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Transthyretin (TTR) tetramer is an important transporter of thyroxine both In plasm and CSF，thyroxine and Its analogues bind with TTR at its central binding channel divided Into two equivalent binding sites which could hold two ligands.Normally the binding manners are negative binding，but hoio-TTR tetramer become more stable than apo-TTR tetramer no matter whether It favorably binds with one or two ligands. TTR tetramer could dissociate Into four monomers and then form partly misfolding intermediates followed by amyloidoses,Therefore，it is an effective therapeutic strategy to design a series of ligands binding with transthyretin in order to prevent the TTR tetramer from dissociation，It is easy to know that the binding channel shapes are not the same while It binds with one ligand and two ligands. It Is Important to characterize changes of binding channel shape to reveal the effect of channel shape on ligand binding ways，In this paper.Molecular dynamics (MD) simulation will complement X-ray crystallography to study the differences in thyroxine binding shapes between one ligands binding TTR and two ligands binding TTR for two kinds of inhibitors，flufenamic acid (FLU)and N-phenyl phenoxazine (BPD). MD simulations provide a valuable insight Into the channel alterations. The results of MD simulations indicate that the binding events may happen in sequence: ligand binding in the first sIte followed by a slight collapse of this site，and then cause the second binding site open. The second bind in the second site followed by collapse of second sites，which is consistent with experimental model. But the events that the second site become smaller If the ligand binding in the first site via bridge interaction with second site leads to unfavorably binding in the second site is not observed. BPD-TTR has a larger second sffe than FLU-TTR for one ligancl binding event. It is interesting that for both TTR-BPD2 and TTR-FLU2 there are not symmetric shape at 300K,which implies two binding sites are not always the same.