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Proceedings of the National Academy of... Dec 1999We use an off-lattice minimalist model to describe the effects of pressure in slowing down the folding/unfolding kinetics of proteins when subjected to increasingly...
We use an off-lattice minimalist model to describe the effects of pressure in slowing down the folding/unfolding kinetics of proteins when subjected to increasingly larger pressures. The potential energy function used to describe the interactions between beads in the model includes the effects of pressure on the pairwise interaction of hydrophobic groups in water. We show that pressure affects the participation of contacts in the transition state. More significantly, pressure exponentially decreases the chain reconfigurational diffusion coefficient. These results are consistent with experimental results on the kinetics of pressure-denaturation of staphylococcal nuclease.
Topics: Computer Simulation; Diffusion; Hydrostatic Pressure; Kinetics; Micrococcal Nuclease; Models, Chemical; Protein Denaturation; Protein Folding; Thermodynamics
PubMed: 10611301
DOI: 10.1073/pnas.96.26.14848 -
Progress in Biophysics and Molecular... Sep 2008The folding of multisubunit proteins is of tremendous biological significance since the large majority of proteins exist as protein-protein complexes. Extensive... (Review)
Review
The folding of multisubunit proteins is of tremendous biological significance since the large majority of proteins exist as protein-protein complexes. Extensive experimental and computational studies have provided fundamental insights into the principles of folding of small monomeric proteins. Recently, important advances have been made in extending folding studies to multisubunit proteins, in particular homodimeric proteins. This review summarizes the equilibrium and kinetic theory and models underlying the quantitative analysis of dimeric protein folding using chemical denaturation, as well as the experimental results that have been obtained. Although various principles identified for monomer folding also apply to the folding of dimeric proteins, the effects of subunit association can manifest in complex ways, and are frequently overlooked. Changes in molecularity typically give rise to very different overall folding behaviour than is observed for monomeric proteins. The results obtained for dimers have provided key insights pertinent to understanding biological assembly and regulation of multisubunit proteins. These advances have set the stage for future advances in folding involving protein-protein interactions for natural multisubunit proteins and unnatural assemblies involved in disease.
Topics: Animals; Biophysics; Dimerization; Humans; Ions; Kinetics; Molecular Conformation; Protein Binding; Protein Conformation; Protein Denaturation; Protein Folding; Protein Interaction Mapping; Proteins; Thermodynamics; Viscosity
PubMed: 18602415
DOI: 10.1016/j.pbiomolbio.2008.05.004 -
Biochemistry May 2019Protein unfolding thermodynamic parameters are conventionally extracted from equilibrium thermal and chemical denaturation experiments. Despite decades of work, the...
Protein unfolding thermodynamic parameters are conventionally extracted from equilibrium thermal and chemical denaturation experiments. Despite decades of work, the degree of structure and the compactness of denatured states populated in these experiments are still open questions. Here, building on previous works, we show that thermally and chemically denatured protein states are distinct from the viewpoint of far-ultraviolet circular dichroism experiments that report on the local conformational status of peptide bonds. The differences identified are independent of protein length, structural class, or experimental conditions, highlighting the presence of two sub-ensembles within the denatured states. The sub-ensembles, U and U for thermally induced and denaturant-induced unfolded states, respectively, can exclusively exchange populations as a function of temperature at high chemical denaturant concentrations. Empirical analysis suggests that chemically denatured states are ∼50% more expanded than the thermally denatured chains of the same protein. Our observations hint that the strength of protein backbone-backbone interactions and identity versus backbone-solvent/co-solvent interactions determine the conformational distributions. We discuss the implications for protein folding mechanisms, the heterogeneity in relaxation rates, and folding diffusion coefficients.
Topics: Circular Dichroism; DNA-Binding Proteins; Escherichia coli Proteins; Hot Temperature; Kinetics; Protein Conformation, alpha-Helical; Protein Denaturation; Protein Folding; Repressor Proteins; Urea
PubMed: 31083972
DOI: 10.1021/acs.biochem.9b00089 -
Structure (London, England : 1993) Oct 2014Models of symmetric protein evolution typically invoke gene duplication and fusion events, in which repetition of a structural motif generates foldable, stable symmetric...
Models of symmetric protein evolution typically invoke gene duplication and fusion events, in which repetition of a structural motif generates foldable, stable symmetric protein architecture. Success of such evolutionary processes suggests that the duplicated structural motif must be capable of nucleating protein folding. If correct, symmetric expansion of a folding nucleus sequence derived from an extant symmetric fold may be an elegant and computationally tractable solution to de novo protein design. We report the efficient de novo design of a β-trefoil protein by symmetric expansion of a β-trefoil folding nucleus, previously identified by ɸ-value analysis. The resulting protein, having exact sequence symmetry, exhibits superior folding properties compared to its naturally evolved progenitor-with the potential for redundant folding nuclei. In principle, folding nucleus symmetric expansion can be applied to any given symmetric protein fold (that is, nearly one-third of the known proteome) provided information of the folding nucleus is available.
Topics: Amino Acid Sequence; Calorimetry, Differential Scanning; Crystallography, X-Ray; Evolution, Molecular; Models, Molecular; Molecular Sequence Data; Protein Conformation; Protein Denaturation; Protein Folding; Proteins
PubMed: 25242458
DOI: 10.1016/j.str.2014.08.008 -
Journal of the American Chemical Society Mar 2009The essential and nontrivial role of the denatured state of proteins in their folding reaction is being increasingly scrutinized in recent years. Single molecule FRET...
The essential and nontrivial role of the denatured state of proteins in their folding reaction is being increasingly scrutinized in recent years. Single molecule FRET (smFRET) experiments show that the denatured state undergoes a continuous collapse (or coil-to-globule) transition as the concentration of a chemical denaturant is decreased, suggesting that conformational entropy of the denatured state is an important part of the free energy of folding. Such observations question the validity of the classical Tanford transfer model, which suggests that the folding free energy can be understood solely based on the difference in amino acid solvation between the folded state and a fixed unfolded state. An alternative to the transfer model is obtained here from a polymer theoretical analysis of a series of published smFRET data. The analysis shows that the free energy of denatured-state collapse has a linear dependence on denaturant concentration, an outcome of the interplay between enthalpic and entropic contributions. Surprisingly, the slope of the free energy of collapse agrees very well with the respective slope of the free energy of folding. This conformity of values obtained from two very different measurements shows that it is the collapse transition in the denatured state which mediates the effect of denaturants on folding. The energetics of folding are thus governed by the competition of solvation and conformational entropy in the denatured state.
Topics: Entropy; Fluorescence Resonance Energy Transfer; Models, Chemical; Models, Molecular; Protein Conformation; Protein Denaturation; Protein Folding; Proteins; Thermodynamics
PubMed: 19239269
DOI: 10.1021/ja808305u -
Proceedings of the American Thoracic... Nov 2010The early steps in the biogenesis of secreted and membrane proteins occur in the lumen of the endoplasmic reticulum (ER), where resident proteins that make up the ER... (Review)
Review
The early steps in the biogenesis of secreted and membrane proteins occur in the lumen of the endoplasmic reticulum (ER), where resident proteins that make up the ER machinery assist in their folding, maturation, and complex assembly. Variation in the load of ER client proteins and in the function of the organelle's aforementioned machinery for coping with that load can lead to an imbalance between the two that is referred to as ER stress. This triggers a cellular response, mediated by highly conserved signaling pathways that collectively restore equilibrium to the protein-folding environment in the organelle by increasing the expression of genes that enhance nearly all aspects of ER function, and by transiently repressing the biosynthesis of new client proteins. Evidence accrued over the past 10 years suggests that ER stress and response to it influence the fate of mutant proteins that fold inefficiently, impact on the functionality of cells and tissues that cope with unusual loads of ER client proteins, and intersect with signaling pathways that influence inflammation and cancer biology. Here, we review some of the basic workings of unfolded protein response and relate them to processes that are of potential relevance to pulmonary disease.
Topics: Endoplasmic Reticulum; Humans; Lung Diseases; Protein Folding; Protein Unfolding; Signal Transduction
PubMed: 21030513
DOI: 10.1513/pats.201001-015AW -
Folding & Design 1997A change in the perception of the protein folding problem has taken place recently. The nature of the change is outlined and the reasons for it are presented. An... (Review)
Review
A change in the perception of the protein folding problem has taken place recently. The nature of the change is outlined and the reasons for it are presented. An essential element is the recognition that a bias toward the native state over much of the effective energy surface may govern the folding process. This has replaced the random search paradigm of Levinthal and suggests that there are many ways of reaching the native state in a reasonable time so that a specific pathway does not have to be postulated. The change in perception is due primarily to the application of statistical mechanical models and lattice simulations to protein folding. Examples of lattice model results on protein folding are presented. It is pointed out that the new optimism about the protein folding problem must be complemented by more detailed studies to determine the structural and energetic factors that introduce the biases which make possible the folding of real proteins.
Topics: Models, Chemical; Protein Folding
PubMed: 9269572
DOI: 10.1016/s1359-0278(97)00067-9 -
Journal of the American Chemical Society May 2007Recent experimental work on fast protein folding brings about an intriguing paradox. Microsecond-folding proteins are supposed to fold near or at the folding speed limit...
Recent experimental work on fast protein folding brings about an intriguing paradox. Microsecond-folding proteins are supposed to fold near or at the folding speed limit (downhill folding), but yet their folding behavior seems to comply with classical two-state analyses, which imply the crossing of high free energy barriers. However, close inspection of chemical and thermal denaturation kinetic experiments in fast-folding proteins reveals systematic deviations from two-state behavior. Using a simple one-dimensional free energy surface approach we find that such deviations are indeed diagnostic of marginal folding barriers. Furthermore, the quantitative analysis of available fast-kinetic data indicates that many microsecond-folding proteins fold downhill in native conditions. All of these proteins are then promising candidates for an atom-by-atom analysis of protein folding using nuclear magnetic resonance.1 We also find that the diffusion coefficient for protein folding is strongly temperature dependent, corresponding to an activation energy of approximately 1 kJ.mol-1 per protein residue. As a consequence, the folding speed limit at room temperature is about an order of magnitude slower than the approximately 1 micros estimates from high-temperature T-jump experiments. Our analysis is quantitatively consistent with the available thermodynamic and kinetic data on slow two-state folding proteins and provides a straightforward explanation for the apparent fast-folding paradox.
Topics: Algorithms; Computer Simulation; Energy Transfer; Entropy; Kinetics; Models, Chemical; Protein Denaturation; Protein Folding; Surface Properties; Temperature; Thermodynamics
PubMed: 17419630
DOI: 10.1021/ja0689740 -
IUBMB Life Jun 2009Protein folding is an important and challenging problem in molecular biology. During the last two decades, molecular dynamics (MD) simulation has proved to be a... (Review)
Review
Protein folding is an important and challenging problem in molecular biology. During the last two decades, molecular dynamics (MD) simulation has proved to be a paramount tool and was widely used to study protein structures, folding kinetics and thermodynamics, and structure-stability-function relationship. It was also used to help engineering and designing new proteins, and to answer even more general questions such as the minimal number of amino acid or the evolution principle of protein families. Nowadays, the MD simulation is still undergoing rapid developments. The first trend is to toward developing new coarse-grained models and studying larger and more complex molecular systems such as protein-protein complex and their assembling process, amyloid related aggregations, and structure and motion of chaperons, motors, channels and virus capsides; the second trend is toward building high resolution models and explore more detailed and accurate pictures of protein folding and the associated processes, such as the coordination bond or disulfide bond involved folding, the polarization, charge transfer and protonate/deprotonate process involved in metal coupled folding, and the ion permeation and its coupling with the kinetics of channels. On these new territories, MD simulations have given many promising results and will continue to offer exciting views. Here, we review several new subjects investigated by using MD simulations as well as the corresponding developments of appropriate protein models. These include but are not limited to the attempt to go beyond the topology based Gō-like model and characterize the energetic factors in protein structures and dynamics, the study of the thermodynamics and kinetics of disulfide bond involved protein folding, the modeling of the interactions between chaperonin and the encapsulated protein and the protein folding under this circumstance, the effort to clarify the important yet still elusive folding mechanism of protein BBL, the development of discrete MD and its application in studying the alpha-beta conformational conversion and oligomer assembling process, and the modeling of metal ion involved protein folding.
Topics: Chaperonins; Computer Simulation; Disulfides; Hydrogen Bonding; Kinetics; Metals; Models, Chemical; Models, Molecular; Peptides; Protein Conformation; Protein Folding; Protein Multimerization; Ribosomal Protein S6; Thermodynamics; Zinc Fingers
PubMed: 19472192
DOI: 10.1002/iub.223 -
International Journal of Molecular... Mar 2009Exploring the landscape of large scale conformational changes such as protein folding at atomistic detail poses a considerable computational challenge. Coarse-grained... (Review)
Review
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.
Topics: Kinetics; Models, Molecular; Protein Folding; Proteins
PubMed: 19399227
DOI: 10.3390/ijms10030889