The free energies of binding, DeltaG(bind), between a diverse set of eight hydroxamate inhibitors with gelatinase-A (MMP-2) were computed by using the recently developed MM/PBSA approach. In this paper, a nonbonded model was used to represent the potentials of the catalytic zinc center. Molecular dynamics (MD) simulations were used to generate the thermally averaged ensemble of conformations of the ligand-protein complexes. On the basis of the trajectories from MD simulations, the free energies of binding were calculated using molecular mechanics, the continuum solvent model, surface area estimation, and normal-mode analysis. The results show that MM/PBSA not only can rank the studied ligands effectively but also can reproduce the experimental binding free energies successfully. The predicted binding free energies correlate well with the experimental values (r = 0.84, q = 0.78). As a comparison, the free energies of binding were also computed by using the linear interaction energy approximation (LIE). The overall agreement between the calculated and experimental values for the diverse set of ligands means that the MM/PBSA approach is a useful tool for the general evaluation of protein-ligand interactions. The analysis of the separate energy terms contributing to MM/PBSA free energy indicates that the association between hydroxamate and MMP-2 is mainly driven by more favorable van der Waals/nonpolar interactions in the complex than in solution.