Solution of Levinthal’s Paradox and a Physical Theory of Protein Folding Times

Ivankov, Dmitry N.; Finkelstein, Alexei V.

doi:10.3390/biom10020250

Cited by 27 publications

(30 citation statements)

References 93 publications

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“…Theories developed for the prediction of protein folding nuclei, experimentally studied by Alan Fersht [182] and others that one can find in [183][184][185][186][187][188][189][190][191][192][193], and a more detailed theoretical consideration of folding times for proteins of different sizes, chain folds, and stabilities, are given in [176,181,[194][195][196][197]. A limited-influence chain knotting and the SS-bonds in the single-domain proteins on the folding rate were estimated in [173,187], and the influence of the native structure stability on the folding rate was estimated in [176] (see also [198]).…”

Section: Kinetics Of the "Unfolded Chain ↔ Native State" Transitionsmentioning

confidence: 99%

Life in Phases: Intra- and Inter- Molecular Phase Transitions in Protein Solutions

Uversky

Finkelstein

2019

Biomolecules

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Proteins, these evolutionarily-edited biological polymers, are able to undergo intramolecular and intermolecular phase transitions. Spontaneous intramolecular phase transitions define the folding of globular proteins, whereas binding-induced, intra- and inter- molecular phase transitions play a crucial role in the functionality of many intrinsically-disordered proteins. On the other hand, intermolecular phase transitions are the behind-the-scenes players in a diverse set of macrosystemic phenomena taking place in protein solutions, such as new phase nucleation in bulk, on the interface, and on the impurities, protein crystallization, protein aggregation, the formation of amyloid fibrils, and intermolecular liquid–liquid or liquid–gel phase transitions associated with the biogenesis of membraneless organelles in the cells. This review is dedicated to the systematic analysis of the phase behavior of protein molecules and their ensembles, and provides a description of the major physical principles governing intramolecular and intermolecular phase transitions in protein solutions.

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Section: Kinetics Of the "Unfolded Chain ↔ Native State" Transitionsmentioning

confidence: 99%

Life in Phases: Intra- and Inter- Molecular Phase Transitions in Protein Solutions

Uversky

Finkelstein

2019

Biomolecules

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“…The problem of protein folding has been described with reference to the Levinthal paradox, in which the initial unfolded state is assumed to be a random coil, and hence, there may exist an astronomically large number of conformations, inaccessible in a reasonable time by a random search, at the beginning of the folding reactions [137][138][139]. Solving the Levinthal paradox is a fundamental problem in folding studies [140][141][142][143][144][145][146]. The presence of the residual structure, if any, in the unfolded state thus invalidates the Levinthal paradox, because such residual structure may form a folding initiation site and guide the subsequent folding reactions.…”

Section: A Case Study: Unfolded Ubiquitin In 6 M Gdmclmentioning

confidence: 99%

DMSO-Quenched H/D-Exchange 2D NMR Spectroscopy and Its Applications in Protein Science

et al. 2022

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Hydrogen/deuterium (H/D) exchange combined with two-dimensional (2D) NMR spectroscopy has been widely used for studying the structure, stability, and dynamics of proteins. When we apply the H/D-exchange method to investigate non-native states of proteins such as equilibrium and kinetic folding intermediates, H/D-exchange quenching techniques are indispensable, because the exchange reaction is usually too fast to follow by 2D NMR. In this article, we will describe the dimethylsulfoxide (DMSO)-quenched H/D-exchange method and its applications in protein science. In this method, the H/D-exchange buffer is replaced by an aprotic DMSO solution, which quenches the exchange reaction. We have improved the DMSO-quenched method by using spin desalting columns, which are used for medium exchange from the H/D-exchange buffer to the DMSO solution. This improvement has allowed us to monitor the H/D exchange of proteins at a high concentration of salts or denaturants. We describe methodological details of the improved DMSO-quenched method and present a case study using the improved method on the H/D-exchange behavior of unfolded human ubiquitin in 6 M guanidinium chloride.

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“…Discussions about the relationship between the primary structure of a protein and the emergence of a native protein conformation have been going on for many decades. The initial ideas that the polypeptide chain should take a strictly defined conformation, which corresponds to the global minimum of the Gibbs free energy, began to be criticized [ 94 , 95 , 96 , 97 , 98 ].…”

Section: Mechanisms Of the Formation Of Misfolded Proteinsmentioning

confidence: 99%

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

Muronetz

Kudryavtseva

Leisi

et al. 2022

IJMS

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The review highlights various aspects of the influence of chaperones on amyloid proteins associated with the development of neurodegenerative diseases and includes studies conducted in our laboratory. Different sections of the article are devoted to the role of chaperones in the pathological transformation of alpha-synuclein and the prion protein. Information about the interaction of the chaperonins GroE and TRiC as well as polymer-based artificial chaperones with amyloidogenic proteins is summarized. Particular attention is paid to the effect of blocking chaperones by misfolded and amyloidogenic proteins. It was noted that the accumulation of functionally inactive chaperones blocked by misfolded proteins might cause the formation of amyloid aggregates and prevent the disassembly of fibrillar structures. Moreover, the blocking of chaperones by various forms of amyloid proteins might lead to pathological changes in the vital activity of cells due to the impaired folding of newly synthesized proteins and their subsequent processing. The final section of the article discusses both the little data on the role of gut microbiota in the propagation of synucleinopathies and prion diseases and the possible involvement of the bacterial chaperone GroE in these processes.

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Solution of Levinthal’s Paradox and a Physical Theory of Protein Folding Times

Cited by 27 publications

References 93 publications

Life in Phases: Intra- and Inter- Molecular Phase Transitions in Protein Solutions

Life in Phases: Intra- and Inter- Molecular Phase Transitions in Protein Solutions

DMSO-Quenched H/D-Exchange 2D NMR Spectroscopy and Its Applications in Protein Science

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

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