Representative Amino Acid Side-Chain Interactions in Protein-DNA Complexes: A Comparison of Highly Accurate Correlated Ab Initio Quantum Mechanical Calculations and Efficient Approaches for Applications to Large Systems.

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).