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题名: A computational analysis of binding modes and conformation changes of MDM2 induced by p53 and inhibitor bindings
作者: Chen, Jianzhong1;  Wang, Jinan2;  Zhu, Weiliang2;  Li, Guohui3
关键词: p53-MDM2 interaction ;  Molecular dynamics simulation ;  PCA ;  MM-GBSA
刊名: JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN
发表日期: 2013-11-01
DOI: 10.1007/s10822-013-9693-z
卷: 27, 期:11, 页:965-974
收录类别: SCI
文章类型: Article
WOS标题词: Science & Technology ;  Life Sciences & Biomedicine ;  Technology
类目[WOS]: Biochemistry & Molecular Biology ;  Biophysics ;  Computer Science, Interdisciplinary Applications
研究领域[WOS]: Biochemistry & Molecular Biology ;  Biophysics ;  Computer Science
英文摘要: Molecular dynamics (MD) simulations followed by principal component analysis were performed to study the conformational change of MDM2 induced by p53 and two inhibitor (P4 and MI63a) bindings. The results show that the hydrophobic cleft of MDM2 is very flexible and adaptive to different structural binding partners. The cleft tends to become wider and more stable as MDM2 binds to the three binding partners, while unbound MDM2 shows a narrower and pretty flexible cleft, which agrees with recent experimental data and theoretical studies. It was also found that the binding of P4 and p53 stabilizes the motion of the loop L2 linking the helix alpha 2 and beta strand (beta 3), but the presence of MI63a makes the motion of L2 disordered. In addition, the binding free energies of the three partners to MDM2 were calculated using molecular mechanics generalized Born surface area to explain the binding modes of these three partners to MDM2. This study will be helpful not only for better understanding the functional, concerted motion of MDM2, but also for the rational design of potent anticancer drugs targeting the p53-MDM2 interaction.
关键词[WOS]: MOLECULAR-DYNAMICS SIMULATIONS ;  PROTEIN-PROTEIN INTERACTION ;  STRUCTURE-BASED DESIGN ;  PARTICLE MESH EWALD ;  FREE-ENERGY ;  P53-MDM2 INTERACTION ;  EFFICIENT GENERATION ;  PEPTIDE INHIBITORS ;  TUMOR-SUPPRESSOR ;  CANCER-THERAPY
语种: 英语
WOS记录号: WOS:000328207000004
Citation statistics: 
内容类型: 期刊论文
URI标识: http://cas-ir.dicp.ac.cn/handle/321008/137525
Appears in Collections:中国科学院大连化学物理研究所_期刊论文

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作者单位: 1.Shandong Jiaotong Univ, Sch Sci, Jinan 250014, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, Shanghai 201203, Peoples R China
3.Chinese Acad Sci, Dalian Inst Chem Phys, State Kay Lab Mol React Dynam, Lab Mol Modeling & Design, Dalian, Peoples R China

Recommended Citation:
Chen, Jianzhong,Wang, Jinan,Zhu, Weiliang,et al. A computational analysis of binding modes and conformation changes of MDM2 induced by p53 and inhibitor bindings[J]. JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN,2013,27(11):965-974.
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