 A hybrid method that has the advantages of both QM and MM
calculations is called QM/MM.Umbrella sampling is another free-energy calculation technique that is typically used for calculating the free-energy change associated with a change in "position" coordinates as opposed to "chemical" coordinates, although Umbrella sampling can also be used for a chemical transformation when the "chemical" coordinate is treated as a dynamic variable (as in the case of the Lambda dynamics approach of Kong and Brooks).An alternative to free energy perturbation for computing potentials of mean force in chemical space is thermodynamic integration.