The V82F/I84V double mutation is considered as the key residue mutation of the HIV-1 protease drug resistance because it can significantly lower the binding affinity of protease inhibitors in clinical uses. In the current work, the binding of amprenavir to both of the wild-type and the drug-resistant V82F/I84V mutant of the HIV-1 protease was investigated by molecular dynamics (MD) simulations and was compared to those of two inhibitors in development, TMC126 and TMC114. Absolute binding free energies were calculated by molecular mechanics/Poisson-Boltzmann surface area (MM/ PBSA) methodology. The predicted binding affinities give a good explanation of structure-affinity relationship (SAR) of three studied inhibitors. Furthermore, in the 18 ns MD simulations on the free wild-type and the mutated proteases, we observed that the free mutated protease shows similar dynamic characteristics of the flap opening and a little higher structural stability than the free wild-type protease. This suggests that the effect of the mutations may not significantly affect the equilibrium between the semiopen and the closed conformations. Finally, decomposition analysis of binding free energies and the further structural analysis indicate that the dominating effect of the V82F/I84V double mutation is to distort the geometry of the binding site and hence weaken the interactions of inhibitors preshaped to the wild-type binding site.