In the current analysis, the 6ezf holo structure without the ligand was identified as the most likely representation of the apo structure for the set of 21 pde2 inhibitors. Interestingly, this structure is predicted to have a lower free energy than the crystallographically resolved apo state. One reason for that might be particular structural details that could have been resolved in a higher resolution structure 6ezf (1.5 Å) as compared to 4htz (2.0 Å) , or larger conformational changes that may be more comparable with the full length apo protein . Comparison of the experimental binding affinities to the values calculated with the 6ezf structure as a template for the apo state provide further support for this methodology (