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Protein folds and folding
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From eons to seconds, proteins exploit the same forces

From eons to seconds, proteins exploit the same forces | Protein folds and folding | Scoop.it
(Phys.org) —Nature's artistic and engineering skills are evident in proteins, life's robust molecular machines. Scientists at Rice University have now employed their unique theories to show how the interplay between evolution and physics developed these skills.

Via Arjen ten Have
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Arjen ten Have's curator insight, August 14, 3:29 PM

How proteins evolve depends on many aspects but according to this the energy landscape is extremely important. Nice combination of physics and evolution, at the heart of where biocomputation should be!

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Spin-dependent electron transport in protein-like single-helical molecules

Ai-Min Guo and Qing-Feng Sun

 

Significance

The control of electron spin transport in molecular systems has been receiving lots of attention among different scientific communities because of possible applications in spintronics and understanding of the spin effects in biological systems. Recent experiments have demonstrated that α-helical protein acts as an efficient spin filter and the chiral-induced spin selectivity may be a general phenomenon. However, no spin selectivity was measured in single-stranded DNA above the experimental noise. In the present study, we propose a physical model to rationalize the above phenomena, and provide an unambiguous physical mechanism for spin-selective phenomenon observed in α-helical protein and for the contradictory behaviors between protein and single-stranded DNA. These results may facilitate engineering of chiral-based spintronic devices.

 

Abstract

We report on a theoretical study of spin-dependent electron transport through single-helical molecules connected by two nonmagnetic electrodes, and explain the experiment of significant spin-selective phenomenon observed in α-helical protein and the contradictory results between the protein and single-stranded DNA. Our results reveal that the α-helical protein is an efficient spin filter and the spin polarization is robust against the disorder. These results are in excellent agreement with recent experiments [Mishra D, et al. (2013) Proc Natl Acad Sci USA 110(37):14872–14876; Göhler B, et al. (2011) Science 331(6019):894–897] and may facilitate engineering of chiral-based spintronic devices.

 
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General Mechanism of Two-State Protein Folding Kinetics - Journal of the American Chemical Society (ACS Publications)

Geoffrey C. Rollins and Ken A. DillJournal of the American Chemical Society 2014 136 (32), 11420-11427

 

 

We describe here a general model of the kinetic mechanism of protein folding. In the Foldon Funnel Model, proteins fold in units of secondary structures, which form sequentially along the folding pathway, stabilized by tertiary interactions. The model predicts that the free energy landscape has a volcano shape, rather than a simple funnel, that folding is two-state (single-exponential) when secondary structures are intrinsically unstable, and that each structure along the folding path is a transition state for the previous structure. It shows how sequential pathways are consistent with multiple stochastic routes on funnel landscapes, and it gives good agreement with the 9 order of magnitude dependence of folding rates on protein size for a set of 93 proteins, at the same time it is consistent with the near independence of folding equilibrium constant on size. This model gives estimates of folding rates of proteomes, leading to a median folding time in Escherichia coli of about 5 s.

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Codon-by-Codon Modulation of Translational Speed and Accuracy Via mRNA Folding

Codon-by-Codon Modulation of Translational Speed and Accuracy Via mRNA Folding | Protein folds and folding | Scoop.it

Authors : Jian-Rong Yang, Xiaoshu Chen, Jianzhi Zhang


Protein synthesis by ribosomal translation is a vital cellular process, but our understanding of its regulation has been poor. Because the number of ribosomes in the cell is limited, rapid growth relies on fast translational elongation. The accuracy of translation must also be maintained, and in an ideal scenario, both speed and accuracy should be maximized to sustain rapid and productive growth. However, existing data suggest a tradeoff between speed and accuracy, making it impossible to simultaneously maximize both. A potential solution is slowing the elongation at functionally or structurally important sites to ensure their translational accuracies, while sacrificing accuracy for speed at other sites. Here, we show that budding yeast and mouse embryonic stem cells indeed use this strategy. We discover that a codon-by-codon adaptive modulation of translational elongation is accomplished by mRNA secondary structures, which serve as brakes to control the elongation speed and hence translational fidelity. Our findings explain why highly expressed genes tend to have strong mRNA folding, slow translational elongation, and conserved protein sequences. The exquisite translational modulation reflects the power of natural selection in mitigating efficiency–accuracy conflicts, and our study offers a general framework for analyzing similar conflicts, which are widespread in biology.

Bernard Offmann's insight:

Simply brillant analysis, fully computational but yet such important insights in protein synthesis #compbio #bioinformatics #plosbiology

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Fast protein folding kinetics

Fast protein folding kinetics | Protein folds and folding | Scoop.it
Fast-folding proteins have been a major focus of computational and experimental study because they are accessible to both techniques: they are small and fast enough to be reasonably simulated with current computational power, but have dynamics slow enough to be observed with specially developed experimental techniques. This coupled study of fast-folding proteins has provided insight into the mechanisms, which allow some proteins to find their native conformation well <1 ms and has uncovered examples of theoretically predicted phenomena such as downhill folding. The study of fast folders also informs our understanding of even folding processes: fast folders are small; relatively simple protein domains and the principles that govern their folding also govern the folding of more complex systems. This review summarizes the major theoretical and experimental techniques used to study fast-folding proteins and provides an overview of the major findings of fast-folding research. Finally, we examine the themes that have emerged from studying fast folders and briefly summarize their application to protein folding in general, as well as some work that is left to do.
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How the folding rates of two- and multi-state proteins depend on the amino acid properties - Huang - Proteins: Structure, Function, and Bioinformatics - Wiley Online Library

Jitao T. Huang, Wei Huang, Shanran R. Huang and Xin Li Abstract Proteins fold by either two-state or multi-state kinetic mechanism. We observe that amino acids play different roles in different mechanism. Many residues that are easy to form regular secondary structures (α helices, β sheets and turns) can promote the two-state folding reactions of small proteins. Most of hydrophilic residues can speed up the multi-state folding reactions of large proteins. Folding rates of large proteins are equally responsive to the flexibility of partial amino acids. Other properties of amino acids (including volume, polarity, accessible surface, exposure degree, isoelectric point, and phase transfer energy) have contributed little to folding kinetics of the proteins. Cysteine is a special residue, it triggers two-state folding reaction and but inhibits multi-state folding reaction. These findings not only provide a new insight into protein structure prediction, but also could be used to direct the point mutations that can change folding rate.
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Protein fold recognition by alignment of amino acid residues using kernelized dynamic time warping

Authors: Lyons J, Sharma A, Dehzangi A, Paliwal KK

 

Abstract

 

In protein fold recognition, a protein is classified into one of its folds. The recognition of a protein fold can be done by employing feature extraction methods to extract relevant information from protein sequences and then by using a classifier to accurately recognize novel protein sequences. In the past, several feature extraction methods have been developed but with limited recognition accuracy only. Protein sequences of varying lengths share the same fold and therefore they are very similar (in a fold) if aligned properly. To this, we develop an amino acid alignment method to extract important features from protein sequences by computing dissimilarity distances between proteins. This is done by measuring distance between two respective position specific scoring matrices of protein sequences which is used in a support vector machine framework. We demonstrated the effectiveness of the proposed method on several benchmark datasets. The method shows significant improvement in the fold recognition performance which is in the range of 4.3-7.6% compared to several other existing feature extraction methods.

 

J Theor Biol. 2014 Mar 31

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Protein folding, structure prediction and design

Authors: Baker D

Abstract
I describe how experimental studies of protein folding have led to advances in protein structure prediction and protein design. I describe the finding that protein sequences are not optimized for rapid folding, the contact order-protein folding rate correlation, the incorporation of experimental insights into protein folding into the Rosetta protein structure production methodology and the use of this methodology to determine structures from sparse experimental data. I then describe the inverse problem (protein design) and give an overview of recent work on designing proteins with new structures and functions. I also describe the contributions of the general public to these efforts through the Rosetta@home distributed computing project and the FoldIt interactive protein folding and design game.

 

Biochem Soc Trans. 2014 Apr 1;42(2):225-9

Bernard Offmann's insight:

Centenary Award and Sir Frederick Gowland Hopkins Memorial Lecture : nice review from David Baker on protein design… 

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Fast protein folding kinetics

Fast protein folding kinetics | Protein folds and folding | Scoop.it

Gelman H, Gruebele M.

 

ABSTRACT

 

Fast-folding proteins have been a major focus of computational and experimental study because they are accessible to both techniques: they are small and fast enough to be reasonably simulated with current computational power, but have dynamics slow enough to be observed with specially developed experimental techniques. This coupled study of fast-folding proteins has provided insight into the mechanisms, which allow some proteins to find their native conformation well <1 ms and has uncovered examples of theoretically predicted phenomena such as downhill folding. The study of fast folders also informs our understanding of even folding processes: fast folders are small; relatively simple protein domains and the principles that govern their folding also govern the folding of more complex systems. This review summarizes the major theoretical and experimental techniques used to study fast-folding proteins and provides an overview of the major findings of fast-folding research. Finally, we examine the themes that have emerged from studying fast folders and briefly summarize their application to protein folding in general, as well as some work that is left to do.

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Glycoprotein folding and quality-control mechanisms in protein-folding diseases

Glycoprotein folding and quality-control mechanisms in protein-folding diseases | Protein folds and folding | Scoop.it

Ferris SP, Kodali VK, Kaufman RJ.

 

ABSTRACT 


Biosynthesis of proteins - from translation to folding to export - encompasses a complex set of events that are exquisitely regulated and scrutinized to ensure the functional quality of the end products. Cells have evolved to capitalize on multiple post-translational modifications in addition to primary structure to indicate the folding status of nascent polypeptides to the chaperones and other proteins that assist in their folding and export. These modifications can also, in the case of irreversibly misfolded candidates, signal the need for dislocation and degradation. The current Review focuses on the glycoprotein quality-control (GQC) system that utilizes protein N-glycosylation and N-glycan trimming to direct nascent glycopolypeptides through the folding, export and dislocation pathways in the endoplasmic reticulum (ER). A diverse set of pathological conditions rooted in defective as well as over-vigilant ER quality-control systems have been identified, underlining its importance in human health and disease. We describe the GQC pathways and highlight disease and animal models that have been instrumental in clarifying our current understanding of these processes.

Bernard Offmann's insight:

Very original review !

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Bernard Offmann's curator insight, March 15, 5:14 PM

Very original review !!

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Expanding Anfinsen’s Principle: Contributions of Synonymous Codon Selection to Rational Protein Design

Expanding Anfinsen’s Principle: Contributions of Synonymous Codon Selection to Rational Protein Design | Protein folds and folding | Scoop.it
Abstract

Anfinsen’s principle asserts that all information required to specify the structure of a protein is encoded in its amino acid sequence. However, during protein synthesis by the ribosome, the N-terminus of the nascent chain can begin to fold before the C-terminus is available. We tested whether this cotranslational folding can alter the folded structure of an encoded protein in vivo, versus the structure formed when refolded in vitro. We designed a fluorescent protein consisting of three half-domains, where the N- and C-terminal half-domains compete with each other to interact with the central half-domain. The outcome of this competition determines the fluorescence properties of the resulting folded structure. Upon refolding after chemical denaturation, this protein produced equimolar amounts of the N- and C-terminal folded structures, respectively. In contrast, translation in Escherichia coli resulted in a 2-fold enhancement in the formation of the N-terminal folded structure. Rare synonymous codon substitutions at the 5′ end of the C-terminal half-domain further increased selection for the N-terminal folded structure. These results demonstrate that the rate at which a nascent protein emerges from the ribosome can specify the folded structure of a protein.

Bernard Offmann's insight:

This very nice paper was quoted by Catherine Goodman in Nature Chemical Biology (Protein Folding; The Inside Scoop).(http://www.nature.com/nchembio/journal/v10/n3/full/nchembio.1465.html)

It shows elegantly how codon usage can affect folding.

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Protein Folding, Interrupted

Globular proteins start their lives as linear chains of amino acids coming off the ribosome. Proteins must then fold into specific three-dimensional structures to be functional. In 1957, the first such structure, of myoglobin, was determined at atomic resolution. Fifty-six years and 90,000-plus protein structures later, we have a very good idea of the necessary requirements for a stable, specific structure. Key to these requirements is the formation of a well-packed, largely anhydrous core. Yet, on page 795 of this issue, Sun et al. report an antifreeze protein with a core mostly consisting of water.

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Assessing the accuracy of physical models used in protein-folding simulations: quantitative evidence from long molecular dynamics simulations

Advances in computer hardware, software and algorithms have now made it possible to run atomistically detailed, physics-based molecular dynamics simulations of sufficient length to observe multiple instances of protein folding and unfolding within a single equilibrium trajectory. Although such studies have already begun to provide new insights into the process of protein folding, realizing the full potential of this approach will depend not only on simulation speed, but on the accuracy of the physical models (‘force fields’) on which such simulations are based. While experimental data are not available for comparison with all of the salient characteristics observable in long protein-folding simulations, we examine here the extent to which current force fields reproduce (and fail to reproduce) certain relevant properties for which such comparisons are possible.

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Nice review from David Shaw from Columbia University

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Global view of the protein universe

Global view of the protein universe | Protein folds and folding | Scoop.it

Sergey Nepomnyachiy, Nir Ben-Tal, and Rachel Kolodny

 

Abstract

To explore protein space from a global perspective, we consider 9,710 SCOP (Structural Classification of Proteins) domains with up to 70% sequence identity and present all similarities among them as networks: In the “domain network,” nodes represent domains, and edges connect domains that share “motifs,” i.e., significantly sized segments of similar sequence and structure. We explore the dependence of the network on the thresholds that define the evolutionary relatedness of the domains. At excessively strict thresholds the network falls apart completely; for very lax thresholds, there are network paths between virtually all domains. Interestingly, at intermediate thresholds the network constitutes two regions that can be described as “continuous” versus “discrete.” The continuous region comprises a large connected component, dominated by domains with alternating alpha and beta elements, and the discrete region includes the rest of the domains in isolated islands, each generally corresponding to a fold. We also construct the “motif network,” in which nodes represent recurring motifs, and edges connect motifs that appear in the same domain. This network also features a large and highly connected component of motifs that originate from domains with alternating alpha/beta elements (and some all-alpha domains), and smaller isolated islands. Indeed, the motif network suggests that nature reuses such motifs extensively. The networks suggest evolutionary paths between domains and give hints about protein evolution and the underlying biophysics. They provide natural means of organizing protein space, and could be useful for the development of strategies for protein search and design.

 

Significance

To globally explore protein space, we use networks to present similarities among a representative set of all known domains. In the “domain network” edges connect domains that share “motifs,” i.e., significantly sized segments of similar sequence and structure, and in the “motif network” edges connect recurring motifs that appear in the same domain. The networks offer a way to organize protein space, and examine how the organization changes upon changing the definition of “evolutionary relatedness” among domains. For example, we use them to highlight and characterize the uniqueness of a class of domains called alpha/beta, in which the alpha and beta elements alternate. The networks can also suggest evolutionary paths between domains, and be used for protein search and design.

 

Bernard Offmann's insight:

Mapping of the protein fold space, revisited by Rachel Kolodny in PNAS.

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Synthesis and folding of a mirror-image enzyme reveals ambidextrous chaperone activity

Matthew T. Weinstock, Michael T. Jacobsen, and Michael S. Kay

 

Abstract

 

Mirror-image proteins (composed of D-amino acids) are promising therapeutic agents and drug discovery tools, but as synthesis of larger D-proteins becomes feasible, a major anticipated challenge is the folding of these proteins into their active conformations. In vivo, many large and/or complex proteins require chaperones like GroEL/ES to prevent misfolding and produce functional protein. The ability of chaperones to fold D-proteins is unknown. Here we examine the ability of GroEL/ES to fold a synthetic D-protein. We report the total chemical synthesis of a 312-residue GroEL/ES-dependent protein, DapA, in both L- and D-chiralities, the longest fully synthetic proteins yet reported. Impressively, GroEL/ES folds both L- and D-DapA. This work extends the limits of chemical protein synthesis, reveals ambidextrous GroEL/ES folding activity, and provides a valuable tool to fold D-proteins for drug development and mirror-image synthetic biology applications.

 

Significance

 

This paper addresses a fundamental question: Can natural chaperones fold mirror-image proteins? Mirror-image proteins (composed of D-amino acids) are only accessible by chemical synthesis, but are protease resistant and therefore have tremendous potential as long-lived drugs. Many large/complex proteins depend on chaperones for efficient folding. Here we describe the total chemical synthesis of a 312-residue chaperone-dependent protein (DapA) in natural (L-) and mirror-image (D-) forms, the longest fully synthetic proteins yet reported. Using these proteins we show that the natural bacterial GroEL/ES chaperone is “ambidextrous”—i.e., it can fold both natural and mirror-image proteins via nonspecific hydrophobic interactions. Our study also provides proof-of-concept for the use of natural GroEL/ES to fold D-proteins for mirror-image drug discovery and synthetic biology applications.

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Predictive energy landscapes for folding α-helical transmembrane proteins

Authors : Bobby L. Kim, Nicholas P. Schafer, and Peter G. Wolynes

Abstract

We explore the hypothesis that the folding landscapes of membrane proteins are funneled once the proteins’ topology within the membrane is established. We extend a protein folding model, the associative memory, water-mediated, structure, and energy model (AWSEM) by adding an implicit membrane potential and reoptimizing the force field to account for the differing nature of the interactions that stabilize proteins within lipid membranes, yielding a model that we call AWSEM-membrane. Once the protein topology is set in the membrane, hydrophobic attractions play a lesser role in finding the native structure, whereas polar–polar attractions are more important than for globular proteins. We examine both the quality of predictions made with AWSEM-membrane when accurate knowledge of the topology and secondary structure is available and the quality of predictions made without such knowledge, instead using bioinformatically inferred topology and secondary structure based on sequence alone. When no major errors are made by the bioinformatic methods used to assign the topology of the transmembrane helices, these two types of structure predictions yield roughly equivalent quality structures. Although the predictive energy landscape is transferable and not structure based, within the correct topological sector we find the landscape is indeed very funneled: Thermodynamic landscape analysis indicates that both the total potential energy and the contact energy decrease as native contacts are formed. Nevertheless the near symmetry of different helical packings with respect to native contact formation can result in multiple packings with nearly equal thermodynamic occupancy, especially at temperatures just below collapse.

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Understanding the Influence of Codon Translation Rates on Cotranslational Protein Folding

Understanding the Influence of Codon Translation Rates on Cotranslational Protein Folding | Protein folds and folding | Scoop.it

Authors: O'Brien EP, Ciryam P, Vendruscolo M, Dobson CM

 

Conspectus

 

Protein domains can fold into stable tertiary structures while they are synthesized by the ribosome in a process known as cotranslational folding. If a protein does not fold cotranslationally, however, it has the opportunity to do so post-translationally, that is, after the nascent chain has been fully synthesized and released from the ribosome. The rate at which a ribosome adds an amino acid encoded by a particular codon to the elongating nascent chain can vary significantly and is called the codon translation rate. Recent experiments have illustrated the profound impact that codon translation rates can have on the cotranslational folding process and the acquisition of function by nascent proteins. Synonymous codon mutations in an mRNA molecule change the chemical identity of a codon and its translation rate without changing the sequence of the synthesized protein. This change in codon translation rate can, however, cause a nascent protein to malfunction as a result of cotranslational misfolding. In some situations, such dysfunction can have profound implications; for example, it can alter the substrate specificity of an ABC transporter protein, resulting in patients who are nonresponsive to chemotherapy treatment. Thus, codon translation rates are crucial in coordinating protein folding in a cellular environment and can affect downstream cellular processes that depend on the proper functioning of newly synthesized proteins. As the importance of codon translation rates makes clear, a necessary aspect of fully understanding cotranslational folding lies in considering the kinetics of the process in addition to its thermodynamics.

 

In this Account, we examine the contributions that have been made to elucidating the mechanisms of cotranslational folding by using the theoretical and computational tools of chemical kinetics, molecular simulations, and systems biology. These efforts have extended our ability to understand, model, and predict the influence of codon translation rates on cotranslational protein folding and misfolding. The application of such approaches to this important problem is creating a framework for making quantitative predictions of the impact of synonymous codon substitutions on cotranslational folding that has led to a novel hypothesis regarding the role of fast-translating codons in coordinating cotranslational folding. In addition, it is providing new insights into proteome-wide cotranslational folding behavior and making it possible to identify potential molecular mechanisms by which molecular chaperones can influence such behavior during protein synthesis. As we discuss in this Account, bringing together these theoretical developments with experimental approaches is increasingly helping answer fundamental questions about the nature of nascent protein folding on the ribosome.

Bernard Offmann's insight:

Everything is said in these two phrases : 

« Synonymous codon mutations in an mRNA molecule change the chemical identity of a codon and its translation rate without changing the sequence of the synthesized protein. This change in codon translation rate can, however, cause a nascent protein to malfunction as a result of cotranslational misfolding. »

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Protein Folding Thermodynamics: A New Computational Approach

Protein Folding Thermodynamics: A New Computational Approach | Protein folds and folding | Scoop.it
Abstract

Folding free energy is the fundamental thermodynamic quantity characterizing the stability of a protein. Yet, its accurate determination based on computational techniques remains a challenge in physical chemistry. A straightforward brute-force approach would be to conduct molecular dynamics simulations and to estimate the folding free energy from the equilibrium population ratio of the unfolded and folded states. However, this approach is not sensible at physiological conditions where the equilibrium population ratio is vanishingly small: it is extremely difficult to reliably obtain such a small equilibrium population ratio due to the low rate of folding/unfolding transitions. It is therefore desirable to have a computational method that solely relies on simulations independently carried out for the folded and unfolded states. Here, we present such an approach that focuses on the probability distributions of the effective energy (solvent-averaged protein potential energy) in the folded and unfolded states. We construct these probability distributions for the protein villin headpiece subdomain by performing extensive molecular dynamics simulations and carrying out solvation free energy calculations. We find that the probability distributions of the effective energy are well-described by the Gaussian distributions for both the folded and unfolded states due to the central limit theorem, which enables us to calculate the protein folding free energy in terms of the mean and the width of the distributions. The computed protein folding free energy (-2.5 kcal/mol) is in accord with the experimental result (ranging from -2.3 to -3.2 kcal/mol depending on the experimental methods).

  
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Tracing Primordial Protein Evolution through Structurally Guided Stepwise Segment Elongation

Authors: Watanabe H, Yamasaki K, Honda S

 

Abstract

 

The understanding of how primordial proteins emerged has been a fundamental and longstanding issue in biology and biochemistry. For a better understanding of primordial protein evolution, we synthesized an artificial protein on the basis of an evolutionary hypothesis, segment-based elongation starting from an autonomously foldable short peptide. A 10-residue protein, chignolin, the smallest foldable polypeptide ever reported, was used as a structural support to facilitate higher structural organization and gain-of-function in the development of an artificial protein. Repetitive cycles of segment elongation and subsequent phage display selection successfully produced a 25-residue protein, termed AF.2A1, with nanomolar affinity against the Fc region of immunoglobulin G. AF.2A1 shows exquisite molecular recognition ability such that it can distinguish conformational differences of the same molecule. The structure determined by NMR measurements demonstrated that AF.2A1 forms a globular protein-like conformation with the chignolin-derived β-hairpin and a tryptophan-mediated hydrophobic core. Using sequence analysis and a mutation study, we discovered that the structural organization and gain-of-function emerged from the vicinity of the chignolin segment, revealing that the structural support served as the core in both structural and functional development. Here, we propose an evolutionary model for primordial proteins in which a foldable segment serves as the evolving core to facilitate structural and functional evolution. This study provides insights into primordial protein evolution and also presents a novel methodology for designing small sized proteins useful for industrial and pharmaceutical applications.

 

J Biol Chem. 2014 Feb 7;289(6):3394-404

 
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Overview of the Regulation of Disulfide Bond Formation in Peptide and Protein Folding

Overview of the Regulation of Disulfide Bond Formation in Peptide and Protein Folding | Protein folds and folding | Scoop.it

Authors: Hidaka Y

 

Abstract

 

Disulfide bonds play a critical role in the maintenance of the native conformation of proteins under thermodynamic control. In general, disulfide bond formation is associated with protein folding, and this restricts the formation of folding intermediates such as misbridged disulfide isomers or kinetically trapped conformations, which provide important information related to how proteins fold into their native conformation. Therefore, numerous studies have focused on the structural analysis of folding intermediates in vitro. However, isolating or trapping folding intermediates, as well as the entire proteins, including mutant proteins, is not an easy task. Several chemical methods have recently been developed for examining peptide and protein folding and for producing, e.g., intact, post-translationally modified, or kinetically trapped proteins, or proteins with misbridged disulfide bonds. This overview introduces chemical methods for regulating the formation of disulfide bonds of peptides and proteins in the context of the thermodynamic and kinetic control of peptide and protein folding.

 

Curr. Protoc. Protein Sci. 76:28.6.1-28.6.6.

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Protein Folding Absent Selection

Protein Folding Absent Selection | Protein folds and folding | Scoop.it

Authors: Labean TH, Butt TR, Kauffman SA, Schultes EA

 

Abstract

 

Biological proteins are known to fold into specific 3D conformations. However, the fundamental question has remained: Do they fold because they are biological, and evolution has selected sequences which fold? Or is folding a common trait, widespread throughout sequence space? To address this question arbitrary, unevolved, random-sequence proteins were examined for structural features found in folded, biological proteins. Libraries of long (71 residue), random-sequence polypeptides, with ensemble amino acid composition near the mean for natural globular proteins, were expressed as cleavable fusions with ubiquitin. The structural properties of both the purified pools and individual isolates were then probed using circular dichroism, fluorescence emission, and fluorescence quenching techniques. Despite this necessarily sparse “sampling” of sequence space, structural properties that define globular biological proteins, namely collapsed conformations, secondary structure, and cooperative unfolding, were found to be prevalent among unevolved sequences. Thus, for polypeptides the size of small proteins, natural selection is not necessary to account for the compact and cooperative folded states observed in nature.

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Random sequences can fold… interesting implications for protein structure analysis and molecular modeling...
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Protein@Home solved conformational transformation : Activation pathway of Src kinase reveals intermediate states as targets for drug design

Protein@Home solved conformational transformation : Activation pathway of Src kinase reveals intermediate states as targets for drug design | Protein folds and folding | Scoop.it

ABSTRACT 

 

Unregulated activation of Src kinases leads to aberrant signalling, uncontrolled growth and differentiation of cancerous cells. Reaching a complete mechanistic understanding of large-scale conformational transformations underlying the activation of kinases could greatly help in the development of therapeutic drugs for the treatment of these pathologies. In principle, the nature of conformational transition could be modelled in silico via atomistic molecular dynamics simulations, although this is very challenging because of the long activation timescales. Here we employ a computational paradigm that couples transition pathway techniques and Markov state model-based massively distributed simulations for mapping the conformational landscape of c-src tyrosine kinase. The computations provide the thermodynamics and kinetics of kinase activation for the first time, and help identify key structural intermediates. Furthermore, the presence of a novel allosteric site in an intermediate state of c-src that could be potentially used for drug design is predicted.



Bernard Offmann's insight:

Another outstanding paper from Standford's genius Vijay Pande : Folding@Home was used to solve the mechanism behind Src activation.

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Towards more accurate prediction of protein folding rates: a review of the existing web-based bioinformatics approaches

Towards more accurate prediction of protein folding rates: a review of the existing web-based bioinformatics approaches | Protein folds and folding | Scoop.it

Chang CC, Tey BT, Song J, Ramanan RN.

 

ABSTRACT

 

The understanding of protein-folding mechanisms is often considered to be an important goal that will enable structural biologists to discover the mysterious relationship between the sequence, structure and function of proteins. The ability to predict protein-folding rates without the need for actual experimental work will assist the research work of structural biologists in many ways. Many bioinformatics tools have emerged in the past decade, and each has showcased different features. In this article, we review and compare eight web-based prediction tools that are currently available and that predominantly predict the protein-folding rate. The prediction performance, usability and utility, together with the prediction tool development and validation methodologies for these tools, are critically reviewed. This article is presented in a comprehensible manner to assist readers in the process of selecting the most appropriate bioinformatics tools to meet their needs.

Bernard Offmann's insight:

People working on protein foldings will find this review very useful. Highly recommended ! Another very good review in Briefings in Bioinformatics !

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Balancing oxidative protein folding: The influences of reducing pathways on disulfide bond formation

Abstract

Oxidative protein folding is confined to few compartments, including the endoplasmic reticulum, the mitochondrial intermembrane space and the bacterial periplasm. Conversely, in compartments in which proteins are translated such as the cytosol, the mitochondrial matrix and the chloroplast stroma proteins are kept reduced by the thioredoxin and glutaredoxin systems that functionally overlap. The highly reducing NADPH pool thereby serves as electron donor that enables glutathione reductase and thioredoxin reductase to keep glutathione pools and thioredoxins in their reduced redox state, respectively. Notably, also compartments containing oxidizing machineries are linked to these reducing pathways. Reducing pathways aid in proofreading of disulfide bond formation by isomerization or they provide reducing equivalents for the reduction of disulfides prior to degradation. In addition, they contribute to the thiol-dependent regulation of protein activities, and they help to counteract oxidative stress. The existence of oxidizing and reducing pathways in the same compartment poses a potential problem as the cell has to avoid futile cycles of oxidation and subsequent reduction reactions. Thus, compartments that contain oxidizing machineries have developed sophisticated ways to spatiotemporally balance and regulate oxidation and reduction. In this review, we discuss oxidizing and reducing pathways in the endoplasmic reticulum, the periplasm and the mitochondrial intermembrane space and highlight the role of glutathione especially in the endoplasmic reticulum and the intermembrane space. This article is part of a Special Issue entitled: Thiol-Based Redox Processes.

Bernard Offmann's insight:

Interesting review on this very important question of the role of disulphide bonds formation in protein folding process...

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Physicochemical bases for protein folding, dynamics, and protein-ligand binding

Physicochemical bases for protein folding, dynamics, and protein-ligand binding | Protein folds and folding | Scoop.it
Abstract Proteins are essential parts of living organisms and participate in virtually every process within cells. As the genomic sequences for increasing number of organisms are completed, research into how proteins can perform such a variety of functions has become much more intensive because the value of the genomic sequences relies on the accuracy of understanding the encoded gene products. Although the static three-dimensional structures of many proteins are known, the functions of proteins are ultimately governed by their dynamic characteristics, including the folding process, conformational fluctuations, molecular motions, and protein-ligand interactions. In this review, the physicochemical principles underlying these dynamic processes are discussed in depth based on the free energy landscape (FEL) theory. Questions of why and how proteins fold into their native conformational states, why proteins are inherently dynamic, and how their dynamic personalities govern protein functions are answered. This paper will contribute to the understanding of structure-function relationship of proteins in the post-genome era of life science research.
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