The folding pathways of procaspases 3, 7, and 8 were studied using a Go-like Hamiltonian and mol. dynamics simulations coupled with a parallel tempering scheme. The folding pathways and the overall structures of procaspases 3 and 7 were similar, and were characterized by monomeric as well as dimeric folding intermediates in agreement with the available structural and thermochem. data. The folding pathway of procaspase 8, on the other hand, was characterized by a larger population of monomers and partially folded dimer intermediates, and only a relatively small population of folded dimer species. The most stable structure predicted for procaspase 8 was a dimer, in which the position of the linker was markedly different from the one obsd. in procaspases 3 and 7, leading to the fact that all of the contacts that stabilize the active site were essentially formed. This novel and unexpected structure provides a rationale for the obsd. activity of the procaspase 8 dimer, and thus could be highly relevant for the initiation of FAS-mediated apoptosis. [on SciFinder (R)]