Departament de Química Inorgànica i Orgànica and Institut de Química Teòrica i Computacional (IQTCUB), Universitat de Barcelona, Martí i Franquès 1, 08028 Barcelona, Spain.
Phys Chem Chem Phys. 2019 Apr 17;21(16):8457-8463. doi: 10.1039/c9cp00778d.
Deciphering the transport through outer-membrane porins is crucial to understand how anti-infectives enter Gram-negative bacteria and perform their function. Here we elucidated the transport mechanism of substrates through the Pseudomonads sugar-specific porin OprB by means of multiscale modeling. We used molecular dynamics simulations to quantify the energetics of transport and thus a diffusion model to quantify the macroscopic flux of molecules through OprB. Our results show that Trp171 and several glutamate residues in the constriction region are key for the transport of glucose, the preferred natural substrate, through OprB. The unveiled transport mechanism suggests that 2-acetamido-1,2-dideoxynojirimycin (DNJ-NAc), an anti-infective structurally similar to glucose, can enter the cell via OprB. We quantified its energetics and macroscopic flux through OprB providing a comparative analysis with the natural substrate. Thus this pore can be considered as a promising gateway for exploiting the Trojan Horse strategy in pathogenic bacteria.
解析外膜孔道蛋白的转运机制对于理解抗微生物药物如何进入革兰氏阴性菌并发挥作用至关重要。在这里，我们通过多尺度建模阐明了 Pseudomonads 糖特异性孔道蛋白 OprB 中底物的转运机制。我们使用分子动力学模拟来量化转运的能量学，从而使用扩散模型来量化分子通过 OprB 的宏观通量。我们的结果表明，色氨酸 171 残基和变窄区的几个谷氨酸残基对于葡萄糖（首选天然底物）通过 OprB 的转运至关重要。揭示的转运机制表明，结构上类似于葡萄糖的抗感染剂 2-乙酰氨基-1,2-二去氧野尻霉素（DNJ-NAc）可以通过 OprB 进入细胞。我们通过 OprB 量化了它的能量学和宏观通量，并与天然底物进行了比较分析。因此，这个孔道可以被认为是在致病菌中利用“特洛伊木马”策略的有前途的途径。
