Molecular Dynamics Simulation Study Of Cyclin-dependent Kinase 2

The cyclin dependent protein kinase family belongs to protein kinase which can regulate cell cycle. In order to be active, CDKs must first bind to a cyclin protein. Cyclin dependent protein kinase, which needs to be combined with a periodic protein, is required for its activity. Moreover, the activity of the kinase is also regulated by other kinases and phosphorylase. CDK2 is a widely studied protein kinase, a large of X-ray structures of CDK2 and its complexes have been published. We get many X-ray crystal structures of CDK2 from PDB database, A complete chain of CDK2 has total 298 residues, since most of the crystal structures miss some amino acid residues, so we first need to complement these missing residues. Based on the location and the number of missing residues, we use different methods to complement. Classification of CDK2 crystal structure using hierarchical clustering analysis, we found that these crystal structure belong to two major categories, one of which binding Cyclin while the other not binding Cyclin. Then we construct CDK2 simulation system and generate about 42 microsecond molecular dynamics simulation trajectories by AMBER software. Eliminate some incorrect structures and analysis the RMSF value of the trajectory to identify fluctuation of each position, we observed that the location whose RMSF value is small corresponds to the helix and folded region. Calculating backbone dihedral angle and according to the number of conversion between groups divided by backbone dihedral angle, we divided trajectories into a quantity of conformational substates at multiple temporal resolutions. And Then judge every X-ray crystal structure of CDK2 locates which conformational substate. Compared with the analytical results of the simulated trajectory of lysozyme under the CHARMM force field, we observed that it exits inaccuracy in both AMBER and CHARMM force field, resulting that when grouping the simulation trajectories in the fine temporal resolution, there would be some crystal structures do not belong to any conformational substate. In other words, some conformational substates which should be in the presence are not found when grouping in the fine temporal resolution. In addition, we found that in the conformational substates which exist crystal structure, the statistical weight of transformation number is smaller, which indicates conformation substates existing crystal structure is relatively stable and is not easily converted to other conformational substates.