Structure based prediction of protein folding intermediates

Research output: Contribution to journalArticle

Abstract

The complete unfolding of a protein involves the disruption of non-covalent intramolecular interactions within the protein and the subsequent hydration of the backbone and amino acid side-chains. The magnitude of the thermodynamic parameters associated with this process is known accurately for a growing number of globular proteins for which high-resolution structures are also available. The existence of this database of structural and thermodynamic information has facilitated the development of statistical procedures aimed at quantifying the relationships existing between protein structure and the thermodynamic parameters of folding/unfolding. Under some conditions proteins do not unfold completely, giving rise to states (commonly known as molten globules) in which the molecule retains some secondary structure and remains in a compact configuration after denaturation. This phenomenon is reflected in the thermodynamics of the process. Depending on the nature of the residual structure that exists after denaturation, the observed enthalpy, entropy and heat capacity changes will deviate in a particular and predictable way from the values expected for complete unfolding. For several proteins, these deviations have been shown to exhibit similar characteristics, suggesting that their equilibrium folding intermediates exhibit some common structural features. Employing empirically derived structure-energetic relationships, it is possible to identify in the native structure of the protein those regions with the higher probability of being structured in equilibrium partly folded states. In this work, a thermodynamic search algorithm aimed at identifying the structural determinants of the molten globule state has been applied to six globular proteins; α-lactalbumin, barnase, III(Glc), interleukin-1β, phage T4 lysozyme and phage 434 repressor. Remarkably, the structural features of the predicted equilibrium intermediates coincide to a large extent with the known structural features of the corresponding intermediates determined by NMR hydrogen-exchange experiments.

Original languageEnglish (US)
Pages (from-to)62-80
Number of pages19
JournalJournal of Molecular Biology
Volume242
Issue number1
DOIs
StatePublished - 1994

Fingerprint

Protein Folding
Thermodynamics
Proteins
Bacteriophage T4
Lactalbumin
Protein Unfolding
Entropy
Muramidase
Interleukin-1
Hydrogen
Hot Temperature
Databases
Amino Acids

Keywords

  • Folding intermediates
  • Folding pathway
  • Protein
  • Structural thermodynamics

ASJC Scopus subject areas

  • Virology

Cite this

Structure based prediction of protein folding intermediates. / Xie, Dong; Freire, Ernesto I.

In: Journal of Molecular Biology, Vol. 242, No. 1, 1994, p. 62-80.

Research output: Contribution to journalArticle

@article{bd7f3373c710420b979c23cf4fa5da06,
title = "Structure based prediction of protein folding intermediates",
abstract = "The complete unfolding of a protein involves the disruption of non-covalent intramolecular interactions within the protein and the subsequent hydration of the backbone and amino acid side-chains. The magnitude of the thermodynamic parameters associated with this process is known accurately for a growing number of globular proteins for which high-resolution structures are also available. The existence of this database of structural and thermodynamic information has facilitated the development of statistical procedures aimed at quantifying the relationships existing between protein structure and the thermodynamic parameters of folding/unfolding. Under some conditions proteins do not unfold completely, giving rise to states (commonly known as molten globules) in which the molecule retains some secondary structure and remains in a compact configuration after denaturation. This phenomenon is reflected in the thermodynamics of the process. Depending on the nature of the residual structure that exists after denaturation, the observed enthalpy, entropy and heat capacity changes will deviate in a particular and predictable way from the values expected for complete unfolding. For several proteins, these deviations have been shown to exhibit similar characteristics, suggesting that their equilibrium folding intermediates exhibit some common structural features. Employing empirically derived structure-energetic relationships, it is possible to identify in the native structure of the protein those regions with the higher probability of being structured in equilibrium partly folded states. In this work, a thermodynamic search algorithm aimed at identifying the structural determinants of the molten globule state has been applied to six globular proteins; α-lactalbumin, barnase, III(Glc), interleukin-1β, phage T4 lysozyme and phage 434 repressor. Remarkably, the structural features of the predicted equilibrium intermediates coincide to a large extent with the known structural features of the corresponding intermediates determined by NMR hydrogen-exchange experiments.",
keywords = "Folding intermediates, Folding pathway, Protein, Structural thermodynamics",
author = "Dong Xie and Freire, {Ernesto I}",
year = "1994",
doi = "10.1006/jmbi.1994.1557",
language = "English (US)",
volume = "242",
pages = "62--80",
journal = "Journal of Molecular Biology",
issn = "0022-2836",
publisher = "Academic Press Inc.",
number = "1",

}

TY - JOUR

T1 - Structure based prediction of protein folding intermediates

AU - Xie, Dong

AU - Freire, Ernesto I

PY - 1994

Y1 - 1994

N2 - The complete unfolding of a protein involves the disruption of non-covalent intramolecular interactions within the protein and the subsequent hydration of the backbone and amino acid side-chains. The magnitude of the thermodynamic parameters associated with this process is known accurately for a growing number of globular proteins for which high-resolution structures are also available. The existence of this database of structural and thermodynamic information has facilitated the development of statistical procedures aimed at quantifying the relationships existing between protein structure and the thermodynamic parameters of folding/unfolding. Under some conditions proteins do not unfold completely, giving rise to states (commonly known as molten globules) in which the molecule retains some secondary structure and remains in a compact configuration after denaturation. This phenomenon is reflected in the thermodynamics of the process. Depending on the nature of the residual structure that exists after denaturation, the observed enthalpy, entropy and heat capacity changes will deviate in a particular and predictable way from the values expected for complete unfolding. For several proteins, these deviations have been shown to exhibit similar characteristics, suggesting that their equilibrium folding intermediates exhibit some common structural features. Employing empirically derived structure-energetic relationships, it is possible to identify in the native structure of the protein those regions with the higher probability of being structured in equilibrium partly folded states. In this work, a thermodynamic search algorithm aimed at identifying the structural determinants of the molten globule state has been applied to six globular proteins; α-lactalbumin, barnase, III(Glc), interleukin-1β, phage T4 lysozyme and phage 434 repressor. Remarkably, the structural features of the predicted equilibrium intermediates coincide to a large extent with the known structural features of the corresponding intermediates determined by NMR hydrogen-exchange experiments.

AB - The complete unfolding of a protein involves the disruption of non-covalent intramolecular interactions within the protein and the subsequent hydration of the backbone and amino acid side-chains. The magnitude of the thermodynamic parameters associated with this process is known accurately for a growing number of globular proteins for which high-resolution structures are also available. The existence of this database of structural and thermodynamic information has facilitated the development of statistical procedures aimed at quantifying the relationships existing between protein structure and the thermodynamic parameters of folding/unfolding. Under some conditions proteins do not unfold completely, giving rise to states (commonly known as molten globules) in which the molecule retains some secondary structure and remains in a compact configuration after denaturation. This phenomenon is reflected in the thermodynamics of the process. Depending on the nature of the residual structure that exists after denaturation, the observed enthalpy, entropy and heat capacity changes will deviate in a particular and predictable way from the values expected for complete unfolding. For several proteins, these deviations have been shown to exhibit similar characteristics, suggesting that their equilibrium folding intermediates exhibit some common structural features. Employing empirically derived structure-energetic relationships, it is possible to identify in the native structure of the protein those regions with the higher probability of being structured in equilibrium partly folded states. In this work, a thermodynamic search algorithm aimed at identifying the structural determinants of the molten globule state has been applied to six globular proteins; α-lactalbumin, barnase, III(Glc), interleukin-1β, phage T4 lysozyme and phage 434 repressor. Remarkably, the structural features of the predicted equilibrium intermediates coincide to a large extent with the known structural features of the corresponding intermediates determined by NMR hydrogen-exchange experiments.

KW - Folding intermediates

KW - Folding pathway

KW - Protein

KW - Structural thermodynamics

UR - http://www.scopus.com/inward/record.url?scp=0028146012&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0028146012&partnerID=8YFLogxK

U2 - 10.1006/jmbi.1994.1557

DO - 10.1006/jmbi.1994.1557

M3 - Article

C2 - 8078072

AN - SCOPUS:0028146012

VL - 242

SP - 62

EP - 80

JO - Journal of Molecular Biology

JF - Journal of Molecular Biology

SN - 0022-2836

IS - 1

ER -