title: Key role of hydrazine to the interaction between oxaloacetic against phosphoenolpyruvic carboxykinase (PEPCK): ONIOM calculations.
abstract: The interactions between oxaloacetic (OAA) and phosphoenolpyruvic carboxykinase (PEPCK) binding pocket in the presence and absence of hydrazine were carried out using quantum chemical calculations, based on the two-layered ONIOM (ONIOM2) approach. The complexes were partially optimized by ONIOM2 (B3LYP/6-31G(d):PM6) method while the interaction energies between OAA and individual residues surrounding the pocket were performed at the MP2/6-31G(d,p) level of theory. The calculated interaction energies (INT) indicated that Arg87, Gly237, Ser286, and Arg405 are key residues for binding to OAA with the INT values of -1.93, -2.06, -2.47, and -3.16 kcal mol(-1), respectively. The interactions are mainly due to the formation of hydrogen bonding interactions with OAA. Moreover, using ONIOM2 (B3LYP/6-31G(d):PM6) applied on the PEPCKHS complex, two proton transfers were observed; first, the proton was transferred from the carboxylic group of OAA to hydrazine while the second one was from Asp311 to Lys244. Such reactions cause the generation of binding strength of OAA to the pocket via electrostatic interaction. The orientations of Lys243, Lys244, His264, Asp311, Phe333, and Arg405 were greatly deviated after hydrazine incorporation. These indicate that hydrazine plays an important role in terms of not only changing the conformation of the binding pocket, but is also tightly bound to OAA resulting in its conformation change in the pocket. The understanding of such interaction can be useful for the design of hydrazine-based inhibitor for antichachexia agents.
authors.affiliation: Department of Chemistry, Faculty of Science, Kasetsart University, Chatuchak, Bangkok, Thailand 10900.
authors.forename: Pongthep
authors.initials: P
authors.lastname: Prajongtat
authors.forename: Darinee Sae-Tang
authors.initials: DS
authors.lastname: Phromyothin
authors.forename: Supa
authors.initials: S
authors.lastname: Hannongbua
mesh_terms: D020816:Amino Acid Motifs; D001665:Binding Sites; D004791:Enzyme Inhibitors / Q000737:chemistry*; D006801:Humans; D006834:Hydrazines / Q000737:chemistry*; D006860:Hydrogen Bonding; D008958:Models, Molecular; D062907:Oxaloacetic Acid / Q000737:chemistry*; D019764:Phosphoenolpyruvate Carboxykinase (ATP) / Q000037:antagonists & inhibitors / Q000737:chemistry*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011522:Protons; D011789:Quantum Theory; D055672:Static Electricity; D013816:Thermodynamics
chemical_list: D004791:Enzyme Inhibitors; D006834:Hydrazines; D011522:Protons; D062907:Oxaloacetic Acid; D019764:Phosphoenolpyruvate Carboxykinase (ATP)