Protein-ligand binding free energy estimation using molecular mechanics and continuum electrostatics. Application to HIV-1 protease inhibitors

A method is proposed for the estn. of abs. binding free energy of interaction between proteins and ligands.  Conformational sampling of the protein-ligand complex is performed by mol. dynamics (MD) in vacuo and the solvent effect is calcd. a posteriori by solving the Poisson or the Poisson-Boltzmann equation for selected frames of the trajectory.  The binding free energy is written as a linear combination of the buried surface upon complexation, SASbur, the electrostatic interaction energy between the ligand and the protein, Eelec, and the difference of the solvation free energies of the complex and the isolated ligand and protein, ΔGsolv.  The method uses the buried surface upon complexation to account for the nonpolar contribution to the binding free energy because it is less sensitive to the details of the structure than the van der Waals interaction energy.  The parameters of the method are developed for a training set of 16 HIV-1 protease-inhibitor complexes of known 3D structure.  A correlation coeff. of 0.91 was obtained with an unsigned mean error of 0.8 kcal/mol.  When applied to a set of 25 HIV-1 protease-inhibitor complexes of unknown 3D structures, the method provides a satisfactory correlation between the calcd. binding free energy and the exptl. pIC50 without reparametrization.