Caspase-3 (I) is a fundamental target for pharmaceutical interventions against a variety of diseases involving disregulated apoptosis. I is active as a dimer with 2 symmetry-related active sites, each featuring a Cys-His catalytic dyad and a selectivity loop, which recognizes the characteristic DEVD pattern of the substrate. Here, a mol. dynamics simulation study of I in complex with 2 pentapeptide substrates, DEVDG, is presented, which provides a characterization of the dynamic properties of the active form in aq. soln. The mobility of the substrate and that of the catalytic residues were rather low indicating a distinct pre-organization effect of the Michaelis complex. An essential mode anal. permitted the authors to identify coupled motions between the 2 monomers. In particular, it was found that the motions of the 2 active site loops were correlated and tended to steer the substrate toward the reactive center, suggesting that dimerization has a distinct effect on the dynamic properties of the active site regions. The selectivity loop of one monomer turned out to be correlated with the N-terminal region of the p12 subunit of the other monomer, an interaction that was also found to play a fundamental role in the electrostatic stabilization of the quaternary structure. To further characterize the specific influence of dimerization on the enzyme essential motions, a mol. dynamics anal. was also performed on the isolated monomer. [on SciFinder (R)]