Catalytic Mechanisms of Non‐Heme Fe(II) and 2‐Oxoglutarate‐Dependent Enzymes: A Computational Perspective

<jats:title>Abstract</jats:title> <jats:p>Non‐heme Fe(II)/2 oxoglutarate dependent (Fe(II)/2OG) oxygenases comprise a diverse enzyme family that catalyzes oxidative transformations such as hydroxylation, desaturation, ring cyclization, and CC bond formation, playing essential roles in various biological pathways. Among Fe(II)/2/2OG oxygenases, histone demethylases, nucleic acid demethylases, aspartate/asparagine‐β‐hydroxylase, and the ethylene‐forming enzyme represent functionally diverse members with critical roles in epigenetic regulation, DNA/RNA processing, post‐translational modification, energy production, and natural product biosynthesis. This review primarily presents computational insights from our groups within the context of the current state of the art in the field. Through molecular dynamics (MD)‐based quantum mechanics/molecular mechanics (QM/MM) calculations, we explored the structural, electronic, and dynamic features governing substrate recognition, catalytic pathways, metal coordination changes, and active‐site rearrangements during catalysis. Furthermore, our research identifies the second coordination sphere and long‐range residues that can be targeted for designing selective inhibitors or improving catalytic efficiency. These computational studies are performed in correlation to experiments, and offer predictive frameworks for designing selective inhibitors and engineered biocatalysts.</jats:p>