Gao Kaifu, Zhao Yunjie
Institute of Biophysics and Department of Physics, Central China Normal University , Wuhan 430079, P. R. China.
J Phys Chem B. 2017 Apr 13;121(14):2952-2960. doi: 10.1021/acs.jpcb.7b00062. Epub 2017 Mar 30.
New Delhi metallo-β-lactamase-1 (NDM-1) is a novel β-lactamase enzyme that confers enteric bacteria with nearly complete resistance to all β-lactam antibiotics, so it raises a formidable and global threat to human health. However, the binding mechanism between apo-NDM-1 and antibiotics as well as related conformational changes remains poorly understood, which largely hinders the overcoming of its antibiotic resistance. In our study, long-time conventional molecular dynamics simulation and Markov state models were applied to reveal both the dynamical and conformational landscape of apo-NDM-1: the MD simulation demonstrates that loop L3, which is responsible for antibiotic binding, is the most flexible and undergoes dramatic conformational changes; moreover, the Markov state model built from the simulation maps four metastable states including open, semiopen, and closed conformations of loop L3 as well as frequent transitions between the states. Our findings propose a possible conformational selection model for the binding mechanism between apo-NDM-1 and antibiotics, which facilitates the design of novel inhibitors and antibiotics.
新德里金属β-内酰胺酶1（NDM-1）是一种新型β-内酰胺酶，可使肠道细菌对所有β-内酰胺抗生素几乎完全耐药，因此对人类健康构成了巨大的全球威胁。然而，脱辅基NDM-1与抗生素之间的结合机制以及相关的构象变化仍知之甚少，这在很大程度上阻碍了对其抗生素耐药性的克服。在我们的研究中，应用了长时间的传统分子动力学模拟和马尔可夫状态模型来揭示脱辅基NDM-1的动力学和构象图景：分子动力学模拟表明，负责抗生素结合的L3环最灵活，且会发生剧烈的构象变化；此外，从模拟构建的马尔可夫状态模型描绘了四个亚稳态，包括L3环的开放、半开放和闭合构象以及这些状态之间的频繁转变。我们的研究结果提出了一种关于脱辅基NDM-1与抗生素结合机制的可能的构象选择模型，这有助于新型抑制剂和抗生素的设计。
