The considerable protein effect on the homolytic Co-C bond cleavage to form the 5'-deoxyadenosyl (Ado) radical and cob(II)alamin and the subsequent hydrogen transfer from the methylmalonyl-CoA substrate to the Ado radical in the methylmalonyl-CoA mulase (MMCM) have been extensively studied by DFT and ONIOM(DFT/MM) methods. Several quantum models have been used to systematically study the protein effect. The calculations have shown that the Co-C bond dissociation energy is very much reduced in the protein, compared to that in the gas phase. The large protein effect can be decomposed into the cage effect, the effect of coenzyme geometrical distortion, and the protein MM effect. The largest contributor is the MM effect, which mainly consists of the interaction of the QM part of the coenzyme with the MM part of the coenzyme and the surrounding residues. In particular, Glu370 plays an important role in the Co-C bond cleavage process. These effects tremendously enhance the stability of the Co-C bond cleavage state in the protein. The initial Co-C bond cleavage and the subsequent hydrogen transfer were found to occur in a stepwise manner in the protein, although the concerted pathway for the Co-C bond cleavage coupled with the hydrogen transfer is more favored in the gas phase. The assumed concerted transition state in the protein has more deformation of the coenzyme and the substrate and has less irteraction with the protein than the stepwise route. Key factors and residues in promoting the enzymatic reaction rate have been discussed in detail.