QTAIM and NCI analysis of intermolecular interactions in steroid ligands binding a cytochrome P450 enzyme – Beyond the most obvious interactions

Abstract

The 17α-hydroxylase-17,20-lyase (CYP17) is a cytochrome P450 enzyme which participates in steroid hormones metabolism. Pregnenolone (PREG) is its natural steroid substrate and abiraterone (ABE) is a well-known steroid inhibitor. In this paper, QTAIM and NCI analysis indicate many non-familiar intermolecular interactions in CYP17-ABE and CYP17-PREG complexes beyond the obvious interactions in these systems. These obvious interactions are two H-bonds in CYP17-PREG and NFe interaction in CYP17-ABE. Docking, molecular dynamics and ONIOM protocol was used to obtain the low-lying geometries for further topological analysis. QTAIM analysis from ωB97XD/6-311G++(d,p) wave function indicated the existence of H-bonds in CYP17-PREG complex and also showed three moderately strong intermolecular interactions in CYP17-ABE complex (besides the strong pyridine N-HEME Fe interaction): (O)HH (Ile205) interaction, (C)HN interaction (Arg239) and HH bond (Asp298), indicating that these interactions play a secondary role on molecular recognition of ABE by CYP17. QTAIM also indicated that HH bonds are important in molecular recognition since they made up half of all pairwise interactions, although being weaker than other usual interaction (hetereoatom-H intermolecular interaction), with two exceptions (which are closer than other HH bonds). Further NCI results give further evidence that ABE pyridine-HEME interaction has multiple interactions besides the obvious NFe interaction which might decrease the flexibility of the yet rigid ABE backbone in order make H-bonds from its (C3)-hydroxyl group with CYP17 binding pocket.