In this work we present a ligand-protein binding study of both DMG-in and DMG-out conformations of cyclin-dependent kinase 8/Cyclin C (CDK8/CycC) and the inhibitors by unbiased all-atom molecular dynamics (MD) simulations with an explicit solvent model. Our results confirmed that Cyclin C plays a critical role in stabilizing the protein and promoting ligand binding. With the presence of Cyclin C the motions of the activation loop and alpha-C helix decreased and the binding modes of ligands were also reduced to a dominant one resembling to the crystal structures. The effects of protein motions on the volume of the CDK8 binding pocket were closely examined and found important to ligand binding.  Although the major driving force for the binding was van der Waals interactions, the hydrogen bonds between protein and ligands were found to be the key factors in determining the rankings of the ligands.

Modeling ligand-protein binding: Explanation of the dynamic processes in the binding between CDK8/CycC and the inhibitors

254th National Meeting (2017)

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