Enfuvirtide　is　a　fusion　inhibitor　that　was　obtained　from　the　C-terminal　region　of　the　ectodomain　of　gp41　in　HIV-1.　Nevertheless,　the　viral　resistance　to　enfuvirtide　limits　the　long-term　efficacy　of　treatment　patients　of　HIV　infection.　In　order　to　study　molecular　mechanism　of　resistance,　we　build　the　ectodomain　of　gp41　trimer　using　the　homology　modeling　and　molecular　dynamics　(MD)　simulations.　A　few　HIV＇s　patients,　using　the　enfuvirtide　treatment,　were　found　an　S649A　mutation　in　the　HR2　domain　accompanied　HR1　mutations　at　site　N554D.　This　demonstrated　that　double　mutations　(N554D/S649A)　of　gp41,　lead　to　viral　resistance　to　enfuvirtide.　Therefore,　we　executed　two　MD　simulations　to　study　the　double　mutations　structure　and　the　wild　type　of　HIV-1　gp41,　respectively.　In　the　wild　type　simulation,　there　were　two　hydrogen　bonds　around　Asn554　and　Ser649　(near　by　the　mutation＇s　site)　and　two　hydrogen　bonds　between　Asn554　and　the　HR2　region　of　gp41.　In　contrast,　these　hydrogen　bonds　do　not　appear　in　the　simulation　of　the　double　mutation　model.　Otherwise,　we　found　that　the　residue　mutations　in　the　HR1　region　increase　the　free　energy,　however,　in　the　HR2　region　decrease　the　free　energy.　Our　results　advise　a　possible　Enfuvirtide-resistance　mechanism:　The　N554D　mutation　in　the　HR1　region　reduced　the　binding　affinity　between　enfuvirtide　and　HR1　trimer　complex　and　leads　to　resistances.　The　N554D/S649A　double　mutation　restores　the　virus　to　a　viably　competent　state.　©2009　IEEE.