Human　P-glycoprotein　(P-gp),　a　kind　of　ATP-Binding　Cassette　transporter,　can　export　a　diverse　variety　of　anti-cancer　drugs　out　of　the　tumor　cell.　Its　overexpression　is　one　of　the　main　reasons　for　the　multidrug　resistance　(MDR)　of　tumor　cells.　It　has　been　confirmed　that　during　the　substrate　transport　process,　P-gp　experiences　a　large-scale　structural　rearrangement　from　the　inward-　to　outward-facing　states.　However,　the　mechanism　of　how　the　nucleotide-binding　domains　(NBDs)　control　the　transmembrane　domains　(TMDs)　to　open　towards　the　periplasm　in　the　outward-facing　state　has　not　yet　been　fully　characterized.　Herein,　targeted　molecular　dynamics　simulations　were　performed　to　explore　the　conformational　rearrangement　of　human　P-gp.　The　results　show　that　the　allosteric　process　proceeds　in　a　coupled　way,　and　first　the　transition　is　driven　by　the　NBDs,　and　then　transmitted　to　the　cytoplasmic　parts　of　TMDs,　finally　to　the　periplasmic　parts.　The　trajectories　show　that　besides　the　translational　motions,　the　NBDs　undergo　a　rotation　movement,　which　mainly　occurs　in　xy　plane　and　ensures　the　formation　of　the　correct　ATP-binding　pockets.　The　analyses　on　the　interaction　energies　between　the　six　structure　segments　(cICLs)　from　the　TMDs　and　NBDs　reveal　that　their　subtle　energy　differences　play　an　important　role　in　causing　the　periplasmic　parts　of　the　transmembrane　helices　to　separate　from　each　other　in　the　established　directions　and　in　appropriate　amplitudes.　This　conclusion　can　explain　the　two　experimental　phenomena　about　human　P-gp　in　some　extent.　These　studies　have　provided　a　detailed　exploration　into　human　P-gp　rearrangement　process　and　given　an　energy　insight　into　the　TMD　reorientation　during　P-gp　transition.