Reduction of the Search Space for the Folding of Proteins at the Level of Formation and Assembly of Secondary Structures: A New View on the Solution of Levinthal′s Paradox

Finkelstein, Alan; Garbuzynskiy, Sergiy O.

doi:10.1002/cphc.201500700

Cited by 16 publications

(7 citation statements)

References 28 publications

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“…Finkelstein and Garbuzinskiy used an alternative idea on how to cluster the protein conformational space [64,65]. They argued that each local minimum has to be more or less compact, with formed secondary structure elements.…”

Section: Enumeration Of Protein Foldsmentioning

confidence: 99%

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

Ivankov

Finkelstein

2020

Biomolecules

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“How do proteins fold?” Researchers have been studying different aspects of this question for more than 50 years. The most conceptual aspect of the problem is how protein can find the global free energy minimum in a biologically reasonable time, without exhaustive enumeration of all possible conformations, the so-called “Levinthal’s paradox.” Less conceptual but still critical are aspects about factors defining folding times of particular proteins and about perspectives of machine learning for their prediction. We will discuss in this review the key ideas and discoveries leading to the current understanding of folding kinetics, including the solution of Levinthal’s paradox, as well as the current state of the art in the prediction of protein folding times.

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Section: Enumeration Of Protein Foldsmentioning

confidence: 99%

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

Ivankov

Finkelstein

2020

Biomolecules

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“…Our answer is that the Levinthal's paradox assumed that the search should be done among all conformations of the protein chain (which is indeed impossible), while the search among low-energy folds only (i.e., only among compact and well-structured globules), which is done at the level of protein secondary structure assembly (Figure 4), is by many orders of magnitude less voluminous, and is therefore, feasible. A rough estimate [181,199,200] leads to the conclusion that at the level of secondary structure assemblies (or, in other words, at the level of potential molten globules), the search volume does not exceed~L…”

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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“… 92 Moreover, if secondary structure is taken as the reference point rather than a random polypeptide chain, there is no “paradox,” as shown by Finkelstein. 93 A similar but even stronger conclusion holds if the cooperative formation of foldons, super‐secondary structure and scaffold elements are taken as the reference.…”

Section: Simulationsmentioning

confidence: 79%

Protein folding ‐ seeing is deceiving

Rose

2021

Protein Science

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This Perspective is intended to raise questions about the conventional interpretation of protein folding. According to the conventional interpretation, developed over many decades, a protein population can visit a vast number of conformations under unfolding conditions, but a single dominant native population emerges under folding conditions. Accordingly, folding comes with a substantial loss of conformational entropy. How is this price paid? The conventional answer is that favorable interactions between and among the side chains can compensate for entropy loss, and moreover, these interactions are responsible for the structural particulars of the native conformation. Challenging this interpretation, the Perspective introduces a proposal that high energy (i.e., unfavorable) excluding interactions winnow the accessible population substantially under physical-chemical conditions that favor folding. Both steric clash and unsatisfied hydrogen bond donors and acceptors are classified as excluding interactions, so called because conformers with such disfavored interactions will be largely excluded from the thermodynamic population. Both excluding interactions and solvent factors that induce compactness are somewhat nonspecific, yet together they promote substantial chain organization. Moreover, proteins are built on a backbone scaffold consisting of α-helices and strands of β-sheet, where the number of hydrogen bond donors and acceptors is exactly balanced. These repetitive secondary structural elements are the only two conformers that can be both completely hydrogen-bond satisfied and extended indefinitely without encountering a steric clash. Consequently, the number of fundamental folds is limited to no more than $10,000 for a protein domain. Once excluding interactions are taken into account, the issue of "frustration" is largely eliminated and the Levinthal paradox is resolved. Putting the "bottom line" at the top: it is likely that hydrogen-bond satisfaction represents a largely under-appreciated parameter in protein folding models.

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Reduction of the Search Space for the Folding of Proteins at the Level of Formation and Assembly of Secondary Structures: A New View on the Solution of Levinthal′s Paradox

Cited by 16 publications

References 28 publications

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

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

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

Protein folding ‐ seeing is deceiving

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