Journal of Chemical Theory and Computation
Journal of Chemical Theory and Computation
5 years ago

Characterization of Ciprofloxacin Permeation Pathways across the Porin OmpC Using Metadynamics and a String Method

Characterization of Ciprofloxacin Permeation Pathways across the Porin OmpC Using Metadynamics and a String Method
Ulrich Kleinekathöfer, Mathias Winterhalter, Carlos José Fernández Solano, Jigneshkumar Dahyabhai Prajapati
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. coli 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.

Publisher URL: http://dx.doi.org/10.1021/acs.jctc.7b00467

DOI: 10.1021/acs.jctc.7b00467

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