Lipid-Dependent Alternating Access Mechanism of a Bacterial Multidrug ABC Exporter

By undergoing conformational changes, active membrane transporters alternate between an inward-facing (IF) and an outward-facing (OF) state to transport their substrates across cellular membrane. The conformational landscape of membrane transporters, however, could be influenced by their environment, and the dependence of the alternating access mechanism on the lipid composition has not been understood at the molecular level. We have performed an extensive set of microsecond-level all-atom molecular dynamics (MD) simulations on bacterial ATP binding cassette (ABC) exporter Sav1866 in six different phosphocholine (PC) and phosphoethanolamine (PE) lipid membrane environments. This study mainly focuses on the energetically downhill OF-to-IF conformational transition of Sav1866 upon the ATP hydrolysis. We observe that the transporter undergoes large-scale conformational changes in the PE environment, particularly in the POPE lipids, resulting in an IF-occluded conformation, a transition that does not occur wh...