As demonstrated by the statistics in the table and shown also on the figure above, the strain energies from the docking solutions are extraordinarily high, even after properly adding all hydrogens and optimizing their geometry using the same QM method employed in constructing our FDA conformational database. The problem lies not only in the extremely high strain energies but also in the large deviations in these strain energies, which are on the same order of magnitude as the protein-ligand binding energies we aim to estimate. The molecular structures of the top 100 hits from the flexible ligand docking results represent non-physical molecular geometries and conformations with very high internal strain energies.