Cysteine-dependent aspartic proteases (caspases) are a family of enzymes which play a crucial role in apoptosis. Caspases accumulate in eukaryotic cells in the form of low-activity proenzyme precursors. Proteolytic cleavage of specific sites triggers conformational changes that lead to full activation and thus to the initiation of the apoptotic cascade. Several exptl. observations suggest that dimerization is crucial for activity and regulation, but the underlying mol. mechanisms have not yet been completely resolved. The authors have used a structure-based thermodn. anal. to calc. the free energy of assocn. and folding for all the caspases and procaspases whose structures are known at present. In all cases, anal. of the single-residue contributions to the dimerization energy shows that 30-50% of the dimer stability originates from the highly specific interaction of 12-14 residues located at the N- and C-termini of the large and small subunits, resp. Moreover, the authors' calcns. indicate that these residues are also crit. for stabilizing the conformation of the active site loops, which in turn is crucial for the binding of substrates and inhibitors. Thus, the results help to rationalize the relation between dimerization and activity in this important class of enzymes and can be used as a starting point for an active manipulation of the monomer-dimer equil. for preparatory and regulatory purposes. [on SciFinder (R)]