Mechanism of CDK5 activation revealed by steered molecular dynamics simulations and energy calculations |
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Authors: | Bing Zhang Zhou Cheng Su Tong Earn Tay Vincent B C Tan |
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Institution: | (1) Department of Mechanical Engineering, National University of Singapore, 9 Engineering Drive 1, 117576 Kent Ridge, Singapore;(2) Research Centre of Excellence for Mechanobiology, National University of Singapore, 117609 Kent Ridge, Singapore; |
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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. |
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Keywords: | |
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