Molecular dynamics simulations of cytochrome P450 aromatases reveal structural variances across the cat family

Context Aromatase (CYP19A1) is a key enzyme in steroidogenesis, converting androgens to oestrogens, essential for reproductive function in vertebrates. While human aromatase has been extensively studied, comparative analyses in mammals, particularly felids, remain limited. Aims This study investigates the structural and functional dynamics of aromatase in various cat species, including the extinct Homotherium latidens and extant species such as Panthera tigris , Puma concolor , Acinonyx jubatus , and Felis catus . The goal is to assess evolutionary differences affecting dimerisation and enzymatic activity. Methods Homology models of feline aromatase were built using the human aromatase crystal structure as a template. Molecular dynamics (MD) simulations were conducted in both solvent and membrane environments to evaluate dimer stability, electrostatic interactions, and haem cofactor retention. Key results Sequence analysis showed over 99% conservation within felids and ~86% identity with human aromatase, with 69 key residue differences. MD simulations revealed that substitutions at the dimerisation interface weakened electrostatic interactions, reducing dimer stability in felids compared to humans. Membrane embedding improved stability, particularly in human aromatase, due to strong hydrogen-bonding interactions. Conclusions Evolutionary divergence has altered dimerisation stability in feline aromatases, potentially influencing enzymatic function. Reduced dimer formation may impact substrate binding and catalytic efficiency. Implications These findings provide insights into aromatase evolution and function, offering a foundation for future research into species-specific steroid biosynthesis and potential drug design strategies.