Chen Jianzhong, Wang Jinan, Zhu Weiliang
School of Science, Shandong Jiaotong University, Jinan, 250014, China.
Drug Discovery and Design Center, CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China.
Phys Chem Chem Phys. 2017 Jan 25;19(4):3067-3075. doi: 10.1039/c6cp08105c.
The hydrolysis of a β-lactam core ring caused by new Delphi metallo-β-lactamase 1 (NDM-1) with the help of two zinc cofactors induces significant resistance toward β-lactam antibiotics. Molecular dynamics (MD) simulations and the umbrella sampling method are integrated to study the conformational change mechanism of NDM-1 mediated by zinc ion binding. The statistical analyses of interaction contacts of the antibiotic ampicillin (AMP) with residues based on MD trajectories suggest that two Zn ions are essential for maintaining the binding of AMP with NDM-1. Umbrella sampling simulations further reveal that double-Zn coordination exerts strong restriction on the motions of loop L10 relative to loops L3 and L4. Principal component (PC) analysis also demonstrates that zinc ion binding totally inhibits the motion extent of NDM-1 and changes internal motion modes in NDM-1. We expect that the current study can provide significant dynamical information involving conformational changes of NDM-1 for the development of efficient inhibitors to decrease drug resistance of NDM-1 toward antibiotics.
新型德尔菲金属β-内酰胺酶1（NDM-1）在两个锌辅因子的帮助下引起的β-内酰胺核心环水解会导致对β-内酰胺抗生素产生显著抗性。结合分子动力学（MD）模拟和伞形抽样方法来研究由锌离子结合介导的NDM-1的构象变化机制。基于MD轨迹对抗生素氨苄青霉素（AMP）与残基的相互作用接触进行统计分析表明，两个锌离子对于维持AMP与NDM-1的结合至关重要。伞形抽样模拟进一步揭示，双锌配位对环L10相对于环L3和L4的运动施加了强烈限制。主成分（PC）分析还表明，锌离子结合完全抑制了NDM-1的运动程度并改变了NDM-1的内部运动模式。我们期望当前的研究能够为开发有效的抑制剂以降低NDM-1对抗生素的耐药性提供涉及NDM-1构象变化的重要动力学信息。
