Two theoretical methodologies - a combined quantum mechanical and molecular mechanical (QM/MM) model and a linear-scaling semiempirical SCF method (MOZYME) - were used to calculate energy profiles for an enzyme reaction path, that for hydride-ion transfer between 8-methylpterin and nicotinamide adenine dinucleotide phosphate (NADPH) in dihydrofolate reductase (DHFR). Profiles from the QM/MM model, which divides the system into QM and MM regions, were compared with those from MOZYME, which treats the entire ligand-protein complex quantum mechanically. If the coordinates of the MM region vary little, it is possible to define a QM/MM model for the DHFR reaction that gives energetics close to those from MOZYME. However, the QM/MM and MOZYME energies diverge when the MM geometry changes, largely due to the MM electrostatic energy. 'Switching off' polarisation of the QM region by the MM region produced larger changes especially in the transition-state region. The results suggest caution should be used when generating reaction paths for QM/MM methods.