Host–Guest Relative Binding Affinities at Density-Functional Theory Level from Semiempirical Molecular Dynamics Simulations

Relative free energies for the binding of nine cyclic carboxylate ligands to the octa-acid deep-cavity host were calculated at the combined density-functional theory and molecular mechanics (DFT/MM) level of theory. The DFT calculations employed the BLYP functional and the 6-31G* basis set for the ligand. We employed free-energy perturbations (FEP) with the reference-potential approach and used molecular dynamics (MD) simulations with the semiempirical quantum mechanical (SQM) PM6-DH+ method for the ligand as an intermediate level between MM and DFT/MM to improve the convergence. Thus, the relative binding free energy of two ligands was first calculated at the MM level by an alchemical transformation from one ligand to another in both the bound and unbound states. Then, for each ligand the free-energy correction for going from the MM to the SQM/MM potentials was calculated using explicit SQM/MM MD simulations. Finally, the free-energy correction for going from the SQM/MM to the DFT/MM potentials was estimated with FEP without running any DFT/MM simulations. Instead, the free energy was calculated by single-step exponential averaging (ssEA) or employing the cumulant approximation to the second order (CA). The results show that CA converges much better than ssEA, and with 500–4500 DFT/MM single-point energy calculations, converged free energies with a precision of 0.3 kJ/mol can be obtained. These free energies reproduce the experimental binding free energy differences with a mean absolute deviation of 3.4 kJ/mol, a correlation (R2) of 0.97, and correct signs for all of the eight free-energy differences. This is appreciably better than the results obtained at the SQM/MM level of theory and also slightly better than those obtained with MM. We show that the convergence of the SQM/MM → DFT/MM perturbations can be monitored by the use of Wu and Kofke’s bias metric Π and by the standard deviation of the difference between the SQM/MM and DFT/MM energies. Finally, we show that the use of the intermediate SQM/MM MD simulations improves the convergence of the free energies by a factor of at least two, compared to doing direct MM → DFT/MM perturbations