Mechanistic picture for conformational transition of a membrane transporter at atomic resolution

摘要: During their transport cycle, ATP-binding cassette (ABC) transporters undergo large-scale conformational changes between inward- and outward-facing states. Using an approach based on designing system-specific reaction coordinates using nonequilibrium work relations, we have performed extensive all-atom molecular dynamics simulations in the presence of explicit membrane/solvent to sample a large number mechanistically distinct pathways for transition MsbA, bacterial ABC exporter whose structure has been solved multiple functional The computational developed here is (i) exploration biasing protocols (e.g., collective variables designed available low-resolution crystal structures) (ii) relations comparing relevance pathways. most relevant pathway identified this involves several stages reflecting complex nature structural associated with function protein. opening cytoplasmic gate during outward- inward-facing apo MsbA found be disfavored when periplasmic open facilitated by twisting motion nucleotide-binding domains that dramatic change relative orientation. These results highlight cooperativity transmembrane exporters. introduced provides framework study other membrane investigation at atomic resolution may not currently feasible conventional methods.