Understanding molecular properties of outer membrane channels of Gram-negative bacteria is of fundamental significance as they are the entry point of polar antibiotics into bacteria. Outer membrane proteomics revealed OccK8 (OprE) to be among the five most expressed substrate specific channels of the clinically important Pseudomonas aeruginosa. The high-resolution X-ray structure and electrophysiology highlighted a very narrow pore. However, experimental in vitro methods showed the transport of natural amino acids and antibiotics, among them ceftazidime. We used molecular dynamics simulations to reveal the importance of the physicochemical properties of ceftazidime in modulating the translocation through OccK8, proposing a structure–function relationship. As in general porins, the internal electric field favors the translocation of polar molecules by gainful energy compensation in the central constriction region. Importantly, the comparatively narrow OccK8 pore can undergo a substrate-induced expansion to accommodate relatively large-sized substrates.

中文翻译：

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通过小毛孔获取药物：利用铜绿假单胞菌的孔蛋白途径

了解革兰氏阴性细菌外膜通道的分子特性具有根本意义，因为它们是极性抗生素进入细菌的切入点。外膜蛋白质组学显示OccK8（OprE）是临床上重要的铜绿假单胞菌的五个表达最多的底物特异性通道之一。高分辨率的X射线结构和电生理学显示出非常狭窄的毛孔。但是，体外实验方法显示了天然氨基酸和抗生素的运输，其中包括头孢他啶。我们使用分子动力学模拟揭示了头孢他啶的理化性质在通过OccK8调节易位中的重要性，并提出了结构与功能的关系。像普通孔雀一样，内部电场通过中央收缩区的有功能量补偿促进极性分子的移位。重要的是，相对较窄的OccK8孔会经历底物诱导的膨胀，以容纳相对较大尺寸的底物。