Paper Citing NAMD - Abstract
Stanton, Courtney L.; Kuo, I-Feng W.; Mundy, Christopher J.; Laino, Teodoro; Houk, K. N.
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
JOURNAL OF PHYSICAL CHEMISTRY B, 111:12573-12581, NOV 1 2007
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 (Delta Delta G(double dagger)) on going from solution to the enzyme is therefore -7 kcal/mol, far less than the experimental change of -23 kcal/ mol (for kappa(cat.)/kappa(cat.): 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.
