A computational analysis of binding modes and conformation changes of MDM2 induced by p53 and inhibitor bindings

doi:10.1007/s10822-013-9693-z

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	A computational analysis of binding modes and conformation changes of MDM2 induced by p53 and inhibitor bindings
	Chen, Jianzhong 2; Wang, Jinan 3; Zhu, Weiliang3 ; Li, Guohui 1
刊名	JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN
	2013-11
卷号	27 期号:11 页码:965-974
关键词	p53-MDM2 interaction Molecular dynamics simulation PCA MM-GBSA
ISSN号	0920-654X
DOI	10.1007/s10822-013-9693-z
文献子类	Article
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.
资助项目	National Natural Science Foundation of China[11104164] ; National Natural Science Foundation of China[11274206] ; National Natural Science Foundation of China[31200545] ; Dr. Start-up Foundation of Shandong Jiaotong University[00000000] ; Natural Science Foundation of Shandong Jiaotong University[00000000]
WOS关键词	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
WOS研究方向	Biochemistry & Molecular Biology ; Biophysics ; Computer Science
语种	英语
出版者	SPRINGER
WOS记录号	WOS:000328207000004
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/277391]
专题	药物发现与设计中心
通讯作者	Chen, Jianzhong
作者单位	1.Chinese Acad Sci, Dalian Inst Chem Phys, State Kay Lab Mol React Dynam, Lab Mol Modeling & Design, Dalian, Peoples R China 2.Shandong Jiaotong Univ, Sch Sci, Jinan 250014, Peoples R China; 3.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, Shanghai 201203, Peoples R China;
推荐引用方式 GB/T 7714	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.
APA	Chen, Jianzhong,Wang, Jinan,Zhu, Weiliang,&Li, Guohui.(2013).A computational analysis of binding modes and conformation changes of MDM2 induced by p53 and inhibitor bindings.JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN,27(11),965-974.
MLA	Chen, Jianzhong,et al."A computational analysis of binding modes and conformation changes of MDM2 induced by p53 and inhibitor bindings".JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN 27.11(2013):965-974.