Casein kinase CK2 catalyzes the transfer of the ? phosphate of ATP to serine and threonine residues of protein substrates. Different conformations for the CK2a catalytic subunit are available in crystal structures, reflecting a high flexibility for two regions near the ATP-binding site. Linked to this flexibility, an hypothetical equilibrum between different conformational and functional states of CK2a has been proposed by Niefind and al. (1). In this talk, we will present molecular dynamics simulations complemented by metadynamics to understand this equilibrium.Metadynamics is a powerful algorithm wherein accelerated sampling is accomplished by biasing the system through the addition to the potential energy function of a sum of repulsive Gaussian terms along the trajectory followed by a suitable chosen set of collectives variables (CVs). However the study of large-scale movements in proteins involves several degrees of freedom. One solution is to use path CVs (PCVs) (2). Given a reference path that connects two states, PCVs are flexible descriptors that represent the progression along the path and the distance from it.Two conformational changes CK2a were studied: the first one is the collapse of the glycin-rich loop of the CK2a and the second corresponds to an �open-to-close� transition of the helix aD/hinge region. Metadynamics was used to reconstruct the free energies surfaces for the two conformational changes. Our theoretical studies show that three conformations of the equilibrium proposed are close in energy. Paths found have low activation barriers (< 20 kcal/mol)). Consequently, these conformations are accessible in water. Our results are certainly an interesting clue to design new inhibitors.(1) Niefind, K.; Issinger, O. Biochim. Biophys. Acta, 2010  , 1804, 484-492.(2) Branduardi, D.; Gervasio, F.L.; Laio, A.; Parrinello, M. J. Chem. Phys, 2007  , 126, 054103.

Understanding of the conformational flexibility of the catalytic a-subunit of human protein kinase CK2

246th National Meeting (2013)

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