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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.