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Computer simulations suggest direct and stable tip to tip interaction between the outer membrane channel TolC and the

Thomas H Schmidt1, Martin Raunest2, Nadine Fischer3

  • 1Department of Membrane Biochemistry, Life and Medical Sciences (LIMES) Institute, University of Bonn, Carl-Troll-Straße 31, 53115 Bonn, Germany.

Biochimica Et Biophysica Acta
|April 6, 2016
PubMed

Insights

Bacteria resist antibiotics via efflux pumps like AcrAB-TolC. Molecular dynamics simulations suggest AcrB and TolC interact directly in a tip-to-tip manner, a key finding for understanding antibiotic resistance mechanisms.

Area of Science:

  • Microbiology
  • Structural Biology
  • Biochemistry

Background:

  • Bacteria develop antibiotic resistance through mechanisms like multi-drug efflux pumps.
  • The resistance nodulation division (RND) protein superfamily includes prominent efflux systems such as AcrAB-TolC in Escherichia coli.
  • The precise interaction between the AcrB and TolC components of this efflux system remains unclear.

Purpose of the Study:

  • To investigate the interaction between the TolC and AcrB proteins in the AcrAB-TolC efflux system.
  • To clarify the mode of interaction between TolC and the AcrB docking domain using computational simulations.

Main Methods:

  • Employed molecular dynamics simulations ranging from 100 nanoseconds to 1 microsecond.
  • Simulated membrane-embedded TolC in the presence of the isolated AcrB docking domain (AcrB(DD)).

Main Results:

  • Observed direct TolC-AcrB(DD) interaction in 5 out of 6 simulations.
  • The observed direct interaction was stable only when proteins engaged in a tip-to-tip manner.
  • TolC demonstrated free opening and closing on the extracellular side but remained closed at the periplasmic bottleneck.

Conclusions:

  • Direct tip-to-tip interaction between TolC and AcrB is a plausible model for this efflux system.
  • The observed TolC dynamics suggest that longer simulation times or additional components may be necessary to fully elucidate its opening mechanism.
Keywords:
Access regulationAntibiotics resistanceMembrane proteinMolecular dynamicsMulti-drug effluxOuter membrane channel

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