A computational analysis of the binding affinities of FKBP12 inhibitors using the MM-PB/SA method.

The FK506-binding proteins have been targets of pharmaceutical interests over years. We have studied the binding of a set of 12 nonimmunosuppressive small-molecule inhibitors to FKBP12 through molecular dynamics simulations. Each complex was subjected to 1-ns MD simulation conducted in an explicit solvent environment under constant temperature and pressure. The binding free energy of each complex was then computed by the MM-PB/SA method in the AMBER program. Our MM-PB/SA computation produced a good correlation between the experimentally determined and the computed binding free energies with a correlation coefficient (R(2)) of 0.93 and a standard deviation as low as 0.30 kcal/mol. The vibrational entropy term given by the normal mode analysis was found to be helpful for achieving this correlation. Moreover, an adjustment to one weight factor in the PB/SA model was essential to correct the absolute values of the final binding free energies to a reasonable range. A head-to-head comparison of our MM-PB/SA model with a previously reported Linear Response Approximation (LRA) model suggested that the MM-PB/SA method is more robust in binding affinity prediction for this class of compounds.