School of Cancer and Pharmaceutical Science, King's College London, London, SE1 9NH, UK.
Public Health England, National Infection Service, Porton Down, Salisbury, Wiltshire, SP4 0JG, UK.
Sci Rep. 2018 Jul 11;8(1):10470. doi: 10.1038/s41598-018-28531-6.
Multidrug efflux pumps confer resistance to their bacterial hosts by pumping out a diverse range of compounds, including most antibiotics. Being more familiar with the details of functional dynamics and conformations of these types of pumps could help in discovering approaches to stop them functioning properly. Computational approaches, particularly conventional molecular dynamics simulations followed by diverse post simulation analysis, are powerful methods that help researchers by opening a new window to study phenomena that are not detectable in as much detail in vitro or in vivo as they are in silico. In this study, accelerated molecular dynamics simulations were applied to study the dynamics of AcrB efflux pump transporters in interaction with PAβN and tetracycline as an inhibitor and a substrate, respectively, to compare the differences in the dynamics and consequently the mechanism of action of the pump. The different dynamics for PAβN -bound form of AcrB compared to the TET-bound form is likely to affect the rotating mechanism typically observed for AcrB transporter. This shows the dynamics of the active AcrB transporter is different in a substrate-bound state compared to an inhibitor-bound state. This advances our knowledge and helps to unravel the mechanism of tripartite efflux pumps.
多药外排泵通过泵出包括大多数抗生素在内的各种化合物，使细菌宿主产生抗药性。更熟悉这些类型的泵的功能动力学和构象的细节，可以帮助我们发现阻止它们正常工作的方法。计算方法，特别是传统的分子动力学模拟，加上各种模拟后分析，是一种强大的方法，为研究人员提供了一个新的窗口，使他们可以在体外或体内无法如此详细地检测到的现象，在计算机模拟中进行研究。在这项研究中，应用加速分子动力学模拟来研究 AcrB 外排泵转运蛋白与 PAβN 和四环素分别作为抑制剂和底物相互作用的动力学，以比较泵的动力学和作用机制的差异。与 TET 结合形式相比，AcrB 与 PAβN 结合形式的不同动力学可能会影响通常观察到的 AcrB 转运蛋白的旋转机制。这表明在底物结合状态下，活性 AcrB 转运蛋白的动力学与在抑制剂结合状态下不同。这提高了我们的认识，并有助于揭示三方外排泵的机制。
