title: Mechanism of CDK5 activation revealed by steered molecular dynamics simulations and energy calculations.
abstract: In the current work, CDK5/p25 complexes were pulled apart by applying external forces with steered molecular dynamics (SMD) simulations. The crucial interactions between the kinase and the activation protein were investigated and the SMD simulations showed that several activation-relevant motifs of CDK5 leave p25 in sequence during the pulling and lead to an apo-CDK2 like CDK5 structure after separation. Based on systematic examination of hydrogen bond breaking and classical MD/molecular mechanics-generalized Born/surface area) (MM-GBSA) calculations, a CDK5 activation mechanism by p25 is suggested. This is the first step towards the systemic development of CDK inhibitors and the mechanism proposed could lead to a better understanding of the protein-protein recognition characteristics between the kinase and its activator.
authors.affiliation: Department of Mechanical Engineering, National University of Singapore, 9 Engineering Drive 1, 117576, Kent Ridge, Singapore.
authors.forename: Bing
authors.initials: B
authors.lastname: Zhang
authors.forename: Zhou Cheng
authors.initials: ZC
authors.lastname: Su
authors.forename: Tong Earn
authors.initials: TE
authors.lastname: Tay
authors.forename: Vincent B C
authors.initials: VB
authors.lastname: Tan
mesh_terms: D000465:Algorithms; D001665:Binding Sites; D051360:Cyclin-Dependent Kinase 5 / Q000737:chemistry* / Q000378:metabolism; D004735:Energy Transfer; D004789:Enzyme Activation; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary
chemical_list: D009419:Nerve Tissue Proteins; C118136:TPPP protein, human; D051360:Cyclin-Dependent Kinase 5