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The Translocation Kinetics of Antibiotics Through Porin OmpC: Insights from Structure-Based Solvation Mapping using WaterMap

Tran, Que Tien and Williams, Sarah and Farid, Ramy and Erdemli, Gul and Pearlstein, Robert (2012) The Translocation Kinetics of Antibiotics Through Porin OmpC: Insights from Structure-Based Solvation Mapping using WaterMap. Proteins: Structure, Function, and Bioinformatics, 81 (2). pp. 291-299. ISSN 0887-3585

Abstract

Poor permeability of the lipopolysaccharide-based outer membrane of Gram-negative bacteria is compensated by the existence of protein channels (porins) that selectively admit small molecules, including many antibiotics. Improved understanding of the translocation mechanisms of these substances through porins could help guide the design of antibiotics capable of achieving high intracellular exposure. Antibiotic fluxes are determined by energy barriers underlying the rates of channel entry and exit. We have previously reported a hypothesis that the costs of transferring protein solvation to and from bulk medium underlie the barriers to protein-ligand association and dissociation, respectively, concomitant with the gain and loss of protein-ligand interactions during those processes. We have now applied this hypothesis to explain the published translocation kinetics of six antibiotics through reconstituted E. coli porin OmpC using WaterMap to estimate the structural and energetic solvation properties of the OmpC channel and total water transfer energies resulting from occupation by each antibiotic. Our results suggest that solvation within the porin cavity is highly stable, and the observed moderately fast entry kinetics of the antibiotics is consistent with replacement of protein-water H-bonds. The observed ultra-fast exit kinetics is consistent with the lack of intra-channel solvation sites that convey unfavorable re-solvation during antibiotic dissociation. These results are aligned with known general relationships between antibiotic efficacy and physico-chemical properties—namely unusually low ClogP, reflecting an abundance of H-bond partners. We conclude that antibiotics figuratively “melt” their way through porin solvation at a rate determined by the cost of exchanging protein-solvent for protein-antibiotic H-bonds.

Item Type: Article
Date Deposited: 13 Oct 2015 13:14
Last Modified: 13 Oct 2015 13:14
URI: https://oak.novartis.com/id/eprint/6921

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