Folding pathways for initiator and effector procaspases from computer simulations

The folding pathways of procaspases 3, 7, and 8 have been studied using a Go-like Hamiltonian and molecular dynamics simulations coupled with a parallel tempering scheme. The folding pathways and the overall structures of procaspases 3 and 7 are similar, and are characterized by monomeric as well as dimeric folding intermediates in agreement with the available structural and thermochemical data. The folding pathway of procaspase 8, on the other hand, is 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 is a dimer, in which the position of the linker is remarkably different from the one observed in procaspases 3 and 7, leading to the fact that all the contacts that stabilize the active site are essentially formed. This novel and unexpected structure provides a rationale for the observed activity of the procaspase 8 dimer, and thus could be highly relevant for the initiation of FAS-mediated apoptosis.