Energy-dependent protein folding: modeling how a protein folding machine may work

Proteins fold robustly and reproducibly in vivo, but many cannot fold in vitro in isolation from cellular components. The pathways to proteins native conformations, either in vitro or in vivo, remain largely unknown. The slow progress in recapitulating protein folding pathways in silico may be an indication of the fundamental deficiencies in our understanding of folding as it occurs in nature. Here we consider the possibility that protein folding in living cells may not be driven solely by the decrease in Gibbs free energy and propose that protein folding in vivo should be modeled as an active energy-dependent process. The mechanism of action of such protein folding machine might include direct manipulation of the peptide backbone. To show the feasibility of a protein folding machine, we conducted molecular dynamics simulations that were augmented by the application of mechanical force to rotate the C-terminal amino acid while simultaneously limiting the N-terminal amino acid movements. Remarkably, the introduction of this simple manipulation of peptide backbones to the standard molecular dynamics simulation indeed facilitated the formation of native structures in five diverse alpha-helical peptides. Such effect may play a role during co-translational protein folding in vivo: considering the rotating motion of the tRNA 3-end in the peptidyltransferase center of the ribosome, it is possible that this motion might introduce rotation to the nascent peptide and influence the peptides folding pathway in a way similar to what was observed in our simulations.