Department of Physics and Earth Sciences, Jacobs University Bremen, 28759 Bremen, Germany.
J Chem Theory Comput. 2021 Jan 12;17(1):549-559. doi: 10.1021/acs.jctc.0c01088. Epub 2020 Dec 30.
To reach their target site inside Gram-negative bacteria, almost all antibiotics need to cross the outer membrane. Computational modeling of such processes can be numerically demanding due to the size of the systems and especially due to the timescales involved. Recently, a hybrid Brownian and molecular dynamics approach, i.e., Brownian dynamics including explicit atoms (BRODEA), has been developed and evaluated for studying the transport of monoatomic ions through membrane channels. Later on, this numerically efficient scheme has been applied to determine the free energy surfaces of the ciprofloxacin and enrofloxacin translocation through the porin OmpC using temperature-accelerated simulations. To improve the usability and accuracy of the approach, schemes to approximate the position-dependent diffusion constant of the molecule while traversing the pore had to be established. To this end, we have studied the translocation of the charged phosphonic acid antibiotic fosfomycin through the porin OmpF from devising and benchmarking several diffusion models. To test the efficiency and sensitivity of these models, the effect of OmpF mutations on the permeation of fosfomycin was analyzed. Permeation events have been recorded over millisecond-long biased and unbiased simulations, from which thermodynamics and kinetics quantities of the translocation processes were determined. As a result, the use of the BRODEA approach, together with the appropriate diffusion model, was seen to accurately reproduce the findings observed in electrophysiology experiments and all-atom molecular dynamics simulations. These results suggest that the BRODEA approach can become a valuable tool for screening numerous compounds to evaluate their outer membrane permeability, a property important in the development of new antibiotics.
为了到达革兰氏阴性菌的靶位，几乎所有抗生素都需要穿过外膜。由于系统的大小，特别是涉及的时间尺度，这些过程的计算建模可能在数值上要求很高。最近，已经开发并评估了一种混合布朗动力学和分子动力学方法，即包含显式原子的布朗动力学（BRODEA），用于研究单原子离子通过膜通道的传输。后来，该高效数值方案已应用于使用温度加速模拟来确定环丙沙星和恩诺沙星通过孔蛋白 OmpC 的易位自由能表面。为了提高方法的可用性和准确性，必须建立在分子穿过孔时近似位置相关扩散常数的方案。为此，我们研究了带电荷的膦酸抗生素磷霉素通过孔蛋白 OmpF 的易位，设计并基准测试了几种扩散模型。为了测试这些模型的效率和敏感性，分析了 OmpF 突变对磷霉素渗透的影响。在有偏和无偏模拟中记录了长达毫秒的渗透事件，从中确定了易位过程的热力学和动力学参数。结果表明，BRODEA 方法与适当的扩散模型一起，可以准确再现电生理学实验和全原子分子动力学模拟中观察到的结果。这些结果表明，BRODEA 方法可以成为筛选大量化合物以评估其外膜通透性的有价值工具，而外膜通透性是开发新抗生素的重要特性。
