E-Mail Alert

Add your e-mail address to receive forthcoming issues of this journal:

Journal Browser

Journal Browser

Special Issue "Protein Folding 2009"

Quicklinks

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry, Molecular Biology and Biophysics".

Deadline for manuscript submissions: closed (31 January 2009)

Special Issue Editors

Guest Editor
Dr. Andrei Alexandrescu

Molecular & Cell Biology, University of Connecticut, BSP 209, 91 North Eagleville Road, Unit 3125, Storrs, CT 06269-3125, USA
Website | E-Mail
Fax: +1 860 486 4331
Interests: protein folding; amyloids; alzheimer\'s disease; parkinson\'s disease; type II diabetes; structural biology; nuclear magnetic resonance spectroscopy; structural bioinformatics; protein misfolding; neuromuscular junction proteins; OB-fold proteins; protein dynamics; biophysics
Editorial Advisor
Prof. Dr. Martin Gruebele

Department of Chemistry, University of Illinois, A220 Chemical & Life Sciences Lab, 600 South Mathews Avenue, Urbana, IL 61801, USA
Website | E-Mail
Fax: +1 217 244 3186
Interests: protein folding; RNA folding; downhill folding; protein-protein interactions; biomolecular simulation; temperature jump; small angle X-ray scattering

Special Issue Information

Dear Colleagues,

In recent years protein folding often seems to have become synonymous with protein structure prediction. The field of protein folding is in fact considerably more encompassing than the ability to stitch together recurrent structural motifs into models that come closer to a target than those of competitors. The targets are moving, and as predictions become more sophisticated with each passing tournament, so does our appreciation of the intricacies of protein structure, function, and dynamics.

The papers in this issue highlight work at the frontiers of protein folding research. Topics include the behaviors of proteins under extreme or non-physiological environments such as the interactions of proteins with surfaces, synthetic matrices, chaotropes and kosmotropes, and the sheltering environment of chaperones. The mechanisms by which protein misfolding leads to disease remains a challenging and medically important problem. New experimental approaches and new ways of thinking about protein folding are described. And finally, there are papers that continue to address the fundamental unresolved problem of how protein sequences encode for the three-dimensional structures of proteins.

In a climate that often emphasizes the "biology" bottom line, it is refreshing to see basic science flourishing and needed as much as ever in research that may not translate to a pharmaceutical pill but that has and will continue to reveal fundamental insights into the roles of molecular structures in health and disease. Yes, protein folding has been "solved" many times over but it keeps presenting interesting problems and opportunities that should continue to challenge the most ambitious investigators for years to come.

Dr. Andrei Alexandrescu
Guest Editor

Keywords

  • folding and docking/binding
  • protein misfolding
  • protein folding and transient aggregation
  • MD simulation of folding
  • folding heterogeneity and intermediates
  • energy landscapes, analysis
  • energy landscapes, computation
  • dynamics and kinetics, experiments
  • single molecule folding, spectroscopy
  • single molecule folding, force
  • elementary reactions, secondary structure
  • downhill folding
  • calorimetric folding/unfolding
  • protein folding and design
  • protein folding and evolution
  • protein dynamics computation, vibrational dynamics
  • chaperoning and in vivo folding
  • transition state analysis
  • crowding and folding

Related Special Issues

Published Papers (25 papers)

View options order results:
result details:
Displaying articles 1-25
Export citation of selected articles as:

Editorial

Jump to: Research, Review

Open AccessEditorial Protein Dynamics: From Molecules, to Interactions, to Biology
Int. J. Mol. Sci. 2009, 10(3), 1360-1368; doi:10.3390/ijms10031360
Received: 19 February 2009 / Revised: 13 March 2009 / Accepted: 17 March 2009 / Published: 20 March 2009
PDF Full-text (164 KB) | HTML Full-text | XML Full-text
Abstract
Proteins have a remarkably rich diversity of dynamical behaviors, and the articles in this issue of the International Journal of Molecular Sciences are a testament to that fact. From the picosecond motions of single sidechains probed by NMR or fluorescence spectroscopy, to aggregation
[...] Read more.
Proteins have a remarkably rich diversity of dynamical behaviors, and the articles in this issue of the International Journal of Molecular Sciences are a testament to that fact. From the picosecond motions of single sidechains probed by NMR or fluorescence spectroscopy, to aggregation processes at interfaces that take months, all time scales play a role. Proteins are functional molecules, so by their nature they always interact with their environment. This environment includes water, other biomolecules, or larger cellular structures. In a sense, it also includes the protein molecule itself: proteins are large enough to fold and interact with themselves. These interactions have been honed by evolution to produce behaviors completely different from those of random polymers. Full article
(This article belongs to the Special Issue Protein Folding 2009)

Research

Jump to: Editorial, Review

Open AccessArticle Relative Stabilities of Conserved and Non-Conserved Structures in the OB-Fold Superfamily
Int. J. Mol. Sci. 2009, 10(5), 2412-2430; doi:10.3390/ijms10052412
Received: 1 April 2009 / Revised: 16 May 2009 / Accepted: 19 May 2009 / Published: 22 May 2009
Cited by 4 | PDF Full-text (1010 KB) | HTML Full-text | XML Full-text
Abstract
The OB-fold is a diverse structure superfamily based on a β-barrel motif that is often supplemented with additional non-conserved secondary structures. Previous deletion mutagenesis and NMR hydrogen exchange studies of three OB-fold proteins showed that the structural stabilities of sites within the conserved
[...] Read more.
The OB-fold is a diverse structure superfamily based on a β-barrel motif that is often supplemented with additional non-conserved secondary structures. Previous deletion mutagenesis and NMR hydrogen exchange studies of three OB-fold proteins showed that the structural stabilities of sites within the conserved β-barrels were larger than sites in non-conserved segments. In this work we examined a database of 80 representative domain structures currently classified as OB-folds, to establish the basis of this effect. Residue-specific values were obtained for the number of Cα-Cα distance contacts, sequence hydrophobicities, crystallographic B-factors, and theoretical B-factors calculated from a Gaussian Network Model. All four parameters point to a larger average flexibility for the non-conserved structures compared to the conserved β-barrels. The theoretical B-factors and contact densities show the highest sensitivity.Our results suggest a model of protein structure evolution in which novel structural features develop at the periphery of conserved motifs. Core residues are more resistant to structural changes during evolution since their substitution would disrupt a larger number of interactions. Similar factors are likely to account for the differences in stability to unfolding between conserved and non-conserved structures. Full article
(This article belongs to the Special Issue Protein Folding 2009)
Figures

Open AccessArticle The Mitochondrial Protein Translocation Motor: Structural Conservation between the Human and Yeast Tim14/Pam18-Tim16/Pam16 co-Chaperones
Int. J. Mol. Sci. 2009, 10(5), 2041-2053; doi:10.3390/ijms10052041
Received: 14 March 2009 / Revised: 11 April 2009 / Accepted: 14 April 2009 / Published: 6 May 2009
Cited by 11 | PDF Full-text (514 KB) | HTML Full-text | XML Full-text
Abstract
Most of our knowledge regarding the process of protein import into mitochondria has come from research employing Saccharomyces cerevisiae as a model system. Recently, several mammalian homologues of the mitochondrial motor proteins were identified. Of particular interest for us is the human Tim14/Pam18-Tim16/Pam16
[...] Read more.
Most of our knowledge regarding the process of protein import into mitochondria has come from research employing Saccharomyces cerevisiae as a model system. Recently, several mammalian homologues of the mitochondrial motor proteins were identified. Of particular interest for us is the human Tim14/Pam18-Tim16/Pam16 complex. We chose a structural approach in order to examine the evolutionary conservation between yeast Tim14/Pam18-Tim16/Pam16 proteins and their human homologues. For this purpose, we examined the structural properties of the purified human proteins and their interaction with their yeast homologues, in vitro. Our results show that the soluble domains of the human Tim14/Pam18 and Tim16/Pam16 proteins interact with their yeast counterparts, forming heterodimeric complexes and that these complexes interact with yeast mtHsp70. Full article
(This article belongs to the Special Issue Protein Folding 2009)
Open AccessArticle Uncovering the Properties of Energy-Weighted Conformation Space Networks with a Hydrophobic-Hydrophilic Model
Int. J. Mol. Sci. 2009, 10(4), 1808-1823; doi:10.3390/ijms10041808
Received: 14 January 2009 / Revised: 30 March 2009 / Accepted: 7 April 2009 / Published: 21 April 2009
Cited by 7 | PDF Full-text (219 KB) | HTML Full-text | XML Full-text
Abstract
The conformation spaces generated by short hydrophobic-hydrophilic (HP) lattice chains are mapped to conformation space networks (CSNs). The vertices (nodes) of the network are the conformations and the links are the transitions between them. It has been found that these networks have “small-world”
[...] Read more.
The conformation spaces generated by short hydrophobic-hydrophilic (HP) lattice chains are mapped to conformation space networks (CSNs). The vertices (nodes) of the network are the conformations and the links are the transitions between them. It has been found that these networks have “small-world” properties without considering the interaction energy of the monomers in the chain, i. e. the hydrophobic or hydrophilic amino acids inside the chain. When the weight based on the interaction energy of the monomers in the chain is added to the CSNs, it is found that the weighted networks show the “scale-free” characteristic. In addition, it reveals that there is a connection between the scale-free property of the weighted CSN and the folding dynamics of the chain by investigating the relationship between the scale-free structure of the weighted CSN and the noted parameter Z score. Moreover, the modular (community) structure of weighted CSNs is also studied. These results are helpful to understand the topological properties of the CSN and the underlying free-energy landscapes. Full article
(This article belongs to the Special Issue Protein Folding 2009)
Open AccessArticle Protein GB1 Folding and Assembly from Structural Elements
Int. J. Mol. Sci. 2009, 10(4), 1552-1566; doi:10.3390/ijms10041552
Received: 11 February 2009 / Revised: 20 March 2009 / Accepted: 31 March 2009 / Published: 8 April 2009
Cited by 8 | PDF Full-text (919 KB) | HTML Full-text | XML Full-text
Abstract
Folding of the Protein G B1 domain (PGB1) shifts with increasing salt concentration from a cooperative assembly of inherently unstructured subdomains to an assembly of partly pre-folded structures. The salt-dependence of pre-folding contributes to the stability minimum observed at physiological salt conditions. Our
[...] Read more.
Folding of the Protein G B1 domain (PGB1) shifts with increasing salt concentration from a cooperative assembly of inherently unstructured subdomains to an assembly of partly pre-folded structures. The salt-dependence of pre-folding contributes to the stability minimum observed at physiological salt conditions. Our conclusions are based on a study in which the reconstitution of PGB1 from two fragments was studied as a function of salt concentrations and temperature using circular dichroism spectroscopy. Salt was found to induce an increase in β-hairpin structure for the C-terminal fragment (residues 41 – 56), whereas no major salt effect on structure was observed for the isolated N-terminal fragment (residues 1 – 41). In line with the increasing evidence on the interrelation between fragment complementation and stability of the corresponding intact protein, we also find that salt effects on reconstitution can be predicted from salt dependence of the stability of the intact protein. Our data show that our variant (which has the mutations T2Q, N8D, N37D and reconstitutes in a manner similar to the wild type) displays the lowest equilibrium association constant around physiological salt concentration, with higher affinity observed both at lower and higher salt concentration. This corroborates the salt effects on the stability towards denaturation of the intact protein, for which the stability at physiological salt is lower compared to both lower and higher salt concentrations. Hence we conclude that reconstitution reports on molecular factors that govern the native states of proteins. Full article
(This article belongs to the Special Issue Protein Folding 2009)
Figures

Open AccessArticle Folding of Trp-cage Mini Protein Using Temperature and Biasing Potential Replica—Exchange Molecular Dynamics Simulations
Int. J. Mol. Sci. 2009, 10(3), 1121-1137; doi:10.3390/ijms10031121
Received: 2 February 2009 / Revised: 5 March 2009 / Accepted: 9 March 2009 / Published: 12 March 2009
Cited by 13 | PDF Full-text (553 KB) | HTML Full-text | XML Full-text
Abstract
The folding process of the 20 residue Trp-cage mini-protein was investigated using standard temperature replica exchange molecular dynamics (T-RexMD) simulation and a biasing potential RexMD (BP-RexMD) method. In contrast to several conventional molecular dynamics simulations, both RexMD methods sampled conformations close to the
[...] Read more.
The folding process of the 20 residue Trp-cage mini-protein was investigated using standard temperature replica exchange molecular dynamics (T-RexMD) simulation and a biasing potential RexMD (BP-RexMD) method. In contrast to several conventional molecular dynamics simulations, both RexMD methods sampled conformations close to the native structure after 10-20 ns simulation time as the dominant conformational states. In contrast, to T-RexMD involving 16 replicas the BP-RexMD method achieved very similar sampling results with only five replicas. The result indicates that the BP-RexMD method is well suited to study folding processes of proteins at a significantly smaller computational cost, compared to T-RexMD. Both RexMD methods sampled not only similar final states but also agreed on the sampling of intermediate conformations during Trp-cage folding. The analysis of the sampled potential energy contributions indicated that Trp-cage folding is favored by both van der Waals and to a lesser degree electrostatic contributions. Folding does not introduce any significant sterical strain as reflected by similar energy distributions of bonded energy terms (bond length, bond angle and dihedral angle) of folded and unfolded Trp-cage structures. Full article
(This article belongs to the Special Issue Protein Folding 2009)
Figures

Open AccessArticle Probing the Nanosecond Dynamics of a Designed Three-Stranded Beta-Sheet with a Massively Parallel Molecular Dynamics Simulation
Int. J. Mol. Sci. 2009, 10(3), 1013-1030; doi:10.3390/ijms10031013
Received: 15 January 2009 / Revised: 4 March 2009 / Accepted: 9 March 2009 / Published: 10 March 2009
Cited by 3 | PDF Full-text (1699 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Recently a temperature-jump FTIR study of a designed three-stranded sheet showing a fast relaxation time of ~140 ± 20 ns was published. We performed massively parallel molecular dynamics simulations in explicit solvent to probe the structural events involved in this relaxation. While our
[...] Read more.
Recently a temperature-jump FTIR study of a designed three-stranded sheet showing a fast relaxation time of ~140 ± 20 ns was published. We performed massively parallel molecular dynamics simulations in explicit solvent to probe the structural events involved in this relaxation. While our simulations produce similar relaxation rates, the structural ensemble is broad. We observe the formation of turn structure, but only very weak interaction in the strand regions, which is consistent with the lack of strong backbone-backbone NOEs in previous structural NMR studies. These results suggest that either DPDP-II folds at time scales longer than 240 ns, or that DPDP-II is not a well-defined three-stranded β-sheet. This work also provides an opportunity to compare the performance of several popular forcefield models against one another. Full article
(This article belongs to the Special Issue Protein Folding 2009)
Figures

Open AccessArticle Chaperonin Structure - The Large Multi-Subunit Protein Complex
Int. J. Mol. Sci. 2009, 10(3), 844-861; doi:10.3390/ijms10030844
Received: 9 February 2009 / Revised: 23 February 2009 / Accepted: 26 February 2009 / Published: 2 March 2009
Cited by 4 | PDF Full-text (544 KB) | HTML Full-text | XML Full-text
Abstract
The multi sub-unit protein structure representing the chaperonins group is analyzed with respect to its hydrophobicity distribution. The proteins of this group assist protein folding supported by ATP. The specific axial symmetry GroEL structure (two rings of seven units stacked back to back
[...] Read more.
The multi sub-unit protein structure representing the chaperonins group is analyzed with respect to its hydrophobicity distribution. The proteins of this group assist protein folding supported by ATP. The specific axial symmetry GroEL structure (two rings of seven units stacked back to back - 524 aa each) and the GroES (single ring of seven units - 97 aa each) polypeptide chains are analyzed using the hydrophobicity distribution expressed as excess/deficiency all over the molecule to search for structure-to-function relationships. The empirically observed distribution of hydrophobic residues is confronted with the theoretical one representing the idealized hydrophobic core with hydrophilic residues exposure on the surface. The observed discrepancy between these two distributions seems to be aim-oriented, determining the structure-to-function relation. The hydrophobic force field structure generated by the chaperonin capsule is presented. Its possible influence on substrate folding is suggested. Full article
(This article belongs to the Special Issue Protein Folding 2009)
Open AccessArticle A New Approach for Characterizing the Intermediate Feature of α-Chymotrypsin Refolding by Hydrophobic Interaction Chromatography
Int. J. Mol. Sci. 2009, 10(2), 616-628; doi:10.3390/ijms10020616
Received: 31 October 2008 / Revised: 15 February 2009 / Accepted: 17 February 2009 / Published: 18 February 2009
Cited by 3 | PDF Full-text (288 KB) | HTML Full-text | XML Full-text
Abstract
A new approach for characterizing the intermediate of urea-denatured α-chymotrypsin (α-Chy) by hydrophobic interaction chromatography (HIC) is presented. The contact surface region (Z, S), affinity (logI), and the character of interaction force (j) of the α-Chy to
[...] Read more.
A new approach for characterizing the intermediate of urea-denatured α-chymotrypsin (α-Chy) by hydrophobic interaction chromatography (HIC) is presented. The contact surface region (Z, S), affinity (logI), and the character of interaction force (j) of the α-Chy to the stationary phase of HIC (STHIC) between the intermediate (M) and native (N) states were found to be quite different as urea concentration (Curea) changes. With the changes in Curea, a linear relationship between logI and Z was found to exist only for its N state, not for M state, indicating the interaction force between α-Chy in N state to the STHIC to be non-selective, but selective one for its M state. Also, the measured magnitude of both logI and Z in M state is only a fifth of that in N state. All three parameters were employed to distinguish protein in the N state from that in the M state. It would be expected that this result could be employed to distinguish any kind of non-functional protein having correct three-, or four-dimensional molecular structure from their stable M state of any kinds of proteins, and/or other proteins in proteome investigation, separation process of protein, and intensively understanding the intrinsic rule of protein folding in molecular biology. Full article
(This article belongs to the Special Issue Protein Folding 2009)
Open AccessArticle A Crosslinking Analysis of GAP-43 Interactions with Other Proteins in Differentiated N1E-115 Cells
Int. J. Mol. Sci. 2008, 9(9), 1753-1771; doi:10.3390/ijms9091753
Received: 13 August 2008 / Revised: 3 September 2008 / Accepted: 13 September 2008 / Published: 16 September 2008
Cited by 4 | PDF Full-text (1142 KB) | HTML Full-text | XML Full-text
Abstract
It has been suggested that GAP-43 (growth-associated protein) binds to various proteins in growing neurons as part of its mechanism of action. To test this hypothesis in vivo, differentiated N1E-115 neuroblastoma cells were labeled with [35S]-amino acids and were treated with
[...] Read more.
It has been suggested that GAP-43 (growth-associated protein) binds to various proteins in growing neurons as part of its mechanism of action. To test this hypothesis in vivo, differentiated N1E-115 neuroblastoma cells were labeled with [35S]-amino acids and were treated with a cleavable crosslinking reagent. The cells were lysed in detergent and the lysates were centrifuged at 100,000 x g to isolate crosslinked complexes. Following cleavage of the crosslinks and analysis by two-dimensional gel electrophoresis, it was found that the crosslinker increased the level of various proteins, and particularly actin, in this pellet fraction. However, GAP-43 was not present, suggesting that GAP-43 was not extensively crosslinked to proteins of the cytoskeleton and membrane skeleton and did not sediment with them. GAP-43 also did not sediment with the membrane skeleton following nonionic detergent lysis. Calmodulin, but not actin or other proposed interaction partners, co-immunoprecipitated with GAP-43 from the 100,000 x g supernatant following crosslinker addition to cells or cell lysates. Faint spots at 34 kDa and 60 kDa were also present. Additional GAP-43 was recovered from GAP-43 immunoprecipitation supernatants with anti-calmodulin but not with anti-actin. The results suggest that GAP-43 is not present in complexes with actin or other membrane skeletal or cytoskeletal proteins in these cells, but it is nevertheless possible that a small fraction of the total GAP-43 may interact with other proteins. Full article
(This article belongs to the Special Issue Protein Folding 2009)

Review

Jump to: Editorial, Research

Open AccessReview Folding Mechanism of Beta-Hairpin Trpzip2: Heterogeneity, Transition State and Folding Pathways
Int. J. Mol. Sci. 2009, 10(6), 2838-2848; doi:10.3390/ijms10062838
Received: 26 May 2009 / Revised: 18 June 2009 / Accepted: 19 June 2009 / Published: 22 June 2009
Cited by 25 | PDF Full-text (221 KB) | HTML Full-text | XML Full-text
Abstract
We review the studies on the folding mechanism of the β-hairpin tryptophan zipper 2 (trpzip2) and present some additional computational results to refine the picture of folding heterogeneity and pathways. We show that trpzip2 can have a two-state or a multi-state folding pattern,
[...] Read more.
We review the studies on the folding mechanism of the β-hairpin tryptophan zipper 2 (trpzip2) and present some additional computational results to refine the picture of folding heterogeneity and pathways. We show that trpzip2 can have a two-state or a multi-state folding pattern, depending on whether it folds within the native basin or through local state basins on the high-dimensional free energy surface; Trpzip2 can fold along different pathways according to the packing order of tryptophan pairs. We also point out some important problems related to the folding mechanism of trpzip2 that still need clarification, e.g., a wide distribution of the computed conformations for the transition state ensemble. Full article
(This article belongs to the Special Issue Protein Folding 2009)
Open AccessReview GroEL-Assisted Protein Folding: Does It Occur Within the Chaperonin Inner Cavity?
Int. J. Mol. Sci. 2009, 10(5), 2066-2083; doi:10.3390/ijms10052066
Received: 27 April 2009 / Revised: 8 May 2009 / Accepted: 11 May 2009 / Published: 12 May 2009
Cited by 10 | PDF Full-text (256 KB) | HTML Full-text | XML Full-text
Abstract
The folding of protein molecules in the GroEL inner cavity under the co-chaperonin GroES lid is widely accepted as a crucial event of GroEL-assisted protein folding. This review is focused on the data showing that GroEL-assisted protein folding may proceed out of the
[...] Read more.
The folding of protein molecules in the GroEL inner cavity under the co-chaperonin GroES lid is widely accepted as a crucial event of GroEL-assisted protein folding. This review is focused on the data showing that GroEL-assisted protein folding may proceed out of the complex with the chaperonin. The models of GroEL-assisted protein folding assuming ligand-controlled dissociation of nonnative proteins from the GroEL surface and their folding in the bulk solution are also discussed. Full article
(This article belongs to the Special Issue Protein Folding 2009)
Figures

Open AccessReview Folding by Numbers: Primary Sequence Statistics and Their Use in Studying Protein Folding
Int. J. Mol. Sci. 2009, 10(4), 1567-1589; doi:10.3390/ijms10041567
Received: 30 January 2009 / Revised: 30 March 2009 / Accepted: 2 April 2009 / Published: 8 April 2009
Cited by 11 | PDF Full-text (204 KB) | HTML Full-text | XML Full-text
Abstract
The exponential growth over the past several decades in the quantity of both primary sequence data available and the number of protein structures determined has provided a wealth of information describing the relationship between protein primary sequence and tertiary structure. This growing repository
[...] Read more.
The exponential growth over the past several decades in the quantity of both primary sequence data available and the number of protein structures determined has provided a wealth of information describing the relationship between protein primary sequence and tertiary structure. This growing repository of data has served as a prime source for statistical analysis, where underlying relationships between patterns of amino acids and protein structure can be uncovered. Here, we survey the main statistical approaches that have been used for identifying patterns within protein sequences, and discuss sequence pattern research as it relates to both secondary and tertiary protein structure. Limitations to statistical analyses are discussed, and a context for their role within the field of protein folding is given. We conclude by describing a novel statistical study of residue patterning in β-strands, which finds that hydrophobic (i,i+2) pairing in β-strands occurs more often than expected at locations near strand termini. Interpretations involving β-sheet nucleation and growth are discussed. Full article
(This article belongs to the Special Issue Protein Folding 2009)
Open AccessReview Early Events, Kinetic Intermediates and the Mechanism of Protein Folding in Cytochrome c
Int. J. Mol. Sci. 2009, 10(4), 1476-1499; doi:10.3390/ijms10041476
Received: 26 February 2009 / Revised: 27 March 2009 / Accepted: 30 March 2009 / Published: 1 April 2009
Cited by 18 | PDF Full-text (230 KB) | HTML Full-text | XML Full-text | Correction
Abstract
Kinetic studies of the early events in cytochrome c folding are reviewed with a focus on the evidence for folding intermediates on the submillisecond timescale. Evidence from time-resolved absorption, circular dichroism, magnetic circular dichroism, fluorescence energy and electron transfer, small-angle X-ray scattering and
[...] Read more.
Kinetic studies of the early events in cytochrome c folding are reviewed with a focus on the evidence for folding intermediates on the submillisecond timescale. Evidence from time-resolved absorption, circular dichroism, magnetic circular dichroism, fluorescence energy and electron transfer, small-angle X-ray scattering and amide hydrogen exchange studies on the t £ 1 ms timescale reveals a picture of cytochrome c folding that starts with the ~ 1-ms conformational diffusion dynamics of the unfolded chains. A fractional population of the unfolded chains collapses on the 1 – 100 ms timescale to a compact intermediate IC containing some native-like secondary structure. Although the existence and nature of IC as a discrete folding intermediate remains controversial, there is extensive high time-resolution kinetic evidence for the rapid formation of IC as a true intermediate, i.e., a metastable state separated from the unfolded state by a discrete free energy barrier. Final folding to the native state takes place on millisecond and longer timescales, depending on the presence of kinetic traps such as heme misligation and proline mis-isomerization. The high folding rates observed in equilibrium molten globule models suggest that IC may be a productive folding intermediate. Whether it is an obligatory step on the pathway to the high free energy barrier associated with millisecond timescale folding to the native state, however, remains to be determined. Full article
(This article belongs to the Special Issue Protein Folding 2009)
Figures

Open AccessReview Slow Unfolding of Monomeric Proteins from Hyperthermophiles with Reversible Unfolding
Int. J. Mol. Sci. 2009, 10(3), 1369-1385; doi:10.3390/ijms10031369
Received: 28 January 2009 / Revised: 19 March 2009 / Accepted: 23 March 2009 / Published: 24 March 2009
Cited by 11 | PDF Full-text (250 KB) | HTML Full-text | XML Full-text
Abstract
Based on the differences in their optimal growth temperatures microorganisms can be classified into psychrophiles, mesophiles, thermophiles, and hyperthermophiles. Proteins from hyperthermophiles generally exhibit greater stability than those from other organisms. In this review, we collect data about the stability and folding of
[...] Read more.
Based on the differences in their optimal growth temperatures microorganisms can be classified into psychrophiles, mesophiles, thermophiles, and hyperthermophiles. Proteins from hyperthermophiles generally exhibit greater stability than those from other organisms. In this review, we collect data about the stability and folding of monomeric proteins from hyperthermophilies with reversible unfolding, from the equilibrium and kinetic aspects. The results indicate that slow unfolding is a general strategy by which proteins from hyperthermophiles adapt to higher temperatures. Hydrophobic interaction is one of the factors in the molecular mechanism of the slow unfolding of proteins from hyperthermophiles. Full article
(This article belongs to the Special Issue Protein Folding 2009)
Open AccessReview Participation of Low Molecular Weight Electron Carriers in Oxidative Protein Folding
Int. J. Mol. Sci. 2009, 10(3), 1346-1359; doi:10.3390/ijms10031346
Received: 3 February 2009 / Revised: 8 March 2009 / Accepted: 17 March 2009 / Published: 20 March 2009
Cited by 5 | PDF Full-text (249 KB) | HTML Full-text | XML Full-text
Abstract
Oxidative protein folding is mediated by a proteinaceous electron relay system, in which the concerted action of protein disulfide isomerase and Ero1 delivers the electrons from thiol groups to the final acceptor. Oxygen appears to be the final oxidant in aerobic living organisms,
[...] Read more.
Oxidative protein folding is mediated by a proteinaceous electron relay system, in which the concerted action of protein disulfide isomerase and Ero1 delivers the electrons from thiol groups to the final acceptor. Oxygen appears to be the final oxidant in aerobic living organisms, although the existence of alternative electron acceptors, e.g. fumarate or nitrate, cannot be excluded. Whilst the protein components of the system are well-known, less attention has been turned to the role of low molecular weight electron carriers in the process. The function of ascorbate, tocopherol and vitamin K has been raised recently. In vitro and in vivo evidence suggests that these redox-active compounds can contribute to the functioning of oxidative folding. This review focuses on the participation of small molecular weight redox compounds in oxidative protein folding. Full article
(This article belongs to the Special Issue Protein Folding 2009)
Open AccessReview Mechanism of Suppression of Protein Aggregation by α-Crystallin
Int. J. Mol. Sci. 2009, 10(3), 1314-1345; doi:10.3390/ijms10031314
Received: 30 January 2009 / Revised: 13 March 2009 / Accepted: 18 March 2009 / Published: 19 March 2009
Cited by 35 | PDF Full-text (474 KB) | HTML Full-text | XML Full-text
Abstract
This review summarizes experimental data illuminating the mechanism of suppression of heat-induced protein aggregation by a-crystallin, one of the small heat shock proteins. The dynamic light scattering data show that the initial stage of thermal aggregation of proteins is the formation of the
[...] Read more.
This review summarizes experimental data illuminating the mechanism of suppression of heat-induced protein aggregation by a-crystallin, one of the small heat shock proteins. The dynamic light scattering data show that the initial stage of thermal aggregation of proteins is the formation of the initial aggregates involving hundreds of molecules of the denatured protein. Further sticking of the starting aggregates proceeds in a regime of diffusion-limited cluster-cluster aggregation. The protective effect of a-crystallin is due to transition of the aggregation process to the regime of reaction-limited cluster-cluster aggregation, wherein the sticking probability for the colliding particles becomes lower than unity. Full article
(This article belongs to the Special Issue Protein Folding 2009)
Figures

Open AccessReview Importance of Translational Entropy of Water in Biological Self-Assembly Processes like Protein Folding
Int. J. Mol. Sci. 2009, 10(3), 1064-1080; doi:10.3390/ijms10031064
Received: 26 January 2009 / Revised: 6 March 2009 / Accepted: 10 March 2009 / Published: 11 March 2009
Cited by 42 | PDF Full-text (287 KB) | HTML Full-text | XML Full-text
Abstract
We briefly review our studies on the folding/unfolding mechanisms of proteins. In biological self-assembly processes such as protein folding, the number of accessible translational configurations of water in the system increases greatly, leading to a large gain in the water entropy. The usual
[...] Read more.
We briefly review our studies on the folding/unfolding mechanisms of proteins. In biological self-assembly processes such as protein folding, the number of accessible translational configurations of water in the system increases greatly, leading to a large gain in the water entropy. The usual view looking at only the water in the close vicinity of the protein surface is capable of elucidating neither the large entropic gain upon apoplastocyanin folding, which has recently been found in a novel experimental study, nor the pressure and cold denaturation. With the emphasis on the translational entropy of water, we are presently constructing a reliable method for predicting the native structure of a protein from its amino-acid sequence. Full article
(This article belongs to the Special Issue Protein Folding 2009)
Open AccessReview The Role of Disordered Ribosomal Protein Extensions in the Early Steps of Eubacterial 50 S Ribosomal Subunit Assembly
Int. J. Mol. Sci. 2009, 10(3), 817-834; doi:10.3390/ijms10030817
Received: 5 February 2009 / Revised: 23 February 2009 / Accepted: 24 February 2009 / Published: 2 March 2009
Cited by 20 | PDF Full-text (6304 KB) | HTML Full-text | XML Full-text
Abstract
Although during the past decade research has shown the functional importance of disorder in proteins, many of the structural and dynamics properties of intrinsically unstructured proteins (IUPs) remain to be elucidated. This review is focused on the role of the extensions of the
[...] Read more.
Although during the past decade research has shown the functional importance of disorder in proteins, many of the structural and dynamics properties of intrinsically unstructured proteins (IUPs) remain to be elucidated. This review is focused on the role of the extensions of the ribosomal proteins in the early steps of the assembly of the eubacterial 50 S subunit. The recent crystallographic structures of the ribosomal particles have revealed the picture of a complex assembly pathway that condenses the rRNA and the ribosomal proteins into active ribosomes. However, little is know about the molecular mechanisms of this process. It is thought that the long basic r-protein extensions that penetrate deeply into the subunit cores play a key role through disorder-order transitions and/or co-folding mechanisms. A current view is that such structural transitions may facilitate the proper rRNA folding. In this paper, the structures of the proteins L3, L4, L13, L20, L22 and L24 that have been experimentally found to be essential for the first steps of ribosome assembly have been compared. On the basis of their structural and dynamics properties, three categories of extensions have been identified. Each of them seems to play a distinct function. Among them, only the coil-helix transition that occurs in a phylogenetically conserved cluster of basic residues of the L20 extension appears to be strictly required for the large subunit assembly in eubacteria. The role of a helix-coil transitions in 23 S RNA folding is discussed in the light of the calcium binding protein calmodulin that shares many structural and dynamics properties with L20. Full article
(This article belongs to the Special Issue Protein Folding 2009)
Open AccessReview Insights from Coarse-Grained Gō Models for Protein Folding and Dynamics
Int. J. Mol. Sci. 2009, 10(3), 889-905; doi:10.3390/ijms10030889
Received: 21 January 2009 / Revised: 23 February 2009 / Accepted: 26 February 2009 / Published: 2 March 2009
Cited by 131 | PDF Full-text (470 KB) | HTML Full-text | XML Full-text
Abstract
Exploring the landscape of large scale conformational changes such as protein folding at atomistic detail poses a considerable computational challenge. Coarse-grained representations of the peptide chain have therefore been developed and over the last decade have proved extremely valuable. These include topology-based Gō
[...] Read more.
Exploring the landscape of large scale conformational changes such as protein folding at atomistic detail poses a considerable computational challenge. Coarse-grained representations of the peptide chain have therefore been developed and over the last decade have proved extremely valuable. These include topology-based Gō models, which constitute a smooth and funnel-like approximation to the folding landscape. We review the many variations of the Gō model that have been employed to yield insight into folding mechanisms. Their success has been interpreted as a consequence of the dominant role of the native topology in folding. The role of local contact density in determining protein dynamics is also discussed and is used to explain the ability of Gō-like models to capture sequence effects in folding and elucidate conformational transitions. Full article
(This article belongs to the Special Issue Protein Folding 2009)
Figures

Open AccessReview Multiple, but Concerted Cellular Activities of the Human Protein Hap46/BAG-1M and Isoforms
Int. J. Mol. Sci. 2009, 10(3), 906-928; doi:10.3390/ijms10030906
Received: 11 January 2009 / Accepted: 23 February 2009 / Published: 2 March 2009
Cited by 7 | PDF Full-text (939 KB) | HTML Full-text | XML Full-text
Abstract
The closely related human and murine proteins Hap46/BAG-1M and BAG-1, respectively, were discovered more than a decade ago by molecular cloning techniques. These and the larger isoform Hap50/BAG-1L, as well as shorter isoforms, have the ability to interact with a seemingly unlimited array
[...] Read more.
The closely related human and murine proteins Hap46/BAG-1M and BAG-1, respectively, were discovered more than a decade ago by molecular cloning techniques. These and the larger isoform Hap50/BAG-1L, as well as shorter isoforms, have the ability to interact with a seemingly unlimited array of proteins of completely unrelated structures. This problem was partially resolved when it was realized that molecular chaperones of the hsp70 heat shock protein family are major primary association partners, binding being mediated by the carboxy terminal BAG-domain and the ATP-binding domain of hsp70 chaperones. The latter, in turn, can associate with an almost unlimited variety of proteins through their substrate-binding domains, so that ternary complexes may result. The protein folding activity of hsp70 chaperones is affected by interactions with Hap46/BAG-1M or isoforms. However, there also exist several proteins which bind to Hap46/BAG-1M and isoforms independent of hsp70 mediation. Moreover, Hap46/BAG-1M and Hap50/BAG-1L, but not the shorter isoforms, can bind to DNA in a sequence-independent manner by making use of positively charged regions close to their amino terminal ends. This is the molecular basis for their effects on transcription which are of major physiological relevance, as discussed here in terms of a model. The related proteins Hap50/BAG-1L and Hap46/BAG-1M may thus serve as molecular links between such diverse bioactivities as regulation of gene expression and protein quality control. These activities are coordinated and synergize in helping cells to cope with conditions of external stress. Moreover, they recently became markers for the aggressiveness of several cancer types. Full article
(This article belongs to the Special Issue Protein Folding 2009)
Open AccessReview Effect of Nanoparticles on Protein Folding and Fibrillogenesis
Int. J. Mol. Sci. 2009, 10(2), 646-655; doi:10.3390/ijms10020646
Received: 18 January 2009 / Revised: 1 February 2009 / Accepted: 10 February 2009 / Published: 20 February 2009
Cited by 71 | PDF Full-text (161 KB) | HTML Full-text | XML Full-text
Abstract
The large surface area and small size of nanoparticles provide properties and applications that are distinct from those of bulk materials. The ability of nanoparticles to influence protein folding and aggregation is interesting, not only because of the potential beneficial applications, but also
[...] Read more.
The large surface area and small size of nanoparticles provide properties and applications that are distinct from those of bulk materials. The ability of nanoparticles to influence protein folding and aggregation is interesting, not only because of the potential beneficial applications, but also the potential risks to human health and the environment. This makes it essential that we understand the effect of nanoparticles on fundamental biological process, like protein folding. Here, we review studies that have examined the effect of nanoparticles on protein folding and aggregation, providing insight both into the mechanisms of these processes and how they may be controlled. Full article
(This article belongs to the Special Issue Protein Folding 2009)
Open AccessReview Folding, Stability and Shape of Proteins in Crowded Environments: Experimental and Computational Approaches
Int. J. Mol. Sci. 2009, 10(2), 572-588; doi:10.3390/ijms10020572
Received: 11 December 2008 / Revised: 10 February 2009 / Accepted: 12 February 2009 / Published: 13 February 2009
Cited by 39 | PDF Full-text (686 KB) | HTML Full-text | XML Full-text
Abstract
How the crowded environment inside cells affects folding, stability and structures of proteins is a vital question, since most proteins are made and function inside cells. Here we describe how crowded conditions can be created in vitro and in silico and how we
[...] Read more.
How the crowded environment inside cells affects folding, stability and structures of proteins is a vital question, since most proteins are made and function inside cells. Here we describe how crowded conditions can be created in vitro and in silico and how we have used this to probe effects on protein properties. We have found that folded forms of proteins become more compact in the presence of macromolecular crowding agents; if the protein is aspherical, the shape also changes (extent dictated by native-state stability and chemical conditions). It was also discovered that the shape of the macromolecular crowding agent modulates the folding mechanism of a protein; in addition, the extent of asphericity of the protein itself is an important factor in defining its folding speed. Full article
(This article belongs to the Special Issue Protein Folding 2009)
Open AccessReview Protein Folding and Misfolding on Surfaces
Int. J. Mol. Sci. 2008, 9(12), 2515-2542; doi:10.3390/ijms9122515
Received: 6 November 2008 / Revised: 3 December 2008 / Accepted: 8 December 2008 / Published: 10 December 2008
Cited by 36 | PDF Full-text (1053 KB) | HTML Full-text | XML Full-text
Abstract
Protein folding, misfolding and aggregation, as well as the way misfolded and aggregated proteins affects cell viability are emerging as key themes in molecular and structural biology and in molecular medicine. Recent advances in the knowledge of the biophysical basis of protein folding
[...] Read more.
Protein folding, misfolding and aggregation, as well as the way misfolded and aggregated proteins affects cell viability are emerging as key themes in molecular and structural biology and in molecular medicine. Recent advances in the knowledge of the biophysical basis of protein folding have led to propose the energy landscape theory which provides a consistent framework to better understand how a protein folds rapidly and efficiently to the compact, biologically active structure. The increased knowledge on protein folding has highlighted its strict relation to protein misfolding and aggregation, either process being in close competition with the other, both relying on the same physicochemical basis. The theory has also provided information to better understand the structural and environmental factors affecting protein folding resulting in protein misfolding and aggregation into ordered or disordered polymeric assemblies. Among these, particular importance is given to the effects of surfaces. The latter, in some cases make possible rapid and efficient protein folding but most often recruit proteins/peptides increasing their local concentration thus favouring misfolding and accelerating the rate of nucleation. It is also emerging that surfaces can modify the path of protein misfolding and aggregation generating oligomers and polymers structurally different from those arising in the bulk solution and endowed with different physical properties and cytotoxicities. Full article
(This article belongs to the Special Issue Protein Folding 2009)
Open AccessReview Discovery of Proteomic Code with mRNA Assisted Protein Folding
Int. J. Mol. Sci. 2008, 9(12), 2424-2446; doi:10.3390/ijms9122424
Received: 18 August 2008 / Revised: 24 November 2008 / Accepted: 2 December 2008 / Published: 3 December 2008
Cited by 5 | PDF Full-text (1241 KB) | HTML Full-text | XML Full-text
Abstract
The 3x redundancy of the Genetic Code is usually explained as a necessity to increase the mutation-resistance of the genetic information. However recent bioinformatical observations indicate that the redundant Genetic Code contains more biological information than previously known and which is additional to
[...] Read more.
The 3x redundancy of the Genetic Code is usually explained as a necessity to increase the mutation-resistance of the genetic information. However recent bioinformatical observations indicate that the redundant Genetic Code contains more biological information than previously known and which is additional to the 64/20 definition of amino acids. It might define the physico-chemical and structural properties of amino acids, the codon boundaries, the amino acid co-locations (interactions) in the coded proteins and the free folding energy of mRNAs. This additional information, which seems to be necessary to determine the 3D structure of coding nucleic acids as well as the coded proteins, is known as the Proteomic Code and mRNA Assisted Protein Folding. Full article
(This article belongs to the Special Issue Protein Folding 2009)

Journal Contact

MDPI AG
IJMS Editorial Office
St. Alban-Anlage 66, 4052 Basel, Switzerland
ijms@mdpi.com
Tel. +41 61 683 77 34
Fax: +41 61 302 89 18
Editorial Board
Contact Details Submit to IJMS
Back to Top