Residue Gly86 is considered as the highly conversed residue in the HIV-1 protease. In our work, the detailed binding free energies for the wild-type (WT) and mutated proteases binding to the TMC-114 are estimated to investigate the protein-inhibitor binding and drug resistance mechanism by molecule dynamic simulations and molecular mechanics Poisson Boltzmann surface area (MM-PBSA) method. The binding affinities between the mutants and inhibitor are different than that in the wild-type complex and the major resistance to Darunavir (DRV) of G86A and G86S originate from the electrostatic energy and entropy, respectively. Furthermore, free energy decomposition analysis for the WT and mutated complexes on the basis of per-residue indicates that the mutagenesis influences the energy contribution of the residue located at three regions: active site region (residue 24-32), the flap region, and the region around the mutated residue G86 (residue 79-88), especially the flap region. Finally, further hydrogen bonds and structure analysis are carried out to detect the relationship between the energy and conformation. In all, the G86 mutations change the flap region's conformation. The experimental results are in good agreement with available results.