The free-energy profiles that are obtained from quantum mechanical/molecular mechanical (QM/MM) free-energy simulations for the first, second and third methyl transfers in DIM-5 (a trimethylase) as well as in some of its mutants with different product specificity has been reported. The free-energy profiles for the first, second and third methyl transfers are plotted or DIM-5 as a function of the reaction coordinates. The QM/MM MD and free-energy (potential of mean force) simulations were applied to characterize the methyl transfers by using the CHARMM program. The stochastic boundary molecular dynamics method was used for the QM/MM MD and free-energy simulations. The initial coordinates for the reactant complexes were based on the crystallographic complex of DIM5. QM/MM MD simulations were carried out for each of the reactant complexes of the methyl transfers, the umbrella sampling method along with the Weighted Histogram Analysis Method (WHAM).