Some additional remarks to the solution of the protein folding puzzle

Finkelstein, Alexei V.

doi:10.1016/j.plrev.2017.06.025

Cited by 5 publications

(3 citation statements)

References 21 publications

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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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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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“…Fortunately, this can be done rather readily, because a recent review published in Biomolecules [6] outlines progress in the field of in vivo protein folding. (See also References [7,8]. ) We can begin by comparing protein structure formation times in vivo and in vitro.…”

Section: Introductionmentioning

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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“…It is worth remembering that some proteins begin to fold even before the entire chain leaves the ribosome, and the pathways leading to the final state may differ significantly for in silico and in vivo 50 . However, we work with relatively small proteins and peptides and can expect our proteins to fold into a conformation that corresponds to the minimum free energy, regardless of the conditions of the experiment.…”

Section: Resultsmentioning

confidence: 99%

Protein structure prediction using the evolutionary algorithm USPEX

et al. 2023

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Protein structure prediction is one of major problems of modern biophysics: current attempts to predict the tertiary protein structure from amino acid sequence are successful mostly when the use of big data and machine learning allows one to reduce the "prediction problem" to the "problem of recognition". Compared with recent successes of deep learning, classical predictive methods lag behind in their accuracy for the prediction of stable conformations. Therefore, in this work we extended the evolutionary algorithm USPEX to predict protein structure based on global optimization starting with the amino acid sequence. Moreover, we compared frequently used force fields for the task of protein structure prediction. Protein structure relaxation and energy calculations were performed using Tinker (with several different force fields) and Rosetta (with REF2015 force field) codes. To create new protein structure models in the USPEX algorithm, we developed novel variation operators. The test of the new method on seven proteins having (for simplicity) no cis-proline (with ω ≈ 0 ) residues, and a length of up to 100 residues, revealed that our algorithm predicts tertiary structures of proteins with high accuracy. The comparison of the final potential energies of the predicted protein structures obtained using the USPEX and the Rosetta Abinitio approach showed that in most cases the developed algorithm found structures with close or even lower energy (Amber/Charmm/Oplsaal) and scoring function (REF2015). While USPEX has clearly demonstrated its ability to find very deep energy minima, our study showed that the existing force fields are not sufficiently accurate for accurate blind prediction of protein structures without further experimental verification.

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Some additional remarks to the solution of the protein folding puzzle

Cited by 5 publications

References 21 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

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

Protein structure prediction using the evolutionary algorithm USPEX

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