functional rotation of the transporter acrb insights into drug extrusion from simulations旋转功能的见解药物转运体acrb挤压模拟.pdfVIP

Functional Rotation of the Transporter AcrB: Insights into Drug Extrusion from Simulations 1. 2 . 2 ¨ 1 2 Robert Schulz , Attilio V. Vargiu * , Francesca Collu , Ulrich Kleinekathofer , Paolo Ruggerone 1 School of Engineering and Science, Jacobs University Bremen, Bremen, Germany, 2 Istituto Officina dei Materiali del CNR, UOS SLACS and Dipartimento di Fisica, Universita’ degli Studi di Cagliari, Monserrato, Italy Abstract The tripartite complex AcrAB-TolC is the major efflux system in Escherichia coli. It extrudes a wide spectrum of noxious compounds out of the bacterium, including many antibiotics. Its active part, the homotrimeric transporter AcrB, is responsible for the selective binding of substrates and energy transduction. Based on available crystal structures and biochemical data, the transport of substrates by AcrB has been proposed to take place via a functional rotation, in which each monomer assumes a particular conformation. However, there is no molecular-level description of the conformational changes associated with the rotation and their connection to drug extrusion. To obtain insights thereon, we have performed extensive targeted molecular dynamics simulations mimicking the functional rotation of AcrB containing doxorubicin, one of the two substrates that were co-crystallized so far. The simulations, including almost half a million atoms, have been used to test several hypotheses concerning the structure-dynamics-f