Scenario 2: Ideal and model structures may correspond to different conformers but the energy barrier connecting them might be too small. In this case, like scenario 1, QM optimization of "ideal" structure would still yield the same conformer as QM optimized "model" structure. We have compared the optimized structures of "ideal" and "model" structures and rejected those with RMSD ≤ 2Å (ideal to model). structure that is mostly affected by nearby atoms (of the bio-macromolecule) and the ligand has a strain energy to a considerable extent. Since we optimized the model structure in the absence of the bio-macromolecule, the ligand relaxes to the closest un-strained conformation, which is too far from the bio-active conformation. Optimization of model structure would change the geometry a lot. Since it is not near a minimum, no optimization algorithm would find these structures. Therefore, we excluded these structures by only accepting RMSD ≤ 2Å of QM optimized "model" against initial (un-optimized) "model" structures. This also avoids miscalculations of the performance by RMSD for the conformer generation since the un-optimized and QM optimized bioactive conformations differ drastically.