[en] Highlights: • A new protocol combining the fast pulling of ligand and linear interaction energy is presented. • Rapid and accurate determination of absolute binding affinity of HIV-1 PR to inhibitor. • Theoretical binding affinity is in good correlation with experiment with $R=0.89$. • Deviation of calculated binding free energy is smaller than 1.5 kcal/mol. The absolute binding free energy of an inhibitor to HIV-1 Protease (PR) was determined throughout evaluation of the non-bonded interaction energy difference between the two bound and unbound states of the inhibitor and surrounding molecules by the fast pulling of ligand (FPL) process using non-equilibrium molecular dynamics (NEMD) simulations. The calculated free energy difference terms help clarifying the nature of the binding. Theoretical binding affinities are in good correlation with experimental data, with $R=0.89$. The paradigm used is able to rank two inhibitors having the maximum difference of ∼1.5 kcal/mol in absolute binding free energies.