Accurate Computation of Thermodynamic Activation Parameters in the Chorismate Mutase Reaction from Empirical Valence Bond Simulations

• Published in: Journal of chemical theory and computation Vol. 20; no. 1; pp. 451 - 458
• Main Authors: Wilkins, Ryan Scott, Lund, Bjarte Aarmo, Isaksen, Geir Villy, Åqvist, Johan, Brandsdal, Bjørn Olav
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 09.01.2024; ACS Publications
• Subjects: Activation energy; Biomolecular Systems; Chemical reactions; Computational chemistry; Empirical analysis; Enthalpy; Entropy of activation; Enzymes; Free energy; Parameters; Software; Structural analysis
• ISSN: 1549-9618; 1549-9626; 1549-9626
• DOI: 10.1021/acs.jctc.3c01105

Chorismate mutase (CM) enzymes have long served as model systems for benchmarking new methods and tools in computational chemistry. Despite the enzymes’ prominence in the literature, the extent of the roles that activation enthalpy and entropy play in catalyzing the conversion of chorismate to prephenate is still subject to debate. Knowledge of these parameters is a key piece in fully understanding the mechanism of chorismate mutases. Within this study, we utilize EVB/MD free energy perturbation calculations at a range of temperatures, allowing us to extract activation enthalpies and entropies from an Arrhenius plot of activation free energies of the reaction catalyzed by a monofunctional Bacillus subtilis CM and the promiscuous enzyme isochorismate pyruvate lyase of Pseudomonas aeruginosa. In comparison to the uncatalyzed reaction, our results show that both enzyme-catalyzed reactions exhibit a substantial reduction in activation enthalpy, while the effect on activation entropy is relatively minor, demonstrating that enzyme-catalyzed CM reactions are enthalpically driven. Furthermore, we observe that the monofunctional CM from B. subtilis more efficiently catalyzes this reaction than its promiscuous counterpart. This is supported by a structural analysis of the reaction pathway at the transition state, from which we identified key residues explaining the enthalpically driven nature of the reactions and also the difference in efficiencies between the two enzymes.