QM and QM/MM studies of the phosphoryl transfer reaction catalyzed by a cyclin-dependent kinase (CDKS)

The study focused on the use of QM/MM simulations to investigate enzymatic reaction in targets of pharmaceutical relevance. The regulation of the eukaryotic cell cycle depends on the action of several related Ser/Thr protein kinases called cyclin-dependent kinases (CDKs), which are transiently activated at specific stages of the cycle, and which are also very promising targets for therapeutic intervention. A key step in the mechanism of action of CDKs is the transfer of γ-phosphate from ATP to a serine or threonine residue of the substrate. In the present study we have used both QM and QM/MM methods to investigate this enzymatic reaction. In this way, we have been able to define a possible reaction pathway for the phosphate transfer reaction, and estimate the role of mechanical and electrostatic effects in the catalysis. An improvement of the understanding of phosphorylation in CDKs family might eventually lead to the design of new inhibitors based on the enzymatic reaction transition state.