A quantum mechanics/molecular mechanics study on the hydrolysis mechanism of New Delhi metallo-beta-lactamase-1

doi:10.1007/s10822-012-9630-6

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	A quantum mechanics/molecular mechanics study on the hydrolysis mechanism of New Delhi metallo-beta-lactamase-1
	Zhu, Kongkai 1,3; Lu, Junyan 3; Liang, Zhongjie 2; Kong, Xiangqian 3; Ye, Fei 3; Jin, Lu 3; Geng, Heji 1,3; Chen, Yong 1; Zheng, Mingyue3 ; Jiang, Hualiang3
刊名	JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN
	2013-03
卷号	27 期号:3 页码:247-256
关键词	QM/MM NDM-1 MD Catalytic mechanism beta-Lactam antibiotics
ISSN号	0920-654X
DOI	10.1007/s10822-012-9630-6
文献子类	Article
英文摘要	New Delhi metallo-beta-lactamase-1 (NDM-1) has emerged as a major global threat to human health for its rapid rate of dissemination and ability to make pathogenic microbes resistant to almost all known beta-lactam antibiotics. In addition, effective NDM-1 inhibitors have not been identified to date. In spite of the plethora of structural and kinetic data available, the accurate molecular characteristics of and details on the enzymatic reaction of NDM-1 hydrolyzing beta-lactam antibiotics remain incompletely understood. In this study, a combined computational approach including molecular docking, molecular dynamics simulations and quantum mechanics/molecular mechanics calculations was performed to characterize the catalytic mechanism of meropenem catalyzed by NDM-1. The quantum mechanics/molecular mechanics results indicate that the ionized D124 is beneficial to the cleavage of the C-N bond within the beta-lactam ring. Meanwhile, it is energetically favorable to form an intermediate if no water molecule coordinates to Zn2. Moreover, according to the molecular dynamics results, the conserved residue K211 plays a pivotal role in substrate binding and catalysis, which is quite consistent with previous mutagenesis data. Our study provides detailed insights into the catalytic mechanism of NDM-1 hydrolyzing meropenem beta-lactam antibiotics and offers clues for the discovery of new antibiotics against NDM-1 positive strains in clinical studies.
资助项目	National High Technology Research and Development Program of China[2012AA020302] ; National Natural Science Foundation of China[20972174] ; National Natural Science Foundation of China[91029704] ; National Natural Science Foundation of China[21073034] ; National Natural Science Foundation of China[21210003] ; National Natural Science Foundation of China[21021063] ; Key Project of Chinese National Programs for Fundamental Research and Development[2009CB918502] ; Natural Science Foundation of the Fujian Province[2010J05023] ; Guangdong ST Dept.[2010A030100006] ; Key New Drug Creation and Manufacturing Program[2013ZX09507-004]
WOS关键词	METALLO-BETA-LACTAMASE ; MOLECULAR-DYNAMICS SIMULATIONS ; AMBER FORCE-FIELD ; BACTEROIDES-FRAGILIS ; ANTIBIOTIC-RESISTANCE ; CRYSTAL-STRUCTURE ; GEOMETRY OPTIMIZATION ; ORBITAL METHOD ; ACTIVE-SITE ; RESP MODEL
WOS研究方向	Biochemistry & Molecular Biology ; Biophysics ; Computer Science
语种	英语
出版者	SPRINGER
WOS记录号	WOS:000318411400004
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/277701]
专题	药物发现与设计中心中科院受体结构与功能重点实验室新药研究国家重点实验室
通讯作者	Chen, Yong
作者单位	1.Fuzhou Univ, Dept Chem, Fuzhou 350108, Fujian, Peoples R China; 2.Soochow Univ, Ctr Syst Biol, Suzhou 215006, Jiangsu, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China;
推荐引用方式 GB/T 7714	Zhu, Kongkai,Lu, Junyan,Liang, Zhongjie,et al. A quantum mechanics/molecular mechanics study on the hydrolysis mechanism of New Delhi metallo-beta-lactamase-1[J]. JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN,2013,27(3):247-256.
APA	Zhu, Kongkai.,Lu, Junyan.,Liang, Zhongjie.,Kong, Xiangqian.,Ye, Fei.,...&Luo, Cheng.(2013).A quantum mechanics/molecular mechanics study on the hydrolysis mechanism of New Delhi metallo-beta-lactamase-1.JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN,27(3),247-256.
MLA	Zhu, Kongkai,et al."A quantum mechanics/molecular mechanics study on the hydrolysis mechanism of New Delhi metallo-beta-lactamase-1".JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN 27.3(2013):247-256.