Molecular mechanisms of activation in CDK2

Cyclin-dependent kinases (CDKs) are enzymes involved in crucial cellular processes. Their biological activity is directly linked to their high conformational variability, which involves large protein conformational rearrangements. We present here the application of an enhancing sampling technique to the study of conformational transitions between the open and closed state of CDKs. The analysis of the conformational intermediates supports the idea that the process is regulated by two important protein regions, which sequentially rearrange in order to allow the protein to reach its final conformation. Furthermore, the two paths involve additional (minor) protein rearrangements which are specific to the paths. Our results show that our procedure can provide reasonable transition pathways between the two protein forms at a very reduced computational cost. The robustness and the simplicity of our approach make it of general application to describe virtually any macromolecular conformational transitions.