Wang, Beibei; Weng, Jingwei; Wang, Wenning
Free energy profiles of ion permeation and doxorubicin translocation in TolC
JOURNAL OF THEORETICAL & COMPUTATIONAL CHEMISTRY, 13 Art. No. 1450031, JUN 2014

The outer membrane protein TolC of Escherichia coli forms a channel-tunnel pore spanning the periplasmic space and outer membrane, serving as the main exit duct for bacteria multidrug resistance and protein export. Many aspects of the transport mechanism of TolC are still unclear. Here, we have investigated the substrate permeability and gating mechanism of TolC by calculating the potential of mean forces (PMFs) for transporting sodium ion and doxorubicin through TolC using the adaptive biasing force (ABF) method. The transport mechanism is turned out to be substrate dependent. It is found that the periplasmic gate is required to open for the passage of both Na+ and doxorubicin, but the conformational gating does not lead to permeation barrier for Na+ at this region. The extracellular loops and K283 residues cause permeation barriers for Na+ at the extracellular entrance, but not for doxorubicin due to the extensive interactions between the drug molecule and the protein. TolC exhibits high conformational exibility during the transport of Na+, while doxorubicin seems to be able to stabilize TolC in the resting state with the periplasmic gate closed. The association of the TolC docking domain of AcrB does not lower the permeation barrier for doxorubicin at the periplasmic gate, while the gate opening induces the dissociation of the TolC-AcrB complex.

DOI:10.1142/S021963361450031X

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