People: Prof. Ulrich Kleinekathöfer, Dr. Fabio Grassi
Cooperations: Prof. Mathias Winterhalter, Prof. Paolo Ruggerone (University Cagliari, Sardinia)
Bacteria, such as E. coli, use multidrug efflux pumps to export toxic substrates through their cell membranes. The RND transporter of the AcrAB-TolC efflux pump is able to export structurally and chemically different substrates. This is one reason of the increasing antibiotic resistance of bacteria. The effects of conformational changes on the extrusion of drugs, which have been located into one of the proposed binding pockets, are assessed using different computational methods like targeted molecular dynamics. Simulations, including almost half a million atoms, are being used to investigate several hypotheses concerning the structure-dynamics-function relationship of the AcrB protein. The results illustrate that, upon induction of conformational changes, the substrate detaches from the binding pocket and approaches the gate to the central funnel. In addition, evidence was provided for the proposed peristaltic transport involving a zipper-like closure of the binding pocket, responsible for the displacement of the drug. Using these atomistic simulations the role of specific amino acids during the transitions can be identified.
 J. M. A. Blair, V. N. Bavro, V. Ricci, N. Modi, P. Cacciotto, U. Kleinekathöfer, P. Ruggerone, A. V. Vargiu, A. J. Baylay, H. E. Smith, Y. Brandon, D. Galloway and L. J. V. Piddock, AcrB Drug-binding Pocket Substitution Confers Clinically Relevant Resistance and Altered Substrate Specificity, Proc. Natl. Acad. Sci. USA 112, 3511–3516 (2015).
 R. Schulz, A. V. Vargiu, P. Ruggerone and U. Kleinekathöfer, Computational Study of Correlated Domain Motions in the AcrB Efflux Transporter, BioMed Res. Int. 2015, 487 298 (2015).
 A. V. Vargiu, F. Collu, R. Schulz, K. M. Pos, M. Zacharias, U. Kleinekathöfer and P. Ruggerone, Effects of the F610A Mutation on Substrate Extrusion in the AcrB Transporter: Explanation and Rationale by Molecular Dynamics Simulations, J. Am. Chem. Soc. 133, 10 704–10 707 (2011).
 R. Schulz, A. V. Vargiu, P. Ruggerone and U. Kleinekathöfer, The Role of Water During the Extrusion of Substrates by the Efflux Transporter AcrB, J. Phys. Chem. B 115, 8278–8287 (2011).
 R. Schulz, A. V. Vargiu, F. Collu, U. Kleinekathöfer and P. Ruggerone, Functional Rotation of the Transporter AcrB: Insights into Drug Extrusion from Simulations, PLoS Comput. Biol. 6, e1000 806 (2010).