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首页> 美国卫生研究院文献>Biophysical Journal >Bridging Timescales and Length Scales: From Macroscopic Flux to the Molecular Mechanism of Antibiotic Diffusion through Porins
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Bridging Timescales and Length Scales: From Macroscopic Flux to the Molecular Mechanism of Antibiotic Diffusion through Porins

机译：桥接时间尺度和长度尺度：从宏观通量到通过孔扩散抗生素的分子机制

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Our aim in this study was to provide an atomic description of ampicillin translocation through OmpF, the major outer membrane channel in Escherichia coli and main entry point for β-lactam antibiotics. By applying metadynamics simulations, we also obtained the energy barriers along the diffusion pathway. We then studied the effect of mutations that affect the charge and size at the channel constriction zone, and found that in comparison to the wild-type, much lower energy barriers are required for translocation. The expected higher translocation rates were confirmed on the macroscopic scale by liposome-swelling assays. A microscopic view on the millisecond timescale was obtained by analysis of temperature-dependent ion current fluctuations in the presence of ampicillin and provide the enthalpic part of the energy barrier. By studying antibiotic translocation over various timescales and length scales, we were able to discern its molecular mechanism and rate-limiting interactions, and draw biologically relevant conclusions that may help in the design of drugs with enhanced permeation rates.
机译：我们在这项研究中的目的是提供氨苄青霉素通过OmpF转运的原子描述，OmpF，大肠杆菌的主要外膜通道和β-内酰胺抗生素的主要进入点。通过应用元动力学模拟，我们还获得了沿扩散路径的能垒。然后，我们研究了影响通道狭窄区电荷和大小的突变的影响，发现与野生型相比，易位所需的能垒低得多。通过脂质体溶胀试验在宏观尺度上证实了预期的更高的易位率。通过分析在存在氨苄青霉素的情况下与温度相关的离子电流波动，获得了毫秒级时标的微观视图，并提供了能量垒的焓部分。通过研究各种时间尺度和长度尺度的抗生素易位，我们能够辨别其分子机制和限速相互作用，并得出生物学上相关的结论，这些结论可能有助于设计渗透率提高的药物。

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