title: QM/MM metadynamics study of the direct decarboxylation mechanism for orotidine-5'-monophosphate decarboxylase using two different QM regions: acceleration too small to explain rate of enzyme catalysis.
abstract: Despite decades of study, the mechanism by which orotidine-5'-monophosphate decarboxylase (ODCase) catalyzes the decarboxylation of orotidine monophosphate remains unresolved. A computational investigation of the direct decarboxylation mechanism has been performed using mixed quantum mechanical/molecular mechanical (QM/MM) dynamics simulations. The study was performed with the program CP2K that integrates classical dynamics and ab initio dynamics based on the Born-Oppenheimer approach. Two different QM regions were explored. The free energy barriers for direct decarboxylation of orotidine-5'-monophosphate (OMP) in solution and in the enzyme (using the larger QM region) were determined with the metadynamics method to be 40 and 33 kcal/mol, respectively. The calculated change in activation free energy (DeltaDeltaG++) on going from solution to the enzyme is therefore -7 kcal/mol, far less than the experimental change of -23 kcal/ mol (for k(cat.)/k(uncat.): Radzicka, A.; Wolfenden, R., Science 1995, 267, 90-92). These results do not support the direct decarboxylation mechanism that has been proposed for the enzyme. However, in the context of QM/MM calculations, it was found that the size of the QM region has a dramatic effect on the calculated reaction barrier.
authors.affiliation: Department of Chemistry and Biochemistry, University of California Los Angeles, 607 Charles E. Young Drive East, Los Angeles, California 90095, USA.
authors.forename: Courtney L
authors.initials: CL
authors.lastname: Stanton
authors.forename: I-Feng W
authors.initials: IF
authors.lastname: Kuo
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Mundy
authors.forename: Teodoro
authors.initials: T
authors.lastname: Laino
authors.forename: K N
authors.initials: KN
authors.lastname: Houk
mesh_terms: D002384:Catalysis; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D003653:Decarboxylation; D007700:Kinetics; D008958:Models, Molecular; D015394:Molecular Structure; D009963:Orotic Acid / Q000737:chemistry; D009964:Orotidine-5'-Phosphate Decarboxylase / Q000737:chemistry*; D011789:Quantum Theory; D012984:Software; D013816:Thermodynamics; D014542:Uridine Monophosphate / Q000031:analogs & derivatives* / Q000737:chemistry
chemical_list: C005417:orotidylic acid; D009963:Orotic Acid; D014542:Uridine Monophosphate; D009964:Orotidine-5'-Phosphate Decarboxylase