand binding in the mid-1980s showed a remarkable agreement between theory and experiment, which led to an explosion of activity in the field of free energy calculations. More recent investigations, however, have demonstrated that significantly longer simulations than those used in the original reports are often required obtaining reliable results in protein–ligand binding studies. The increasing number of applications of free energy calculations also showed that the use of these methods was not as straightforward as expected; therefore, much effort was spent on improving the methodology. The free energy perturbation (FEP)/thermodynamic integration (TI) type of method has not really fulfilled its promise of being able to open a major new avenue to structure-based drug design due to slow convergence and sampling difficulties. In particular, in this type of extrapolation process in which one may want to look at 20 or so new ligands, arriving at the correct end-points by long perturbation paths sometimes seems hopeless. It appears that a better solution to this problem can often be provided by automated docking of individual compounds, at least when they differ significantly from each other, and then to try to evaluate the binding energetic by a method that does not require the unphysical transformations involved in FEP/TI and related methods. The docking problem resembles the protein-folding one in many respects, and the only way to attack difficult cases seems to be by extensive conformational searching in combination with more reliable scoring methods.