A molecular dynamics investigation of CDK8/CycC and ligand binding: conformational flexibility and implication in drug discovery

The activities of CDK8 with partner Cyclin C (CycC) are a common feature of many diseases, especially cancers. Here we report the study of dynamic behaviors and energy profiles of 13 CDK8/CycC systems, including the DMG-in and DMG-out conformations as well as 5 type I ligands and 5 type II ligands, with all-atom unbiased molecular dynamics (MD) simulations. We observed numerous regional motions within CDK8, which move in concert to form five major protein motions. The motion of the activation loop doesn’t appear to influence the binding of both types of ligands. Type I ligands remarkably reduce the motion of the C-terminal tail through the strong cation-π interaction between the ligands and ARG356, and type II ligands stabilize the αC helix by forming stable hydrogen bonds with GLU66. The MD calculations also confirmed the importance of CycC to the stability of the CDK8 system as well as the ligand binding. The MMPB/SA results show that van der Waals interaction is the main driving force for the binding of both types of ligands, but electrostatic energy and entropy penalty plays important roles in the binding of type II ligands. The volume analysis results indicate that the induced fitting theory applies in the binding of type I ligands. These results would help to improve the affinities of the existing ligands. Our MD work is complementary to crystal structures and may have implications in the development of new CDK8 inhibitors as well as in the field of drug discovery.