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

Abstract

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).

Sequence-Specific Recognition of DNA by Proteins: Binding Motifs Discovered Using a Novel Statistical/Computational Analysis

“…In this work, we combine an approach based on statistical analysis of existing experimental structures of protein—DNA complexes with molecular mechanical (MM) calculations. We have recently shown the very satisfactory performance of these computational methods when calculating the interaction energies of dimers of amino acids with DNA bases in vacuo in comparison with mid-level DFT calculations [ 41 ], and a similar level of agreement has been observed in comparison with high-level correlated QM results [ 42 ]. Here, we probe the explicit contribution of the charged phosphate group to the recognition of DNA bases on a physical basis for the first time.…”

A Nexus between Theory and Experiment: Non‐Empirical Quantum Mechanical Computational Methodology Applied to Cucurbit[n]uril⋅Guest Binding Interactions

“…The coupled cluster method with singles, doubles, and non‐iterative connected triples [CCSD(T)] level of theory at the complete basis set limit (CBS) is generally considered to provide high‐confidence ‘benchmark’ interaction energies for many small complexes of up to about 50 atoms . We used the MP2.5 method for benchmark calculations of larger systems containing a few tens of atoms . Detailed descriptions of the MP2.5 and CCSD(T) methods including their components Δ E int MP2 and respective correction terms are provided in the Supporting Information.…”

Assessing How Correlated Molecular Orbital Calculations Can Perform versus Kohn–Sham DFT: Barrier Heights/Isomerizations

“…Clearly, any known weaknesses of MP2 (e.g., its single‐reference nature) remain, but this too must be cautioned for KS DFT. Finally, work is being performed to convey on MP2, or slightly more sophisticated versions of MP theory, the quality of CCSD(T) through spin‐component scaling approaches . Eventually, this may lead to a linear scaling algorithm to efficiently compute intermolecular interactions, and hence, reduce the cost of MP2 even further.…”