Mechanism of CDK5 activation revealed by steered molecular dynamics simulations and energy calculations

被引：11

作者：

Zhang, Bing ^{[1
,2
]}

Su, Zhou Cheng ^{[1
]}

Tay, Tong Earn ^{[1
]}

Tan, Vincent B. C. ^{[1
]}

机构：

[1] Natl Univ Singapore, Dept Mech Engn, Kent Ridge 117576, Singapore

[2] Natl Univ Singapore, Res Ctr Excellence Mechanobiol, Kent Ridge 117609, Singapore

来源：

JOURNAL OF MOLECULAR MODELING | 2010年 / 16卷 / 06期

关键词：

Cyclin-dependent kinase; Molecular dynamics; Protein-protein interaction; Steered molecular dynamics; CYCLIN-DEPENDENT KINASES; UNBINDING FORCES; PROTEIN-KINASE; ALZHEIMERS-DISEASE; STRUCTURAL BASIS; LIGAND-BINDING; CANCER-THERAPY; INHIBITORS; PHOSPHORYLATION; ROSCOVITINE;

D O I：

10.1007/s00894-009-0629-4

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：1159 / 1168

页数：10

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