Structure-based computational study of the hydrolysis of New Delhi metallo-¦Â-lactmase-1

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• 作者：Kongkai Zhu^a ; ^b ; ¹ ; Junyan Lu^b ; ¹ ; Fei Ye^b ; Lu Jin^b ; Xiangqian Kong^b ; Zhongjie Liang^c ; Yong Chen^a ; ^{heishh@fzu.edu.cn} ; Kunqian Yu^b ; Hualiang Jiang^b ; Jun-Qian Li^a ; Cheng Luo^b ; ^c ; ^{cluo@mail.shcnc.ac.cn}
• 关键词：New Delhi metallo-¦Â-lactmase-1 ; Metallo-¦Â-lactamase ; Molecular dynamics simulations ; Molecular mechanics/Poisson&ndash ; Boltzmann surface area
• 刊名：Biochemical and Biophysical Research Communications
• 出版年：2013
• 出版时间：1 February, 2013
• 年：2013
• 卷：431
• 期：1
• 页码：2-7
• 全文大小：791 K

文摘

New Delhi metallo-¦Â-lactmase-1 (NDM-1) is an enzyme that confers antibiotic resistance to bacteria and is thus a serious threat to human health. Almost all clinically available ¦Â-lactam antibiotics can be hydrolyzed by NDM-1. To determine the mechanism behind the wide substrate diversity and strong catalytic ability of NDM-1, we explored the molecular interactions between NDM-1 and different ¦Â-lactam antibiotics using computational methods. Molecular dynamics simulations and binding free energy calculations were performed on enzyme-substrate (ES) complex models of NDM-1-Meropenem, NDM-1-Nitrocefin, and NDM-1-Ampicillin constructed by molecular docking. Our computational results suggest that mutant residues Ile35 and Lys216, and active site loop L1 residues 65-73 in NDM-1 play crucial roles in substrate recognition and binding. The results of our study provide new insights into the mechanism behind the enhanced substrate binding and wider substrate spectrum of NDM-1 compared with its homologous enzymes CcrA and IMP-1. These insights may be useful in the discovery and design of specific and potent inhibitors against NDM-1.