There are numerous studies, relying on both experimental and theoretical observations, illustrating the active role of the heme propionates in regulating electron delivery to the iron center as well as biochemical properties of the heme. Evidences for this come from a wide variety of heme containing systems: cytochromes, heme peroxidases, globins, etc. Here, we shortly summarize these studies and revisit previous theoretical calculations (V. Guallar, M.H. Baik, S.J. Lippard, R.A. Friesner, Proc. Natl. Acad. Sci. USA 100 (2003) 6998–7002) where the propionate groups induced the delocalization of the spin density in the cytochrome P450cam putative active species, Compound I. We introduce novel data, obtained by means of mixed quantum mechanics and molecular mechanics methods, indicating a larger electron delocalization into the protein. We also present novel results based on the recent migration of spin density observed by Barrows et al. (T.P. Barrows, T.L. Poulos, Biochemistry 44 (2005) 14062–68) on an ascorbate peroxidase mutant. All this data strongly supports the importance of the propionate groups in tuning the heme electronic properties.