title: Protein conformational transitions: the closure mechanism of a kinase explored by atomistic simulations.
abstract: Kinase large-scale conformational rearrangement is an issue of enormous biological and pharmacological relevance. Atomistic simulations able to capture the dynamics and the energetics of kinase large-scale motions are still in their infancy. Here, we present a computational study in which the atomistic dynamics of the "open-to-closed" movement of the cyclin-dependent kinase 5 (CDK5) have been simulated. Simulations were carried out using a new sampling method that is able to find the lowest free-energy channel between an initial state and a final state. This large-scale movement has a two-step mechanism: first, the alphaC-helix rotates by approximately 45 degrees , allowing the interaction between Glu51 and Arg149; then the CDK5 activation loop refolds to assume the closed conformation. We have also estimated the free-energy profile associated with the global motion and identified a CDK5 intermediate, which could be exploited for drug-design purposes. Our new sampling method turned out to be well-suited for investigating at an atomistic level the energetics and dynamics of kinase large-scale conformational motions.
authors.affiliation: Scuola Normale Superiore, Piazza dei Cavalieri, I-56126 Pisa, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Berteotti
authors.forename: Andrea
authors.initials: A
authors.lastname: Cavalli
authors.forename: Davide
authors.initials: D
authors.lastname: Branduardi
authors.forename: Francesco Luigi
authors.initials: FL
authors.lastname: Gervasio
authors.forename: Maurizio
authors.initials: M
authors.lastname: Recanatini
authors.forename: Michele
authors.initials: M
authors.lastname: Parrinello
mesh_terms: D003198:Computer Simulation; D051360:Cyclin-Dependent Kinase 5 / Q000737:chemistry* / Q000378:metabolism; D004789:Enzyme Activation; D008956:Models, Chemical; D008958:Models, Molecular; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000378:metabolism; D010766:Phosphorylation; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D013816:Thermodynamics
chemical_list: D009419:Nerve Tissue Proteins; C089495:neuronal Cdk5 activator (p25-p35); D051360:Cyclin-Dependent Kinase 5