Probing Origin of Binding Difference of inhibitors to MDM2 and MDMX by Polarizable Molecular Dynamics Simulation and QM/MM-GBSA Calculation

doi:10.1038/srep17421

CORC > 上海药物研究所 > 中国科学院上海药物研究所 > 药物发现与设计中心

	Probing Origin of Binding Difference of inhibitors to MDM2 and MDMX by Polarizable Molecular Dynamics Simulation and QM/MM-GBSA Calculation
	Chen, Jianzhong 3; Wang, Jinan 2; Zhang, Qinggang 1; Chen, Kaixian2 ; Zhu, Weiliang2
刊名	SCIENTIFIC REPORTS
	2015-11-30
卷号	5
ISSN号	2045-2322
DOI	10.1038/srep17421
文献子类	Article
英文摘要	Binding abilities of current inhibitors to MDMX are weaker than to MDM2. Polarizable molecular dynamics simulations (MD) followed by Quantum mechanics/molecular mechanics generalized Born surface area (QM//MM-GBSA) calculations were performed to investigate the binding difference of inhibitors to MDM2 and MDMX. The predicted binding free energies not only agree well with the experimental results, but also show that the decrease in van der Walls interactions of inhibitors with MDMX relative to MDM2 is a main factor of weaker bindings of inhibitors to MDMX. The analyses of dihedral angles based on MD trajectories suggest that the closed conformation formed by the residues M53 and Y99 in MDMX leads to a potential steric clash with inhibitors and prevents inhibitors from arriving in the deep of MDMX binding cleft, which reduces the van der Waals contacts of inhibitors with M53, V92, P95 and L98. The calculated results using the residue-based free energy decomposition method further prove that the interaction strength of inhibitors with M53, V92, P95 and L98 from MDMX are obviously reduced compared to MDM2. We expect that this study can provide significant theoretical guidance for designs of potent dual inhibitors to block the p53-MDM2/MDMX interactions.
资助项目	National Natural Science Foundation of China[11274206] ; National Natural Science Foundation of China[81273435] ; National Natural Science Foundation of China[21403283] ; Shandong province university science and technology project[J14LJ07] ; Shandong Jiaotong University[00000000] ; Postdoctoral Science Foundation of China[2014M560362]
WOS关键词	SUPPRESSOR TRANSACTIVATION DOMAIN ; PROTEIN-PROTEIN INTERACTIONS ; SOLVATED INTERACTION ENERGY ; STRUCTURE-BASED DESIGN ; CHARGE FORCE-FIELD ; LIGAND-BINDING ; HIV-1 PROTEASE ; ELECTROSTATIC POLARIZATION ; ELECTRONIC POLARIZATION ; MAGNETIC-PROPERTIES
WOS研究方向	Science & Technology - Other Topics
语种	英语
出版者	NATURE PUBLISHING GROUP
WOS记录号	WOS:000365417500001
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/276314]
专题	药物发现与设计中心
通讯作者	Chen, Jianzhong
作者单位	1.Shandong Normal Univ, Coll Phys & Elect, Jinan 250014, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Discovery & Design Ctr, Shanghai 201203, Peoples R China; 3.Shandong Jiaotong Univ, Sch Sci, Jinan 250014, Peoples R China;
推荐引用方式 GB/T 7714	Chen, Jianzhong,Wang, Jinan,Zhang, Qinggang,et al. Probing Origin of Binding Difference of inhibitors to MDM2 and MDMX by Polarizable Molecular Dynamics Simulation and QM/MM-GBSA Calculation[J]. SCIENTIFIC REPORTS,2015,5.
APA	Chen, Jianzhong,Wang, Jinan,Zhang, Qinggang,Chen, Kaixian,&Zhu, Weiliang.(2015).Probing Origin of Binding Difference of inhibitors to MDM2 and MDMX by Polarizable Molecular Dynamics Simulation and QM/MM-GBSA Calculation.SCIENTIFIC REPORTS,5.
MLA	Chen, Jianzhong,et al."Probing Origin of Binding Difference of inhibitors to MDM2 and MDMX by Polarizable Molecular Dynamics Simulation and QM/MM-GBSA Calculation".SCIENTIFIC REPORTS 5(2015).