Conformational plasticity of kinases: molecular dynamics simulation of the conformational changes in the activation loop and the PSSARLE helix of Cdk5

Cyclin-dependent kinases (CDKs) are mostly known for their role in the cell cycle regulation. The activation mechanism of all CDKs involves the association with a regulatory protein, generally a cyclin, that binds to the kinase unit and stabilizes a catalytically active conformation. Active and inactive conformations of CDKs are characterized by the different spatial localization of two typical elements, namely the activation loop and an alpha-helix, whose amino-acid composition varies throughout the family. Extensive X-ray crystallographic studies carried out in recent years allowed to elucidate the 3D structure of both the active and inactive CDK conformations, but the details of the conformational change remained elusive. Yet, it is generally accepted that specific CDK inhibitors will be obtained only exploiting the subtle structural differences existing among the protein family members. Considering Cdk5, a neuronal CDK whose deregulation has been associated with the neurofibrillary tangles formation in Alzheimer’s disease, we aimed at modeling the conformational transition with a particular attention at finding possible stable intermediate states. To pursue this goal, different molecular dynamics-based tools were employed, like classical molecular dynamics, essential dynamics, and the recently developed metadynamics.