Sterol 14α-demethylase (cytochrome P450 family 51) is an essential enzyme occurring in all biological kingdoms and locates in the endoplastic reticulum membrane in eukaryotes. Specific inhibitors of trypanosomal CYP51s that do not affect the human CYP51 have been discovered in vitro and found to cure acute and chronic mouse Chagas disease in vivo. However, how the dynamics of CYP51s differ from the other CYPs and how the membrane can influence the dynamics of CYP51s are unknown which can be important for drug design. We built a membrane-bound model of Trypanosma brucei CYP51.
The dynamics of both soluble and membrane-bound forms of this CYP51 were studied and compared to those of human CYP2C9 and CYP2E1. We found that: (i) CYP51 has a higher rigidity in the substrate recognition sites of the binding cavity, particularly in the B-C loop and C helix region. This rigidity may result in the high substrate selectivity of CYP51 family. (ii) The proximal water tunnel which is mostly closed in other CYPs, is accessible to the solvent in most crystal structures and in the simulations of T. brucei CYP51. The water tunnel opened structures may be more efficient for the binding of the reductases. (iii) The two heme propionate groups of CYP51 have higher plasticity than other CYPs suggested by the different conformations in the crystal structures and in the simulations. The conformations of the propionate groups are modulated by hydrogen bonds. The conformational changes of the two propionate groups can be induced by the binding of ligands.