Inclusion of solvation in ligand binding free energy calculations using the generalized-born model

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.