Molecular Dynamics Study of Multidrug Efflux Transporter AcrA-AcrB-AcrA-TolC Complex Embedded in Lipid Bilayer

Abstract

The multidrug efflux transporter AcrA-AcrB-AcrZ-TolC complex is a multidrug efflux transport system in Escherichia coli and plays a major role in the intrinsic resistance of Gram-negative bacteria. The complex is a large modular-built protein complex composed of AcrB, which is responsible for the pump function, TolC of the external channel, AcrZ reported being involved in substrate selectivity and AcrA that connects AcrB and TolC. Because the entire structure had not been reported until 2017 by cryo-EM experiment (Wang et al., eLIFE 2017), many studies using MD simulation have focused the AcrB, and a close relationship between structural changes in the porter domain and drug extrusion has been reported. In the complex, what types of interactions exist and how do they work? How does the lipid membrane affect the dynamics of AcrB? To investigate the protein-protein and protein-lipid interactions in the complex and their dynamics, we performed molecular dynamics simulations of AcrA-AcrB-AcrZ-TolC complex embedded in inner and outer POPE bilayers. We show that AcrA affects the dynamics of the substrate-bound to AcrB, and that conformational change of Asp408, which exists in the TM region of the AcrB and known as one of the key residues regarding the driving forces for the substrate extrusion function is promoted in the transporter complex.