A two-pronged computational approach was taken to study the promiscuity of the SAM + -dependent methyl transferase AtHTMT1 from thale cress with several nucleophiles (Cl – , Br – , I – , NCO – , NCS – ). First, enzyme-free methyl transfer reactions were studied with M05/6-311+G(2d,p) DFT calculations and electrostatic continuum models (PCM/SMD) for various chemical environments. Second, QM/MM MD simulations with semiempirical Hamiltonians (PM7, PM6-D3, AM1, PM6-D3H4) and the AMBER 14SB force field were used to study the enzyme catalyzed reaction in silico . The combination of the DFT and MD results shows that reactant desolvation generally accelerates the reaction, but it cannot explain the selectivity of the enzyme. The critical position of H 2 O molecules at the reactive site favors the reaction of NCS – over Cl – and Br – in agreement with experiments, but not observed in the quantum calculations for the cytosol. The addition of selected H 2 O molecules to the N terminus of NCS – greatly increases its reactivity, while H 2 O molecules attached to Cl – slow the reaction. The partial solvation of the nucleophiles in the reactive pouch holds the key to understanding the reactivity of AtHTMT1.