A quantum mechanical/molecular mechanical (QM/MM) approach based on an approximate density functional theory, the so-called self-consistent charge density functional tight binding (SCC-DFTB) method, has been implemented in the CHARMM program and tested on a number of systems of biological interest. In the gas phase, SCC-DFTB gives reliable energetics for models of the triosephosphate isomerase (TIM) catalyzed reactions. The rms errors in the energetics compared to B3LYP/6-31+G(d,p) are about 2−4 kcal/mol; this is to be contrasted with AM1, where the corresponding errors are 9−11 kcal/mol. The method also gives accurate vibrational frequencies. For the TIM reactions in the presence of the enzyme, the overall SCC-DFTB/CHARMM results are in somewhat worse agreement with the B3LYP/6-31+G(d,p)/CHARMM values; the rms error in the energies is 5.4 kcal/mol. Single-point B3LYP/CHARMM energies at the SCC-DFTB/CHARMM optimized structures were found to be very similar to the full B3LYP/CHARMM values. The relative sta...