In the second cycle, where the force field is re-optimized with the additional QM data, the RMSE for the energies calculated at the MM minimized structures significantly decreases to 1.54 kcal/mol. In the third cycle the RMSE has a minor decrease from Cycle 2 to 0.92 kcal/mol, indicating that the reoptimization procedure has essentially converged. ). The points represent predicted minimum energy structures from the force field, which are eliminated through multiple cycles of adding the QM energies and gradients for these points back into the objective function.