Three-dimensional model of the cyclin-dependent kinase 1 (CDK1): Ab initio active site parameters for molecular...

Cyclin-dependent kinase 1 (CDK1) is an interesting target for potential anticancer drugs, and its three-dimensional (3D) structure is presently unknown. The purpose of this work was to build a 3D model of CDK1, which could be used in drug design studies. The protein 3D structure was homology modeled, based on the known crystal structure of CDK2, and new nonbonded parameters for the Mg(2+) coordination complex were developed by means of ab initio quantum chemical calculations. These parameters were both obtained and validated using the CDK2 structure as reference, and then they were used for the refinement of the CDK1 model. The resulting CDK1 structure was satisfactory and stable at room temperature, as shown by the molecular dynamics simulations carried out over a 1-ns time interval on the entire protein. A number of representative kinases in the active and inactive form, including the inactive CDK1 modeled in this work, were compared. The results illustrate the conformational variability of the activation loop of the inactive form of the kinases and suggest a way for selectively targeting the single CDKs.