Insights into the Phosphoryl Transfer Mechanism of Cyclin-Dependent Protein Kinases from ab Initio QM/MM Free-EnergyStudies
Journal of Physical Chemistry B
Phosphorylation reactions catalyzed by kinases and phosphatases play an indispensible role in cellular signaling, and their malfunctioning is implicated in many diseases. A better understanding of the catalytic mechanism will help design novel and effective mechanism-based inhibitors of these enzymes. In this work, ab initio quantum mechanical/molecular mechanical studies are reported for the phosphoryl transfer reaction catalyzed by a cyclin-dependent kinase, CDK2. Our results suggest that an active-site Asp residue, rather than ATP as previously proposed, serves as the general base to activate the Ser nucleophile. The corresponding transition state features a dissociative, metaphosphate-like structure, stabilized by the Mg2+ ion and several hydrogen bonds. The calculated free-energy barrier is consistent with experimental values. Implications of our results in this and other protein kinases are discussed.
Gregory K. Smith, Zhihong Ke, Hua Guo, and Alvan C. Hengge. “Insights into the Phosphoryl Transfer Mechanism of Cyclin-Dependent Protein Kinases from ab Initio QM/MM Free-Energy Studies.” J. Phys. Chem. B, 2011, 115 (46), 13713-13722.