BAR-based multi-dimensional nonequilibrium pulling for indirect construction of QM/MM free energy landscapes: from semi-empirical to ab initio

The indirect method for the construction of quantum mechanics (QM)/molecular mechanics (MM) free energy landscapes provides a cheaper alternative for free energy simulations at the QM level. The indirect method features a direct calculation of the free energy profile with a computationally efficient but less accurate Hamiltonian (i.e. low-level Hamiltonian) and a low-level-to-high-level correction. In the thermodynamic cycle, the direct low-level calculation along the physically meaningful reaction coordinate is corrected via the alchemical method, which is often achieved with perturbation-based techniques. In our previous work, a multi-dimensional nonequilibrium pulling framework is proposed for the indirect construction of QM/MM free energy landscapes. Previously, we focused on obtaining semi-empirical QM (SQM) results indirectly from direct MM simulations and MM to SQM corrections. In this work, we apply this method to obtain results under ab initio QM Hamiltonians by combining direct SQM results and SQM to QM corrections. A series of SQM and QM Hamiltonians are benchmarked. It is observed that PM6 achieves the best performance among the low-level Hamiltonians. Therefore, we recommend using PM6 as the low-level theory in the indirect free energy simulation. Considering its higher similarity to the high-level Hamiltonians, PM6 corrected with the bond charge correction could be more accurate than the existing AM1-BCC model. Another central result in the current work is a basic protocol of choosing the strength of restraints and an appropriate time step in nonequilibrium free energy simulation at the stiff spring limit. We provide theoretical derivations to emphasize the importance of using a sufficiently large force constant and choosing an appropriate time step. It is worth noting that a general rule of thumb for choosing the time step, according to our derivation, is that a time step of 1 fs or smaller should be used, as long as the stiff spring approximation is employed, even in simulations with constraints on bonds involving hydrogen atoms.