Département de chimie moléculaire

Casein kinase CK2 is an essential enzyme in higher organisms, catalyzing the transfer of the $\gamma$-phosphate from ATP to Ser and Thr residues in protein substrates. In a no. of animal tumors, CK2 activity has been shown to escape normal cellular control, making it a potential target for cancer therapy. Several crystal structures of human CK2 have been published with different conformations for the CK2$\alpha$ catalytic subunit. This variability reflects a high flexibility for 2 regions of CK2$\alpha$: the interdomain hinge region, and the glycine-rich loop (p-loop). Here, the authors present a computational study simulating the equil. between 3 conformations involving these regions. Mol. dynamics simulations were performed using well-tempered metadynamics combined with a path collective variables approach. This provided a ref. pathway describing the conformational changes being studied, based on anal. of free energy surfaces. The free energies of the 3 conformations were found to be close and the paths proposed had low activation barriers. The results indicated that these conformations could exist in water. This information should be useful when designing inhibitors specific to one conformation. [on SciFinder(R)]