Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.09.01.277582v1?rss=1 Authors: Sahakyan, H., Nazaryan, K., Mushegian, A., Sorokina, I. Abstract: 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. It is possible that the slow progress in recapitulating protein folding pathways in silico is due not to a lack of computational power but to fundamental deficiencies in our understanding of folding as it occurs in nature. We consider the possibility that protein folding in living cells may not be driven solely by the decrease in Gibbs free energy. We propose that protein folding in vivo should be modeled as an active energy-dependent process and that the mechanism of action of such a protein-folding machine might include direct manipulation of the peptide backbone. Considering the rotating motion of the tRNA 3(prime)-end in the peptidyl transferase center of the ribosome, we hypothesized that this motion might introduce rotation to the nascent peptide and influence the peptide folding pathway. We tested whether the formation of protein native conformations could be facilitated by the application of mechanical force to rotate one part of the folding polypeptide while simultaneously restricting rotation of another part of the peptide. We ran molecular dynamics simulations augmented by the application of torsion to the peptide backbones. The directional rotation of the C-terminal amino acid, with the simultaneous limitation of the N-terminal amino acid movements, indeed facilitated the formation of native structures in five diverse alpha-helical peptides. These simulations demonstrate the feasibility of a protein-folding machine. Copy rights belong to original authors. Visit the link for more info