Calculating binding free energies with quan-tum-mechanical (QM) methods is notoriously time-consum-ing. In this work, we studied whether such calculations can beaccelerated by using nonequilibrium (NE) moleculardynamics simulations employing Jarzynski’s equality. Westudied the binding of nine cyclic carboxylate ligands to theocta-acid deep-cavity host from the SAMPL4 challenge withthe reference potential approach. The binding free energieswere first calculated at the molecular mechanics (MM) levelwith free energy perturbation using the generalized Amberforce field with restrained electrostatic potential charges forthe host and the ligands. Then the free energy corrections for going from the MM Hamiltonian to a hybrid QM/MM Hamiltonian were estimated by averaging over many short NE molecular dynamics simulations. In the QM/MM calculations, the ligand was described at the semiempirical PM6-DH+ level. We show that this approach yields MM → QM/MM free energy corrections that agree with those from other approaches within statistical uncertainties. The desired precision can be obtained by running a proper number of independent NE simulations. For the systems studied in this work, a total simulation length of 20 ps was appropriate for most of the ligands, and 36−324 simulations were necessary in order to reach a precision of 0.3 kJ/ mol
