Mol. dynamics simulations (MDS) of the structural rearrangements on the pathway leading to procaspase 3 (I) activation are presented. A retrostructural approach was used to build I from mature caspase 3 (II). The peptide bond that was cleaved during enzyme maturation was gradually reformed during the MDS and the most relevant structural changes that occurred as a consequence were analyzed. The main structural features that characterized this I model were compared with the available x-ray structure of procaspase 7 as the only zymogen structure that has been crystd. so far. The MDS indicated that in free II, the flexible selectivity loop is already pre-organized to accommodate the substrate. Such a pre-organization is not present in either monomeric II or in the I dimer, indicating that the structure of the selectivity loop is highly sensitive to perturbations. [on SciFinder (R)]