Because all of these methods make approximations for the sake of computational efficiency, it becomes essential to evaluate their accuracy. As a consequence, a range of other QM methods have been developed. (23) However, the computational demands of such CCSD(T)/CBS CP calculations make them too time consuming for routine use in force field parametrization and prohibit direct application to biomolecular systems. ![]() It would be ideal if such applications could take advantage of the highly accurate QM approach often viewed as the gold standard for computing noncovalent interactions, that is, counterpoise-corrected couple-cluster theory with single, double, and perturbative triple excitations extrapolated to the completed basis set limit. (11-15) In addition, concerns regarding the accuracy of empirical force fields (16, 17) are motivating the direct application of QM methods to the study of noncovalent binding in host–guest (18, 19) and protein–ligand (20-22) systems. (10) Although the parameters in an empirical force field are typically adjusted to optimize agreement with experimental data, growing computer power and a shortage of suitable experimental data are also driving increased use of quantum mechanical (QM) calculations to parametrize and test force fields. (3-9) These account for electrostatic and van der Waals interactions and may also include terms to account for time-varying changes in electronic polarization during the simulation. (1, 2) In molecular simulations, noncovalent interactions are typically modeled by the nonbonded terms in an empirical force field. A reliable representation of noncovalent interactions therefore is critically important to computational modeling of biomolecules, with applications that include rational drug design and protein engineering. Noncovalent interactions are of fundamental importance to biomolecular systems, as they help determine the structures and functions of proteins and nucleic acids and play a central role in molecular recognition. The latter can be used to guide the parametrization of molecular mechanics force fields on a term-by-term basis. The energies of all the dimer systems from the various QM approaches are included in the Supporting Information, as are the full SAPT2+(3) energy decomposition for a subset of over 1000 systems. We also show that a linear scaling of the perturbative energy terms provided by the fast SAPT0 method yields similar high accuracy, at particularly low computational cost. We find that all DFT methods with dispersion corrections, as well as SAPT at orders above SAPT2, consistently provide dimer interaction energies within 1.0 kcal/mol RMSE across all systems. Several orders of the SAPT expansion are also compared, ranging from SAPT0 up to SAPT2+3, where computationally feasible. ![]() ![]() For the PM6 and DFT methods, we also examine the effects of post hoc corrections for hydrogen bonding (PM6-DH+, PM6-DH2), halogen atoms (PM6-DH2X), and dispersion (DFT-D3 with zero and Becke–Johnson damping). In particular, we study the semiempirical PM6 and PM7 methods density functional theory (DFT) approaches B3LYP, B97-D, M062X, and ωB97X-D and symmetry-adapted perturbation theory (SAPT) approach. Here, we use the extensive Benchmark Energy and Geometry Database (BEGDB) of CCSD(T)/CBS reference results to evaluate the accuracy and speed of widely used QM methods for over 1200 chemically varied gas-phase dimers. Because the more computationally tractable QM methods necessarily include approximations, which risk degrading accuracy, it is essential to evaluate such methods by comparison with high-level reference calculations. Quantum mechanical (QM) calculations of noncovalent interactions are uniquely useful as tools to test and improve molecular mechanics force fields and to model the forces involved in biomolecular binding and folding.
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