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

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Abstract

New Delhi metallo-β-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 β-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 β-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 β-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 β-lactam antibiotics and offers clues for the discovery of new antibiotics against NDM-1 positive strains in clinical studies.

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Abbreviations

NDM-1:

New Delhi metallo-β-lactamase-1

MBLs:

Metallo-β-lactamases

MD:

Molecular dynamics

QM/MM:

Quantum mechanics/molecular mechanics

RMSD:

Root mean square deviation

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Acknowledgments

This work was support by grants from National High Technology Research and Development Program of China (2012AA020302), National Natural Science Foundation of China (20972174, 91029704, 21073034, 21210003 and 21021063), the Key Project of Chinese National Programs for Fundamental Research and Development (2009CB918502), the Natural Science Foundation of the Fujian Province (2010J05023), the Guangdong S&T Dept. (2010A030100006) and the “Key New Drug Creation and Manufacturing Program” (2013ZX09507-004).

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Authors and Affiliations

  1. Department of Chemistry, Fuzhou University, Fujian, 350108, China

    Kongkai Zhu, Heji Geng, Yong Chen & Jun-Qian Li

  2. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China

    Kongkai Zhu, Junyan Lu, Xiangqian Kong, Fei Ye, Lu Jin, Heji Geng, Mingyue Zheng, Hualiang Jiang & Cheng Luo

  3. Center for Systems Biology, Soochow University, Jiangsu, 215006, China

    Zhongjie Liang & Cheng Luo

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  1. Kongkai Zhu
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Correspondence to Yong Chen or Cheng Luo.

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Kongkai Zhu and Junyan Lu contributed equally to this work.

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Zhu, K., Lu, J., Liang, Z. et al. A quantum mechanics/molecular mechanics study on the hydrolysis mechanism of New Delhi metallo-β-lactamase-1. J Comput Aided Mol Des 27, 247–256 (2013). https://doi.org/10.1007/s10822-012-9630-6

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