Xq. Zou et al., Inclusion of solvation in ligand binding free energy calculations using the generalized-born model, J AM CHEM S, 121(35), 1999, pp. 8033-8043
Accounting for the effect of solvent on the strength of molecular interacti
ons has been a longstanding problem for molecular calculations in general a
nd for structure-based drug design in particular. Here, we explore the gene
ralized-Born (GB/SA) model of solvation (Still, W. C.; Tempczyk, A.; Hawley
, R. C.; Hendrickson, T. J. Am. Chem. Sec. 1990, 112, 6127-9) to calculate
ligand-receptor binding energies. The GB/SA approach allows for the estimat
ion of electrostatic, van der Waals, and hydrophobic contributions to the f
ree energy of binding. The GB/SA formulation provides a good balance betwee
n computational speed and accuracy in these calculations. We have derived a
formula to estimate the binding free energy. We have also developed a proc
edure to penalize any unoccupied embedded space that might form between the
ligand and the receptor during the docking process. To improve the computa
tional speed, the protein contribution to the electrostatic screening is pr
ecalculated and stored on a grid. Refinement of the ligand position is requ
ired to optimize the nonbonded interactions between ligand and receptor. Ou
r version of the GB/SA algorithm takes approximately 10 s per orientation (
with minimization) on a Silicon Graphics R10000 workstation. In two test sy
stems, dihydrofolate reductase (dhfr) and trypsin, we obtain much better re
sults than the current DOCK (Ewing, T. J. A.; Kuntz, I. D. J. Comput. Chem.
1997, 18, 1175-89) force field scoring method (Meng, E. C.; Shoichet, B. K
.; Kuntz, I. D. J. Comput. Chem. 1992, 13, 505-24). We also suggest a metho
dology to identify an appropriate parameter regime to balance the specifici
ty and the generality of the equations.