A NEW METHOD FOR PREDICTING BINDING FREE-ENERGY BETWEEN RECEPTOR AND LIGAND

A practical method to estimate binding free energy, Delta G(bind), Of a given ligand structure to the target receptor has been developed. Th e method assumes that Delta G(bind) is given by the summation of inter molecular interaction energy, Delta G(inter) and partial desolvation e nergy, Delta G(desolv). Delta G(desolv) is calculated from the buried surface area in the complex between the ligand and receptor, based on solvation energy, Delta G(solv), formulated by an equation which can b e calibrated with observed values. Then, the method was applied to ara binose-binding protein (ABP) and dihydrofolate reductase (DHFR), after recalibrating the weights for dG(inter) and each term of Delta G(deso lv) using observed Delta G(bind) data for 29 known ligands to avidin ( AV). The usefulness of our method was confirmed by the fact that corre lation coefficients between the calculated and observed Delta G(bind') S in AV, ABP and DHFR were 0.92, 0.77, and 0.88, whereas the correspon ding values obtained by simple force field calculation were 0.79, 0.30 , and 0.79, respectively. Further investigations to improve the method and validate the parameters are in progress. (C) 1998 Wiley-Liss, Inc .