Is Protein Folding a Thermodynamically Unfavorable, Active, Energy-Dependent Process?
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Publication Date
2022-01-04Journal Title
Int J Mol Sci
ISSN
1422-0067
Publisher
MDPI AG
Volume
23
Issue
1
Language
eng
Type
Article
This Version
VoR
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Sorokina, I., Mushegian, A. R., & Koonin, E. V. (2022). Is Protein Folding a Thermodynamically Unfavorable, Active, Energy-Dependent Process?. Int J Mol Sci, 23 (1) https://doi.org/10.3390/ijms23010521
Abstract
The prevailing current view of protein folding is the thermodynamic hypothesis, under which the native folded conformation of a protein corresponds to the global minimum of Gibbs free energy G. We question this concept and show that the empirical evidence behind the thermodynamic hypothesis of folding is far from strong. Furthermore, physical theory-based approaches to the prediction of protein folds and their folding pathways so far have invariably failed except for some very small proteins, despite decades of intensive theory development and the enormous increase of computer power. The recent spectacular successes in protein structure prediction owe to evolutionary modeling of amino acid sequence substitutions enhanced by deep learning methods, but even these breakthroughs provide no information on the protein folding mechanisms and pathways. We discuss an alternative view of protein folding, under which the native state of most proteins does not occupy the global free energy minimum, but rather, a local minimum on a fluctuating free energy landscape. We further argue that ΔG of folding is likely to be positive for the majority of proteins, which therefore fold into their native conformations only through interactions with the energy-dependent molecular machinery of living cells, in particular, the translation system and chaperones. Accordingly, protein folding should be modeled as it occurs in vivo, that is, as a non-equilibrium, active, energy-dependent process.
Keywords
Protein folding, Molecular chaperones, Free energy, Entropy, Free Energy Landscape, Co-translational Protein Folding, Energy-Dependent Protein Folding, Physical Model Of Protein Folding
Sponsorship
NIH HHS (Intramural Research Program)
Identifiers
35008947, PMC8745595
External DOI: https://doi.org/10.3390/ijms23010521
This record's URL: https://www.repository.cam.ac.uk/handle/1810/333898
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