The spread of HIV-1 in the world is a serious threat to people’s physical and mental health. Residue mutation of HIV-1 protease seriously weakened the effect of drug treatment. In order to study the effects of mutations D30N, I54M and V82A on the interaction between protease and the inhibitor GRL-0519, we carried out four 30 ns molecular dynamics (MD) simulations combined with the solvated interaction energy (SIE) method to calculate the binding free energies of protease and inhibitor. The results show that polar interactions are unfavorable for the mutated protease bonding to the inhibitor, and slightly favorable for WT, the polar interactions are the main driven force for the drug resistance. The calculated total free energies are consistent with the experimental data. In order to show the contribution of each residue to drug resistance, the van der Walls energies of each residue were calculated by the molecular force field method, the hydrogen bonds between inhibitor and protease were also analyzed. The van der Walls analysis implies that the V82A has smaller influence on the binding model. There are five residues with van der Waals contribution larger than 0.4 kcal/mol for D30N, and six residues for I54M. The hydrogen bond analysis suggests that D30N and I54M lost several hydrogen bonds relative to in WT. The result was in accordance with the SIE results. Our study provides theoretical guidance for the design of new and more potent inhibitors against HIV-1 protease variants.