Representative Amino Acid Side-Chain Interactions in Protein-DNA Complexes: A Comparison of Highly Accurate...

Representative pairs of amino acid side chains and nucleic acid bases extracted from available high-quality structures of protein-DNA complexes were analyzed using a range of computational methods. CCSD(T)/CBS interaction energies were calculated for the chosen 272 pairs. These reference interaction energies were used to test the MP2.5/CBS, MP2.X/CBS, MP2-F12, DFT-D3, PM6, and Amber force field methods. Method MP2.5 provided excellent agreement with reference data (root-mean-square error (RMSE) of 0.11 kcal/mol), which is more than 1 order of magnitude faster than the CCSD(T) method. When MP2-F12 and MP2.5 were combined, the results were within reasonable accuracy (0.20 kcal/mol), with a computational savings of almost 2 orders of magnitude. Therefore, this method is a promising tool for accurate calculations of interaction energies in protein-DNA motifs of up to ∼100 atoms, for which CCSD(T)/CBS benchmark calculations are not feasible. B3-LYP-D3 calculated with def2-TZVPP and def2-QZVP basis sets yielded sufficiently good results with a reasonably small RMSE. This method provided better results for neutral systems, whereas positively charged species exhibited the worst agreement with the benchmark data. The Amber force field yielded unbalanced results-performing well for systems containing nonpolar amino acids but severely underestimating interaction energies for charged complexes. The semiempirical PM6 method with corrections for hydrogen bonding and dispersion energy (PM6-D3H4) exhibited considerably smaller error than the Amber force field, which makes it an effective tool for modeling extended protein-ligand complexes (of up to 10,000 atoms).