HIV-1　membrane　fusion　plays　an　important　role　in　the　process　that　HIV-1　entries　host　cells.　As　a　treatment　strategy　targeting　HIV-1　entry　process,　fusion　inhibitors　have　been　proposed.　Nevertheless,　development　of　a　short　peptide　possessing　high　anti-HIV　potency　is　considered　a　daunting　challenge.　He　et　al.　found　that　two　residues,　Met626　and　Thr627,　located　the　upstream　of　the　C-terminal　heptad　repeat　of　the　gp41,　formed　a　unique　hook-like　structure　(M-T　hook)　that　can　dramatically　improve　the　binding　stability　and　anti-HIV　activity　of　the　inhibitors.　In　this　work,　we　explored　the　molecular　mechanism　why　M-T　hook　structure　could　improve　the　anti-HIV　activity　of　inhibitors.　Firstly,　molecular　dynamic　simulation　was　used　to　obtain　information　on　the　time　evolution　between　gp41　and　ligands.　Secondly,　based　on　the　simulations,　molecular　mechanics　Poisson-Boltzmann　surface　area　(MM-PBSA)　and　molecular　mechanics　Generalized　Born　surface　area　(MM-GBSA)　methods　were　used　to　calculate　the　binding　free　energies.　The　binding　free　energy　of　the　ligand　with　M-T　hook　was　considerably　higher　than　the　other　without　M-T.　Further　studies　showed　that　the　hydrophobic　interactions　made　the　dominant　contribution　to　the　binding　free　energy.　The　numbers　of　Hydrogen　bonds　between　gp41　and　the　ligand　with　M-T　hook　structure　were　more　than　the　other.　These　findings　should　provide　insights　into　the　inhibition　mechanism　of　the　short　peptide　fusion　inhibitors　and　be　useful　for　the　rational　design　of　novel　fusion　inhibitors　in　the　future.　(C)　2016　Elsevier　Ltd.　All　rights　reserved.