Relative Ligand-Binding Free Energies Calculated from Multiple Short QM/MM MD Simulations.

We have devised a new efficient approach to compute combined quantum mechanical (QM) and molecular mechanical (MM, i.e. QM/MM) ligand-binding relative free energies. Our method employs the reference-potential approach with free-energy perturbation both at the MM level (between the two ligands) and from MM to QM/MM (for each ligand). To ensure that converged results are obtained for the MM → QM/MM perturbations, explicit QM/MM molecular dynamics (MD) simulations are performed with two intermediate mixed states. To speed up the calculations, we utilize the fact that the phase space can be extensively sampled at the MM level. Therefore, we run many short QM/MM MD simulations started from snapshots of the MM simulations, instead of a single long simulation. As a test case, we study the binding of nine cyclic carboxylate ligands to the octa-acid deep cavitand. Only the ligand is in the QM system, treated with the semiempirical PM6-DH+ method. We show that for eight of the ligands, we obtain well converged results with short MD simulations (1-15 ps). However, in one case, the convergence is slower (∼50 ps) owing to a mismatch between the conformational preferences of the MM and QM/MM potentials. We test the effect of initial minimization, the need of equilibration, and how many independent simulations are needed to reach a certain precision. The results show that the present approach is about four times faster than using standard MM → QM/MM free-energy perturbations with the same accuracy and precision.