A crucial component in understanding the function of enzymes is knowledge of the activation enthalpy-entropy balance and its role in catalyzing the reaction. Current studies of the significance of entropy effects in enzyme catalysis sometimes challenge the celebrated Circe effect hypothesis that ground-state destabilization of the substrate is responsible for catalytic effect. Hence, Kazemi et al. proposed that the traditional view of activation entropies being interpreted solely in terms of a loss of translational and rotational entropies upon substrate binding is oversimplified, and that a complete representation should also include contributions from the reorganization of the surrounding protein and solvent. Further understanding of the role of entropy in enzyme catalysis plays an important part in the optimization of catalytic rates and enzyme stability in the rational design of enzymes for industrial and scientific purposes. A common model system used to study the entropy-enthalpy balance in enzymes is chorismate mutase (CM), which has served as a benchmark for QM/MM calculations of enzymatic reactions. Chorismate mutase (CM) catalyses the pericyclic rearrangement of chorismate to prephenate (Figure ), which is a key step in the shikimate pathway for biosynthesis of phenylalanine and tyrosine in bacteria, fungi, and higher plants. There is some debate over the degree to which entropy plays a role in this reaction. In the AroH-class chorismate mutase from Streptomyces aurofaciens, the enzyme catalysed reaction exhibits a significantly less negative entropy than the uncatalyzed reaction. This suggests that the conversion of chorismate to prephenate is driven by entropic effects. This is hypothesized to be due to an electrostatic stabilization of the transition state as the average C9-C1 distance in the transition state decreases, an energetically costly effect in the water reaction. While Hur and Bruice considered this to be an example of the formation of a so-called near-attack-complex (NAC), Warshel and co-workers argued that this conformation is the result of transition state stabilization, rather than the reason for the catalytic effect of the enzyme. On the other hand, in the chorismate mutase reaction catalysed by the B. subtilis chorismate mutase (BsCM) and the promiscuous enzyme isochorismate pyruvate lyase from Pseudomonas aeruginosa (PchB), the activation entropy from experimental studies is comparable to that of the reaction in water, suggesting entropy plays only a small role in the reaction. In the latter enzyme, the conversion of chorismate to prephenate is secondary to the conversion of isochorismate to pyruvate and salicylate. The two reactions share an active site; however, the former reaction is approximately two orders of magnitude less efficient than the latter. In the first reported QM/MM study on the entropic contributions of PchB, Xie et al. used DFTB2/MIO/MM to calculate thermodynamic activation parameters for the conversion of chorismate to pyruvate in PchB, finding a significantly less negative activation entropy than the uncatalyzed reaction. By including a correctional term obtained from quasiharmonic analysis, they could match experimental entropy values. However, the activation free energies of the enzymatic and aqueous reactions reported by Xie et al. are also significantly lower than experimental values, indicating that their calculated entropy from the Arrhenius plot approach is likely incorrect.