Dihydrofolate reductase (DHFR) catalyzes the reduction of 7,8-dihydrofolate by nicotinamide adenine dinucleotide phosphate hydride (NADPH) to form 5,6,7,8-tetrahydrofolate and oxidized nicotinamide. DHFR is a small, flexible, monomeric protein with no metals or SS bonds and serves as one of the enzymes commonly used to examine basic aspects in enzymology. In the current work, we present extensive benchmark calculations for several model reactions in the gas phase that are relevant to the DHFR catalyzed hydride transfer. To this end, we employ G4MP2 and CBS-QB3 ab initio calculations as well as numerous density functional theory methods. Using these results, we develop two specific reaction parameter (SRP) Hamiltonians based on the semiempirical AM1 method. The first generation SRP Hamiltonian does not account for dispersion, while the second generation SRP accounts for dispersion implicitly via the AM1 core-repulsion functions. These SRP semiempirical Hamiltonians are subsequently used in hybrid quantum mechanics/molecular mechanics simulations of the DHFR catalyzed reaction. Finally, kinetic isotope effects are computed using a mass-perturbation-based path-integral approach.