The　transporter　MsbA　is　a　kind　of　multidrug　resistance　ATP-binding　cassette　transporter　that　can　transport　lipid　A,　lipopolysaccharides,　and　some　amphipathic　drugs　from　the　cytoplasmic　to　the　periplasmic　side　of　the　inner　membrane.　In　this　work,　we　explored　the　allosteric　pathway　of　MsbA　from　the　inward-　to　outward-facing　states　during　the　substrate　transport　process　with　the　adaptive　anisotropic　network　model.　The　results　suggest　that　the　allosteric　transitions　proceed　in　a　coupled　way.　The　large-scale　closing　motions　of　the　nucleotide-binding　domains　occur　first,　accompanied　with　a　twisting　motion　at　the　same　time,　which　becomes　more　obvious　in　middle　and　later　stages,　especially　for　the　later.　This　twisting　motion　plays　an　important　role　for　the　rearrangement　of　transmembrane　helices　and　the　opening　of　transmembrane　domains　on　the　periplasmic　side　that　mainly　take　place　in　middle　and　later　stages　respectively.　The　topological　structure　plays　an　important　role　in　the　motion　correlations　above.　The　conformational　changes　of　nucleotide-binding　domains　are　propagated　to　the　transmembrane　domains　via　the　intracellular　helices　IH1　and　IH2.　Additionally,　the　movement　of　the　transmembrane　domains　proceeds　in　a　nonrigid　body,　and　the　two　monomers　move　in　a　symmetrical　way,　which　is　consistent　with　the　symmetrical　structure　of　MsbA.　These　results　are　helpful　for　understanding　the　transport　mechanism　of　the　ATP-binding　cassette　exporters.　Proteins　2015;　83:1643-1653.　(c)　2015　Wiley　Periodicals,　Inc.