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Computer simulations suggest direct and stable tip to tip interaction between the outer membrane channel TolC and the isolated docking domain of the multidrug RND efflux transporter AcrB

 
: Schmidt, Thomas H.; Raunest, Martin; Fischer, Nadine; Reith, Dirk; Kandt, Christian

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Biochimica et Biophysica Acta. Biomembranes 1858 (2016), Nr.7, Pt.A, S.1419-1426
ISSN: 0005-2736
ISSN: 1879-2642
Englisch
Zeitschriftenaufsatz
Fraunhofer SCAI ()

Abstract
One way by which bacteria achieve antibiotics resistance is preventing drug access to its target molecule for example through an overproduction of multi-drug efflux pumps of the resistance nodulation division (RND) protein super family of which AcrAB–TolC in Escherichia coli is a prominent example. Although representing one of the best studied efflux systems, the question of how AcrB and TolC interact is still unclear as the available experimental data suggest that either both proteins interact in a tip to tip manner or do not interact at all but are instead connected by a hexamer of AcrA molecules. Addressing the question of TolC–AcrB interaction, we performed a series of 100 ns - 1 µs– molecular dynamics simulations of membrane-embedded TolC in presence of the isolated AcrB docking domain (AcrBDD). In 5/6 simulations we observe direct TolC–AcrBDD interaction that is only stable on the simulated time scale when both proteins engage in a tip to tip manner. At the same time we find TolC opening and closing freely on extracellular side while remaining closed at the inner periplasmic bottleneck region, suggesting that either the simulated time is too short or additional components are required to unlock TolC.

: http://publica.fraunhofer.de/dokumente/N-426238.html