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

Abstract

Background: Proteins fold robustly and reproducibly in vivo, but many cannot fold in vitro in isolation from cellular components. Despite the remarkable progress that has been achieved by the artificial intelligence approaches in predicting the protein native conformations, the pathways that lead to such 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 a protein folding machine might include direct manipulation of the peptide backbone. Methods: 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. Results: Remarkably, the addition 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. Steric clashes that arise in the peptides due to the forced directional rotation resulted in the behavior of the peptide backbone no longer resembling a freely jointed chain. Conclusions: These simulations show the feasibility of a protein folding machine operating under the conditions when the movements of the polypeptide backbone are restricted by applying external forces and constraints. Further investigation is needed to see whether such an effect may play a role during co-translational protein folding in vivo and how it can be utilized to facilitate folding of proteins in artificial environments.

A Study of a Protein-Folding Machine: Transient Rotation of the Polypeptide Backbone Facilitates Rapid Folding of Protein Domains in All-Atom Molecular Dynamics Simulations

“…In an earlier work on helical peptide folding, we used all-atom molecular dynamics simulations in the explicit water environment, in which the simulation was augmented with a rotatory force applied to the C-terminal amino acid, while the motions of the N-terminal amino acid were restrained [ 26 ]. The five peptides started with the extended state and attained their native α-helical structure at least eight to ten times faster than when the folding was free, i.e., unassisted by rotation.…”

“…To explore the feasibility of a protein-folding machine facilitating the acquisition of native structure by mechanical manipulation of the peptide backbone, we have performed steered molecular dynamics simulations, augmented by application of torsion to the peptide backbones. In our experiments, directional rotation of the C-terminal amino acids with simultaneous limitation of the movements of the N-termini indeed facilitated the formation of native structures in five helical peptides [ 26 ]. Here we simulate the folding of the entire protein domains, and report that a transient twist of the protein backbone similarly enhances the formation of native structures in domains with different types of structure.…”

Is Protein Folding a Thermodynamically Unfavorable, Active, Energy-Dependent Process?

“…Recently, our all-atom molecular dynamics simulations have revealed the situations when the backbone indeed is not FJC. When rotational force is applied to the protein backbone during the simulation, diverse helical peptides, despite their purported freedom to rotate about the psi and phi bonds, rapidly fold into the native structure, which remains stable [ 153 ].…”

“…We recently reported the results of all-atom molecular dynamics simulations, in which the standard force field was augmented by the application of a mechanical force that rotated a single N-terminal amino acid of peptides, while simultaneously restricting the movements of a distal amino acid. Such directional rotation changed the peptide backbone behavior, facilitating rapid formation of native structures in several diverse alpha-helical peptides [ 153 ]. Apparently, steric clashes arising due to the forced directional rotation resulted in the behavior of the peptide backbone that no longer resembled an FJC.…”

Regulation by Different Types of Chaperones of Amyloid Transformation of Proteins Involved in the Development of Neurodegenerative Diseases

“…Thus, the article by Koonin [ 123 ] and the previous works of his co-authors [ 108 , 124 , 125 , 126 ] consider an alternative hypothesis of protein folding, the kinetic one, according to which the native conformation of most proteins is not in the global but rather at a local minimum in the fluctuating free energy landscape. Moreover, the free energy values are probably positive for most proteins, which implies the energy costs to adopt a native conformation, which is only possible as a result of the interaction of these proteins with the molecular machines of the cell, such as translation systems or chaperones.…”