期刊
JOURNAL OF CHEMICAL THEORY AND COMPUTATION
卷 13, 期 9, 页码 4553-4566出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jctc.7b00467
关键词
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资金
- Innovative Medicines Joint Undertaking [115525]
- European Union's seventh framework programme (FP7)
- EFPIA
The rapid spreading of antimicrobial resistance in Gram-negative bacteria has become a major threat for humans as well as animals As one of the main factors involved, the permeability of the outer membrane has attracted a great deal of attention recently. However, the knowledge regarding the translocation mechanisms for most available antibiotics is so far rather limited. Here, a theoretical study concerning the diffusion route of ciprofloxacin across the outer membrane porin OmpC from E. coil is presented. To this end, we establish a protocol to characterize meaningful permeation pathways by combining metadynamics with the zero-temperature string method. It was found that the lowest-energy pathway requires a reorientation of ciprofloxacin in the extracellular side of the porin before reaching the constriction region with its carboxyl group ahead. Several affinity sites have been identified, and their metastability has been evaluated using unbiased simulations. Such a detailed understanding is potentially very helpful in guiding the development of next generation antibiotics.
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