Vanni, StefanoCampomanes, PabloMarcia, MarcoRothlisberger, Ursula2012-02-172012-02-172012-02-17201210.1021/bi2015184https://infoscience.epfl.ch/handle/20.500.14299/77844WOS:000300132900022Recently, a 3.65 angstrom resolution structure of the transporter, NorM from the multidrug and toxic compound extrusion family has been determined in the outward-facing conformation. This antiporter uses electrochemical gradients to drive substrate export of a large class of antibiotic and toxic compounds in exchange for small monovalent cations (H+ and Na+), but the molecular details of this mechanism are still largely unknown. Here we report all-atom molecular dynamics simulations of NorM, with and without the bound Na+ cation and at different ion concentrations. Spontaneous binding of Na+ is observed in several independent simulations with transient ion binding to D36 being necessary to reach the final binding site for which two competitive binding modes occur. Finally, the simulations indicate that the extracellular vestibule of the transporter invariably loses its characteristic V shape indicated by the crystallographic data, and it is reduced to a narrow permeation pathway lined by polar residues that can act as a specific pore for the transport of small cations. This event, together with the available structures of evolutionarily related transporters of the major facilitator superfamily (MFS), suggests that differences in the hydrophobic content of the extracellular vestibule may be characteristic of multidrug resistance transporters in contrast to substrate-selective members of the MFS.Amino-Acid-ResiduesEscherichia-ColiForce-FieldIdentificationMechanismGromacsProteinModelsWatertext::journal::journal article::research article