Recent crystal structures of DMSO reductases show that the active site is deeply buried inside the protein matrix. We have evaluated the effect of encapsulation on the reduction potential of the oxo-Mo(V) center by designing new thiol-containing ligands. The molybdenum complexes exhibit little variation in the S --> Mo charge transfer transition and in the EPR g values; however, they exhibit a variation in the Mo(V/IV) reduction potential. Taken together, the results strongly indicate that, in these molecules, solvent modulates the reduction potential. The results led us to suggest that the difference in the Mo(V/IV) reduction potential for different DMSO reductases may be modulated by solvent.