Comparative docking studies of CYP1b1 and its PCG-associated mutant forms

Molecular docking has been used to compare and contrast the binding modes of oestradiol with the wild-type and some disease-associated mutant forms of the human CYP1b1 protein. The receptor structures used for docking were derived from molecular dynamics simulations of homology-modelled structures. Earlier studies involving molecular dynamics and principal component analysis indicated that mutations could have a disruptive effect on function, by destabilizing the native properties of the functionally important regions, especially those of the haem-binding and substrate-binding regions, which constitute the site of catalytic activity of the enzyme. In order to gain more insights into the possible differences in substrate-binding and catalysis between the wild-type and mutant proteins, molecular docking studies were carried out. Mutants showed altered protein-ligand interactions compared with the wild-type as a consequence of changes in the geometry of the substrate-binding region and in the position of haem relative to the active site. An important difference in ligand-protein interactions between the wild-type and mutants is the presence of stacking interaction with phenyl residues in the wild-type, which is either completely absent or considerably weaker in mutants. The present study revealed essential differences in the interactions between ligand and protein in wild-type and disease mutants, and helped in understanding the deleterious nature of disease mutations at the level of molecular function.