School of Sciences, Constructor University, Campus Ring 1, 28759 Bremen, Germany.
J Phys Chem B. 2024 Sep 5;128(35):8376-8387. doi: 10.1021/acs.jpcb.4c03327. Epub 2024 Aug 23.
Experimental studies on the translocation and accumulation of antibiotics in Gram-negative bacteria have revealed details of the properties that allow efficient permeation through bacterial outer membrane porins. Among the major outer membrane diffusion channels, OmpF has been extensively studied to understand the antibiotic translocation process. In a few cases, this knowledge has also helped to improve the efficacy of existing antibacterial molecules. However, the extension of these strategies to enhance the efficacy of other existing and novel drugs require comprehensive molecular insight into the permeation process and an understanding of how antibiotic and channel properties influence the effective permeation rates. Previous studies have investigated how differences in antibiotic charge distribution can influence the observed permeation pathways through the OmpF channel, and have shown that the dynamics of the L3 loop can play a dominant role in the permeation process. Here, we perform all-atom simulations of the OmpF orthologs, OmpE35 from and OmpK35 from . Unbiased simulations of the porins and biased simulations of the ciprofloxacin permeation processes through these channels provide insight into the differences in the permeation pathway and energetics. In addition, we show that similar to the OmpF channel, antibiotic-induced dynamics of the L3 loop are also operative in the orthologs. However, the sequence and structural differences, influence the extent of the L3 loop fluctuations with OmpK35 showing greater stability in unbiased runs and subdued fluctuations in simulations with ciprofloxacin.
实验研究表明，抗生素在革兰氏阴性菌中的转移和积累揭示了允许其通过细菌外膜孔蛋白有效渗透的特性。在外膜扩散通道中，OmpF 被广泛研究以了解抗生素的转运过程。在某些情况下，这些知识也有助于提高现有抗菌分子的疗效。然而，将这些策略扩展到增强其他现有和新型药物的疗效，需要对渗透过程有全面的分子认识，并了解抗生素和通道特性如何影响有效的渗透速率。以前的研究已经调查了抗生素电荷分布的差异如何影响通过 OmpF 通道观察到的渗透途径，并表明 L3 环的动力学在渗透过程中起着主导作用。在这里，我们对 OmpF 的同源物 OmpE35 进行了全原子模拟，该同源物来自 和 OmpK35 来自 。对这些通道的通透性进行无偏模拟和环丙沙星渗透过程的有偏模拟提供了对渗透途径和能量学差异的深入了解。此外，我们表明，与 OmpF 通道类似，抗生素诱导的 L3 环动力学也在同源物中起作用。然而，序列和结构的差异影响了 L3 环波动的程度，与 OmpK35 相比，OmpK35 在无偏运行中显示出更大的稳定性，而在环丙沙星模拟中波动较小。
