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Encyclopedia > Protein folding
Protein before and after folding.

Protein folding is the physical process by which a polypeptide folds into its characteristic three-dimensional structure.[1] Image File history File links Size of this preview: 800 × 354 pixelsFull resolution (994 × 440 pixels, file size: 70 KB, MIME type: image/png) Illustration of the process of protein folding. ... Image File history File links Size of this preview: 800 × 354 pixelsFull resolution (994 × 440 pixels, file size: 70 KB, MIME type: image/png) Illustration of the process of protein folding. ... Peptides are the family of molecules formed from the linking, in a defined order, of various amino acids. ... Proteins are an important class of biological macromolecules present in all biological organisms, made up of such elements as carbon, hydrogen, nitrogen, oxygen, and sulfur. ...


Each protein begins as a polypeptide, translated from a sequence of mRNA as a linear chain of amino acids. This polypeptide lacks any developed three-dimensional structure (the left hand side of the neighboring figure). However each amino acid in the chain can be thought of having certain 'gross' chemical features. These may be hydrophobic, hydrophilic, or electrically charged, for example. These interact with each other and their surroundings in the cell to produce a well-defined, three dimensional shape, the folded protein (the right hand side of the figure), known as the native state. The resulting three-dimensional structure is determined by the sequence of the amino acids.[2] The mechanism of protein folding is not completely understood. Peptides are the family of molecules formed from the linking, in a defined order, of various amino acids. ... The interaction of mRNA in a eukaryote cell. ... In chemistry, an amino acid is any molecule that contains both amino and carboxylic acid functional groups. ... In chemistry, hydrophobic or lipophilic species, or hydrophobes, tend to be electrically neutral and nonpolar, and thus prefer other neutral and nonpolar solvents or molecular environments. ... The adjective hydrophilic describes something that likes water (from Greek hydros = water; philos = friend). ... In biochemistry, the native state of a protein is its operative or functional form. ...


Experimentally determining the three dimensional structure of a protein is often very difficult and expensive. However the sequence of that protein is often known. Therefore scientists have tried to use different biophysical techniques to manually fold a protein. That is, to predict the structure of the complete protein from the sequence of the protein. Biophysics (also biological physics) is an interdisciplinary science that applies the theories and methods of physics, to questions of biology. ...


For many proteins the correct three dimensional structure is essential to function.[3] Failure to fold into the intended shape usually produces inactive proteins with different properties (details found under prion). Several neurodegenerative and other diseases are believed to result from the accumulation of misfolded (incorrectly folded) proteins.[4] A prion (IPA: [1] ) — short for proteinaceous infectious particle (-on by analogy to virion) — is a type of infectious agent composed only of protein. ... Neurodegenerative disease is a condition which affects brain function. ... A disease is any abnormal condition of the body or mind that causes discomfort, dysfunction, or distress to the person affected or those in contact with the person. ...

Contents

Known facts about the process

The relationship between folding and amino acid sequence

The amino-acid sequence (or primary structure) of a protein predisposes it towards its native conformation or conformations. It will fold spontaneously during or after synthesis. While these macromolecules may be regarded as "folding themselves", the mechanism depends equally on the characteristics of the cytosol, including the nature of the primary solvent (water or lipid), the concentration of salts, the temperature, and molecular chaperones. A protein primary structure is a chain of amino acids. ... Translation is the second stage of protein biosynthesis (part of the overall process of gene expression). ... Illustration of a polypeptide macromolecule Structure of a polyphenylene dendrimer macromolecule reported by Müllen and coworkers in Chem. ... The cytosol (cf. ... For other uses, see Solvent (disambiguation). ... Impact from a water drop causes an upward rebound jet surrounded by circular capillary waves. ... Some common lipids. ... For other uses, see Salt (disambiguation). ... For other uses, see Temperature (disambiguation). ... In biology, chaperones are proteins whose function is to assist other proteins in achieving proper folding. ...


Most folded proteins have a hydrophobic core in which side chain packing stabilizes the folded state, and charged or polar side chains on the solvent-exposed surface where they interact with surrounding water molecules. It is generally accepted that minimizing the number of hydrophobic sidechains exposed to water is the principal driving force behind the folding process,[5] although a recent theory has been proposed which reassesses the contributions made by hydrogen bonding.[6] The hydrophobic effect is the property that nonpolar molecules like to self-associate in the presence of aqueous solution. ... A commonly-used example of a polar compound is water (H2O). ...


The process of folding in vivo often begins co-translationally, so that the N-terminus of the protein begins to fold while the C-terminal portion of the protein is still being synthesized by the ribosome. Specialized proteins called chaperones assist in the folding of other proteins.[7] A well studied example is the bacterial GroEL system, which assists in the folding of globular proteins. In eukaryotic organisms chaperones are known as heat shock proteins. Although most globular proteins are able to assume their native state unassisted, chaperone-assisted folding is often necessary in the crowded intracellular environment to prevent aggregation; chaperones are also used to prevent misfolding and aggregation which may occur as a consequence of exposure to heat or other changes in the cellular environment. In vivo (Latin for (with)in the living). ... Translation is the second process of protein biosynthesis (part of the overall process of gene expression). ... The N-terminal end refers to the extremity of a protein or polypeptide terminated by an amino acid with a free amine group (NH2). ... The C-terminal end refers to the extremity of a protein or polypeptide terminated by an amino acid with a free carboxyl group (COOH). ... An overview of protein synthesis. ... Figure 1: Ribosome structure indicating small subunit (A) and large subunit (B). ... In biology, chaperones are proteins whose function is to assist other proteins in achieving proper folding. ... Phyla Actinobacteria Aquificae Chlamydiae Bacteroidetes/Chlorobi Chloroflexi Chrysiogenetes Cyanobacteria Deferribacteres Deinococcus-Thermus Dictyoglomi Fibrobacteres/Acidobacteria Firmicutes Fusobacteria Gemmatimonadetes Lentisphaerae Nitrospirae Planctomycetes Proteobacteria Spirochaetes Thermodesulfobacteria Thermomicrobia Thermotogae Verrucomicrobia Bacteria (singular: bacterium) are unicellular microorganisms. ... GroEL is a protein chaperone required for the proper folding of many proteins in prokaryotes. ... 3-dimensional structure of hemoglobin, a globular protein. ... Kingdoms Eukaryotes are organisms with complex cells, in which the genetic material is organized into membrane-bound nuclei. ... Life on Earth redirects here. ... Heat shock proteins (HSP) are a group of proteins whose expression is increased when the cells are exposed to elevated temperatures. ...


For the most part, scientists have been able to study many identical molecules folding together en masse. At the coarsest level, it appears that in transitioning to the native state, a given amino acid sequence takes on roughly the same route and proceeds through roughly the same intermediates and transition states. Often folding involves first the establishment of regular secondary and supersecondary structures, particularly alpha helices and beta sheets, and afterwards tertiary structure. Formation of quaternary structure usually involves the "assembly" or "coassembly" of subunits that have already folded. The regular alpha helix and beta sheet structures fold rapidly because they are stabilized by intramolecular hydrogen bonds, as was first characterized by Linus Pauling. Protein folding may involve covalent bonding in the form of disulfide bridges formed between two cysteine residues or the formation of metal clusters. Shortly before settling into their more energetically favourable native conformation, molecules may pass through an intermediate "molten globule" state. Side view of an α-helix of alanine residues in atomic detail. ... Diagram of β-pleated sheet with H-bonding between protein strands The β sheet (also β-pleated sheet) is the second form of regular secondary structure in proteins — the first is the alpha helix — consisting of beta strands connected laterally by three or more hydrogen bonds, forming a generally twisted, pleated sheet. ... In biochemistry, the tertiary structure of a protein is its overall shape. ... In biochemistry, many proteins are actually assemblies of more than one protein (polypeptide) molecule, which in the context of the larger assemblage are known as protein subunits. ... Side view of an α-helix of alanine residues in atomic detail. ... Diagram of β-pleated sheet with H-bonding between protein strands The β sheet (also β-pleated sheet) is the second form of regular secondary structure in proteins — the first is the alpha helix — consisting of beta strands connected laterally by three or more hydrogen bonds, forming a generally twisted, pleated sheet. ... An example of a quadruple hydrogen bond between a self-assembled dimer complex reported by Meijer and coworkers. ... Linus Carl Pauling (February 28, 1901 – August 19, 1994) was an American quantum chemist and biochemist. ... Covalent redirects here. ... In chemistry, a disulfide bond is a single covalent bond derived from the coupling of thiol groups. ... Cysteine is a naturally occurring, sulfur-containing amino acid that is found in most proteins, although only in small quantities. ... In thermodynamics, the Gibbs free energy (IUPAC recommended name: Gibbs energy or Gibbs function) is a thermodynamic potential which measures the useful or process-initiating work obtainable from an isothermal, isobaric thermodynamic system. ... A molten globule (MG) is a stable, partially folded protein structure found in mildly denaturing conditions such as low pH (generally pH = 2), mild denaturant, or high temperature. ...


The essential fact of folding, however, remains that the amino acid sequence of each protein contains the information that specifies both the native structure and the pathway to attain that state. This is not to say that identical amino acid sequences always fold similarly. Conformations differ based on environmental factors as well; similar proteins fold differently based on where they are found. Folding is a spontaneous process independent of energy inputs from nucleoside triphosphates. The passage of the folded state is mainly guided by hydrophobic interactions, formation of intramolecular hydrogen bonds, and van der Waals forces, and it is opposed by conformational entropy, which must be overcome by extrinsic factors such as chaperones. A spontaneous process in chemical reaction terms is one which occurs with the system releasing free energy in some form (often, but not always, heat) and moving to a lower energy, hence more thermodynamically stable, state. ... Nucleoside triphosphate (NTP) is a nucleotide with three phosphates. ... An example of a quadruple hydrogen bond between a self-assembled dimer complex reported by Meijer and coworkers. ... The title given to this article is incorrect due to technical limitations. ... Conformational entropy is the entropy associated with the physical arrangement of a polymer chain that assumes a compact or globular state in solution. ...


Disruption of the native state

In certain solutions and under some conditions proteins will not fold into their biochemically functional forms. Temperatures above (and sometimes those below) the range that cells tend to live in will cause proteins to unfold or "denature" (this is why boiling makes the white of an egg opaque). High concentrations of solutes, extremes of pH, mechanical forces, and the presence of chemical denaturants can do the same. A fully denatured protein lacks both tertiary and secondary structure, and exists as a so-called random coil. Under certain conditions some proteins can refold; however, in many cases denaturation is irreversible.[8] Cells sometimes protect their proteins against the denaturing influence of heat with enzymes known as chaperones or heat shock proteins, which assist other proteins both in folding and in remaining folded. Some proteins never fold in cells at all except with the assistance of chaperone molecules, which either isolate individual proteins so that their folding is not interrupted by interactions with other proteins or help to unfold misfolded proteins, giving them a second chance to refold properly. This function is crucial to prevent the risk of precipitation into insoluble amorphous aggregates. Irreversible egg protein denaturation and loss of solubility, caused by the high temperature (while cooking it) Denaturation is the alteration of a protein or nucleic acids shape through some form of external stress (for example, by applying heat, acid or alkali), in such a way that it will no... A substance is soluble in a fluid if it dissolves in the fluid. ... For other uses, see PH (disambiguation). ... Illustration of a 3-dimensional polypeptide A random coil is a polymer conformation where the monomer subunits are oriented randomly while still being bonded to adjacent units. ... Ribbon diagram of the enzyme TIM, surrounded by the space-filling model of the protein. ... In biology, chaperones are proteins whose function is to assist other proteins in achieving proper folding. ... Heat shock proteins (HSP) are a group of proteins whose expression is increased when the cells are exposed to elevated temperatures. ... Insoluble Not soluble ...


Incorrect protein folding and neurodegenerative disease

Misfolded proteins are responsible for prion-related illnesses such as Creutzfeldt-Jakob disease, bovine spongiform encephalopathy (mad cow disease), amyloid-related illnesses such as Alzheimer's Disease, and a number of other forms of proteopathy such as cystic fibrosis. These diseases are associated with the multimerization of misfolded proteins into insoluble, extracellular aggregates and/or intracellular inclusions; it is not clear whether the plaques are the cause or merely a symptom of illness. A prion (IPA: [1] ) — short for proteinaceous infectious particle (-on by analogy to virion) — is a type of infectious agent composed only of protein. ... Creutzfeldt-Jakob disease (CJD) is a very rare and incurable degenerative neurological disorder (brain disease) that is ultimately fatal. ... Classic image of a cow with BSE. A notable feature of such disease is the inability (of the infected animal) to stand. ... For other uses, see Amyloid (disambiguation). ... Proteopathy (Proteo- [pref. ...


Kinetics and the Levinthal Paradox

The entire duration of the folding process varies dramatically depending on the protein of interest. The slowest folding proteins require many minutes or hours to fold, primarily due to proline isomerizations or wrong disulfide bond formations, and must pass through a number of intermediate states, like checkpoints, before the process is complete.[9] On the other hand, very small single-domain proteins with lengths of up to a hundred amino acids typically fold in a single step.[10] Time scales of milliseconds are the norm and the very fastest known protein folding reactions are complete within a few microseconds.[11] --RAG 01:54, 16 March 2007 (UTC) The concept of the domain was first proposed in 1973 by Wetlaufer after X-ray crystallographic studies of hen lysozyme (Phillips, 1966), papain (Drenth et al. ...


The Levinthal paradox[12] observes that if a protein were to fold by sequentially sampling all possible conformations, it would take an astronomical amount of time to do so, even if the conformations were sampled at a rapid rate (on the nanosecond or picosecond scale). Based upon the observation that proteins fold much faster than this, Levinthal then proposed that a random conformational search does not occur in folding, and the protein must, therefore, fold by a directed process. The Levinthal paradox is a thought experiment in the theory of protein folding dynamics. ... To help compare orders of magnitude of different times this page lists times between 10−9 seconds and 10−8 seconds (1 nanosecond and 10 nanoseconds) See also times of other orders of magnitude. ... A picosecond is an SI unit of time equal to 10-12 of a second. ...


Techniques for studying protein folding

Modern studies of folding with high time resolution

The study of protein folding has been greatly advanced in recent years by the development of fast, time-resolved techniques. These are experimental methods for rapidly triggering the folding of a sample of unfolded protein, and then observing the resulting dynamics. Fast techniques in widespread use include ultrafast mixing of solutions, photochemical methods, and laser temperature jump spectroscopy. Among the many scientists who have contributed to the development of these techniques are Heinrich Roder, Harry Gray, Martin Gruebele, Brian Dyer, William Eaton, Sheena Radford, Chris Dobson, Sir Alan R. Fersht and Bengt Nölting. Harry B. Gray received his Ph. ... Sir Alan Roy Fersht (born April 21, 1943) is Herchel Smith Professor of Organic Chemistry at Cambridge University and is the current director of the Cambridge Centre for Protein Engineering (UK). ... Bengt Nölting (born May 1, 1962) is the current director of the Prussian Private Institute of Technology at Berlin, Germany. ...


Energy landscape theory of protein folding

The protein folding phenomenon was largely an experimental endeavor until the formulation of energy landscape theory by Joseph Bryngelson and Peter Wolynes in the late 1980s and early 1990s. This approach introduced the principle of minimal frustration, which asserts that evolution has selected the amino acid sequences of natural proteins so that interactions between side chains largely favor the molecule's acquisition of the folded state. Interactions that do not favor folding are selected against, although some residual frustration is expected to exist. A consequence of these evolutionarily selected sequences is that proteins are generally thought to have globally "funneled energy landscapes" (coined by José Onuchic) that are largely directed towards the native state. This "folding funnel" landscape allows the protein to fold to the native state through any of a large number of pathways and intermediates, rather than being restricted to a single mechanism. The theory is supported by both computational simulations of model proteins and numerous experimental studies, and it has been used to improve methods for protein structure prediction and design. It has been suggested that this article or section be merged into hypersurface. ... The folding funnel hypothesis is a specific version of the energy landscape theory of protein folding, which assumes that a proteins native state corresponds to its energetic minimum under the solution conditions usually encountered in cells. ... Lattice proteins are highly simplified computer models of proteins which are used to investigate protein folding. ... Protein structure prediction is one of the most significant technologies pursued by computational structural biology and theoretical chemistry. ... Protein design is the design of new protein molecules from scratch. ...


Computational prediction of protein tertiary structure

De novo or ab initio techniques for computational protein structure prediction is related to, but strictly distinct from, studies involving protein folding. Molecular Dynamics (MD) is an important tool for studying protein folding and dynamics in silico. Because of computational cost, ab initio MD folding simulations with explicit water are limited to peptides and very small proteins. MD simulations of larger proteins remain restricted to dynamics of the experimental structure or its high-temperature unfolding. In order to simulate long time folding processes (beyond about 1 microsecond), like folding of small-size proteins (about 50 residues) or larger, some approximations or simplifications in protein models need to be introduced. An approach using reduced protein representation (pseudo-atoms representing groups of atoms are defined) and statistical potential is not only useful in protein structure prediction, but is also capable of reproducing the folding pathways.[13] Protein structure prediction is one of the most significant technologies pursued by computational structural biology and theoretical chemistry. ... Molecular dynamics (MD) is a form of computer simulation wherein atoms and molecules are allowed to interact for a period of time under known laws of physics, giving a view of the motion of the atoms. ... In Silico is a full length artist album by Deepsky View From a Stairway Jareths Church The Mansion World (Deepskys Trippin In Unknown Territory Mix) Ride Three Sheets to the Wind Atia Metro Smile Cosmic Dancer (2002 remix) Until the End of the World Let Me Live Categories... In protein structure prediction, a statistical potential (also knowledge-based potential, empirical potential, or residue contact potential) is an energy function derived from an analysis of known structures in the Protein Data Bank. ... Protein structure prediction is one of the most significant technologies pursued by computational structural biology and theoretical chemistry. ...


Because of the many possible ways of folding, there can be many possible structures. A peptide consisting of just five amino acids can fold into over 100 billion possible structures. [1]


Techniques for determination of protein structure

The determination of the folded structure of a protein is a lengthy and complicated process, involving methods like X-ray crystallography and NMR. One of the major areas of interest is the prediction of native structure from amino-acid sequences alone using bioinformatics and computational simulation methods. X-ray crystallography, also known as single-crystal X-ray diffraction, is the oldest and most common crystallographic method for determining the structure of molecules. ... Pacific Northwest National Laboratorys high magnetic field (800 MHz) NMR spectrometer being loaded with a sample. ... Protein structure prediction is one of the most significant technologies pursued by computational structural biology and theoretical chemistry. ... Map of the human X chromosome (from the NCBI website). ...


See also

Crystal structure of a foldamer reported by Lehn and coworkers in Helv. ... This article does not cite its references or sources. ... The Levinthal paradox is a thought experiment in the theory of protein folding dynamics. ... Irreversible egg protein denaturation and loss of solubility, caused by the high temperature (while cooking it) Denaturation is the alteration of a protein or nucleic acids shape through some form of external stress (for example, by applying heat, acid or alkali), in such a way that it will no... Protein design is the design of new protein molecules from scratch. ... The backbone dihedral angles are included in the molecular model of a protein. ... A typical chevron plot observed in protein folding experiments. ... Assuming two-state protein folding, denaturation midpoint is defined as that temperature (Tm) or denaturant concentration (Cm) at which both the folded and unfolded states are equally populated. ... In biochemistry, equilibrium unfolding is the process of unfolding a protein or RNA molecule by gradually changing its solution conditions, i. ... Folding@Home (also known as FAH or F@H) is a distributed computing project designed to perform computationally intensive simulations of protein folding and other molecular dynamics. ... Downhill folding, a key prediction of the energy landscape theory, is a process in which there is no free energy barrier between the unfolded state and the folded state. ...

References

  1. ^ Alberts, Bruce; Alexander Johnson, Julian Lewis, Martin Raff, Keith Roberts, and Peter Walters (2002). "The Shape and Structure of Proteins", Molecular Biology of the Cell; Fourth Edition. New York and London: Garland Science. ISBN 0-8153-3218-1. 
  2. ^ Anfinsen C (1972). "The formation and stabilization of protein structure". Biochem. J. 128 (4): 737-49. PMID 4565129. 
  3. ^ Jeremy M. Berg, John L. Tymoczko, Lubert Stryer; Web content by Neil D. Clarke (2002). "3. Protein Structure and Function", Biochemistry. San Francisco: W.H. Freeman. ISBN 0-7167-4684-0. 
  4. ^ Science of Folding@Home (July 18, 2005). Retrieved on 2007-04-22.
  5. ^ Pace C, Shirley B, McNutt M, Gajiwala K (1996). "Forces contributing to the conformational stability of proteins". FASEB J. 10 (1): 75-83. PMID 8566551. 
  6. ^ Rose G, Fleming P, Banavar J, Maritan A (2006). "A backbone-based theory of protein folding". Proc. Natl. Acad. Sci. U.S.A. 103 (45): 16623-33. PMID 17075053. 
  7. ^ Lee S, Tsai F (2005). "Molecular chaperones in protein quality control". J. Biochem. Mol. Biol. 38 (3): 259-65. PMID 15943899. 
  8. ^ Shortle D (1996). "The denatured state (the other half of the folding equation) and its role in protein stability". FASEB J. 10 (1): 27-34. PMID 8566543. 
  9. ^ P.S. Kim & R.L. Baldwin (1990). "Intermediates in the folding reactions of small proteins". Annu. Rev. Biochem. 59: 631-660. 
  10. ^ S.E. Jackson (Aug 1998). "How do small single-domain proteins fold?". Fold. Des. 3: R81-R91. ISSN 1359-0278. 
  11. ^ J. Kubelka, et al. (2004). "The protein folding "speed limit"". Curr. Opin. Struct. Biol. 14: 76-88. doi:10.1016/j.sbi.2004.01.013. 
  12. ^ C. Levinthal (1968). "Are there pathways for protein folding?". J. Chim. Phys. 65: 44-45. 
  13. ^ Kmiecik S and Kolinski A (2007). "Characterization of protein-folding pathways by reduced-space modeling". Proc. Natl. Acad. Sci. U.S.A. 104 (30): 12330-12335. PMID 17636132. 

Year 2007 (MMVII) is the current year, a common year starting on Monday of the Gregorian calendar and the AD/CE era in the 21st century. ... is the 112th day of the year (113th in leap years) in the Gregorian calendar. ... ISSN, or International Standard Serial Number, is the unique eight-digit number applied to a periodical publication including electronic serials. ... A digital object identifier (or DOI) is a standard for persistently identifying a piece of intellectual property on a digital network and associating it with related data, the metadata, in a structured extensible way. ... Cyrus Levinthal (May 2, 1922 – November 4, 1990) was an American molecular biologist. ...

External links

  • Folding @ Home Help decode the riddles of protein folding.
  • Rosetta @ Home Help predict protein structures and complexes.

  Results from FactBites:
 
Protein folding - definition of Protein folding in Encyclopedia (745 words)
While these macromolecules may be seen as "folding themselves," in fact their folding depends a great deal on the characteristics of their surrounding solution, including the identity of the primary solvent (either water or lipid inside cells), the concentration of salts, the temperature, and molecular chaperones.
Folding is a spontaneous process that is mainly guided by Van der Waals forces and entropic contributions to the Gibbs free energy: an increase in entropy is achieved by moving the hydrophobic parts of the protein inwards, and the hydrophilic ones outwards.
During the folding process, the amount of hydrogen bonds does not change appreciably, because for every internal hydrogen bond in the protein, a hydrogen bond of the unfolded protein with the aqueous medium has to be broken.
  More results at FactBites »

 
 

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