Protein–Ligand Interaction Energies with Dispersion Corrected Density Functional Theory and High-Level Wave Function Based Methods

With dispersion-corrected density functional theory (DFT-D3) intermolecular interaction energies for a diverse set of noncovalently bound protein–ligand complexes from the Protein Data Bank are calculated. The focus is on major contacts occurring between the drug molecule and the binding site. Generalized gradient approximation (GGA), meta-GGA, and hybrid functionals are used. DFT-D3 interaction energies are benchmarked against the best available wave function based results that are provided by the estimated complete basis set (CBS) limit of the local pair natural orbital coupled-electron pair approximation (LPNO-CEPA/1) and compared to MP2 and semiempirical data. The size of the complexes and their interaction energies (ΔEPL) varies between 50 and 300 atoms and from −1 to −65 kcal/mol, respectively. Basis set effects are considered by applying extended sets of triple- to quadruple-ζ quality. Computed total ΔEPL values show a good correlation with the dispersion contribution despite the fact that the protein–ligand complexes contain many hydrogen bonds. It is concluded that an adequate, for example, asymptotically correct, treatment of dispersion interactions is necessary for the realistic modeling of protein–ligand binding. Inclusion of the dispersion correction drastically reduces the dependence of the computed interaction energies on the density functional compared to uncorrected DFT results. DFT-D3 methods provide results that are consistent with LPNO-CEPA/1 and MP2, the differences of about 1–2 kcal/mol on average (<5% of ΔEPL) being on the order of their accuracy, while dispersion-corrected semiempirical AM1 and PM3 approaches show a deviating behavior. The DFT-D3 results are found to depend insignificantly on the choice of the short-range damping model. We propose to use DFT-D3 as an essential ingredient in a QM/MM approach for advanced virtual screening approaches of protein–ligand interactions to be combined with similarly "first-principle" accounts for the estimation of solvation and entropic effects.