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 interactions has been a longstanding problem for molecular calculations in general and for structure-based drug design in particular. Here, we explore the generalized-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 estimation of electrostatic, van der Waals, and hydrophobic contributions to the free energy of binding. The GB/SA formulation provides a good balance between computational speed and accuracy in these calculations. We have derived a formula to estimate the binding free energy. We have also developed a procedure to penalize any unoccupied embedded space that might form between the ligand and the receptor during the docking process. To improve the computational speed, the protein contribution to the electrostatic screening is precalculated and stored on a grid. Refinement of the ligand position is required to optimize the nonbonded interactions between ligand and receptor. Our version of the GB/SA algorithm takes approximately 10 s per orientation (with minimization) on a Silicon Graphics R10000 workstation. In two test systems, dihydrofolate reductase (dhfr) and trypsin, we obtain much better results 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 methodology to identify an appropriate parameter regime to balance the specificity and the generality of the equations.