All constrained geometry optimizations were performed in ORCA 108 v.4.0.1.2 and v.4.2.1 with the generalized gradient approximation (GGA) global hybrid PBE0 109 (with 25% exchange) density functional and the def2-TZVP basis set 110 . Semi-empirical D3 111 dispersion correction with Becke-Johnson 112 damping was incorporated in these optimizations. All optimizations were carried out using the BFGS algorithm in redundant internal coordinates with default thresholds of 5 x 10 -6 hartree for self-consistent field (SCF) convergence and 3 x 10 -4 hartree/bohr for the maximum gradient. In all optimizations, the methyl carbon atoms of all His and Glu ligands, the five heavy atoms of succinate, and the heavy atoms in the metal-distal carboxylate group of aKG were held fixed to mimic the ligand positions in the enzyme (Supporting Information Figure ).