Abstract
With known antibiotics losing their efficiency faster than new ones can be developed, a better understanding of the underlying molecular mechanisms is paramount. Multidrug resistance is often caused by an over-production of efflux transporters that expel drug molecules before they can affect their targets inside the bacterial cell.In Escherichia coli, AcrAB-TolC serves as the major multidrug efflux pump using proton-motive force over the inner membrane to extrude drugs out of the cell. While X-ray structures have been solved separately for the individual components, the best structural information on the assembled efflux pump is a docking structure based on biochemical cross-linking data [1]. To gain insight into the conformational dynamics of AcrB, AcrA & TolC in complex, we have embedded the docking structure in two phospholipid bilayers solvated in a 150 mM NaCl solution. Asymmetric AcrB was considered and each monomer simulated in a different protonation state as suggested in [2]. To assess the influence of AcrA, we set up a second model without the periplasmic adaptor protein.To study subunit interplay, complex stability, flexibility, protein-membrane interactions and the dynamics of transport pathways, we carried out multiple molecular dynamics simulations of Acr(A)B-TolC in atomistic and coarse-grained representations on a nanosecond and microsecond time scale. All simulations were carried out in GroMACS 4.0 using the GROMOS96 53a6 and MARTINI force fields.[1] Symmons et al. (2008)-PNAS_106(17):7173–8[2] Pos (2009)-BBA_1794(5):782–93
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