In this study, an extensive sampling of the conformational space of nine HIV-1 protease inhibitors was performed to estimate the uncertainty with which a single-conformation scoring scheme approximates the ligand-protein binding free energy. The SMD implicit solvation/desolvation energy and gas-phase PM6-DH2 energy were calculated for a set of 1600 conformations of each ligand. The probability density functions of the energies were compared with the values obtained from the single-conformation approach and from a short ab initio molecular dynamics simulation. The relative uncertainty in the score within the set of nine inhibitors was calculated to be 3.5 kcal·mol(-1) and 2.7 kcal·mol(-1) for the single-conformation and short dynamics, respectively. These results, though limited to the consideration of flexible ligands, provide a valuable insight into the precision of rigid models in the current computer-aided drug design.