期刊
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
卷 131, 期 1, 页码 244-250出版社
AMER CHEMICAL SOC
DOI: 10.1021/ja806846q
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资金
- Italian MUR [RBNE03FH5Y]
- CSCS
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 alpha C-helix rotates by similar to 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.
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