Manzoor Sana, Hofer Thomas S, Moin Syed Tarique
Third World Center for Science and Technology, H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan.
Theoretical Chemistry Division, Institute of General, Inorganic and Theoretical Chemistry, University of Innsbruck, Innrain 80-82, Innsbruck A-6020, Austria.
J Chem Inf Model. 2025 May 12;65(9):4602-4619. doi: 10.1021/acs.jcim.5c00103. Epub 2025 Apr 28.
Molecular dynamics simulations were applied to human aromatase (HA) complexed with cytochrome P450 reductase (CPR) within a realistic endoplasmic reticulum membrane environment to evaluate its structural and dynamical properties. CPR was examined to have a specific point mutation (P281T), where proline was substituted by threonine, which is envisaged to demonstrate a far-reaching influence on its structure, dynamics, and electron transfer behavior. Since CPR plays a key role in the electron transfer to HA, catalyzing steroidogenesis, obtaining detailed information on the mutation effect of CPR on HA was crucial. This compelled us to study the interaction of HA with CPR in its wild-type and mutant forms, enabling the investigation of different properties of CPR and its effect on HA dynamics. Pursuing these objectives, different analytical parameters, notably, root-mean-square deviation, root-mean-square fluctuation, dynamic cross-correlation matrix, and principal component analysis were applied to gain insight into the conformational dynamics of the HA/CPR complex. These analyses demonstrated the CPR shifts in the complexes' dynamics, in the context of the effect of CPR mutation effects on HA behavior. Based on this information, the electron transfer within the HA/CPR complex was also envisaged to be influenced by the contrast dynamics between the two complexes as the mutation was evaluated to significantly alter the dynamics of CPR as well as HA. Furthermore, the electron transfer within the complexes was determined by applying Marcus theory of electron transfer, revealing a contrast between the HA/wild-type and mutant CPR complexes. The latter was found to alter the electron transfer efficiency, demonstrating a direct effect of changes in the protein dynamics observed within the HA/mutant CPR complex. This study therefore provides valuable insights into the conformational dynamics of HA in conjunction with CPR, affecting the electron transfer process and their potential implications for understanding estrogen-related physiological conditions influenced by these proteins.
