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Protein folding is the
physical process Physical changes are changes affecting the form of a chemical substance, but not its chemical composition. Physical changes are used to separate mixtures into their component Chemical compound, compounds, but can not usually be used to separate co ...
by which a
protein Proteins are large biomolecule , showing alpha helices, represented by ribbons. This poten was the first to have its suckture solved by X-ray crystallography by Max Perutz and Sir John Cowdery Kendrew in 1958, for which they received a No ...

protein
chain is
translated Translation is the communication of the meaning of a source-language text by means of an equivalent target-language text. The English language draws a terminological distinction (which does not exist in every language) between ''transla ...

translated
to its native three-dimensional structure, typically a "folded"
conformation Conformation generally means structural arrangement and may refer to: * Conformational isomerism, a form of stereoisomerism in chemistry ** Carbohydrate conformation ** Cyclohexane conformation ** Protein conformation ** Conformation activity relat ...

conformation
by which the protein becomes biologically functional. Via an expeditious and reproducible process, a
polypeptide Peptides (from Greek language Greek ( el, label=Modern Greek Modern Greek (, , or , ''Kiní Neoellinikí Glóssa''), generally referred to by speakers simply as Greek (, ), refers collectively to the dialects of the Greek language spoken ...
folds into its characteristic three-dimensional structure from a
random coil A random coil is a polymer A polymer (; Greek ''wikt:poly-, poly-'', "many" + ''wikt:-mer, -mer'', "part") is a Chemical substance, substance or material consisting of very large molecules, or macromolecules, composed of many Repeat unit, repe ...
. Each protein exists first as an unfolded polypeptide or random coil after being translated from a sequence of
mRNA In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of Protein biosynthesis, synthesizing a protein. mRNA i ...

mRNA
to a linear chain of
amino acid Amino acids are organic compound In , organic compounds are generally any s that contain - . Due to carbon's ability to (form chains with other carbon s), millions of organic compounds are known. The study of the properties, reactions, a ...

amino acid
s. At this stage the polypeptide lacks any stable (long-lasting) three-dimensional structure (the left hand side of the first figure). As the polypeptide chain is being synthesized by a
ribosome Ribosomes ( ), also called Palade granules, are molecular machine, macromolecular machines, found within all cell (biology), cells, that perform Translation (biology), biological protein synthesis (mRNA translation). Ribosomes link amino acids ...

ribosome
, the linear chain begins to fold into its three-dimensional structure. Folding of many proteins begins even during translation of the polypeptide chain. Amino acids interact with each other to produce a well-defined three-dimensional structure, the folded protein (the right hand side of the figure), known as the
native state In biochemistry Biochemistry or biological chemistry, is the study of es within and relating to living s. A sub-discipline of both and , biochemistry may be divided into three fields: , and . Over the last decades of the 20th century, b ...
. The resulting three-dimensional structure is determined by the amino acid sequence or primary structure (
Anfinsen's dogma Anfinsen's dogma, also known as the thermodynamic hypothesis, is a postulate in molecular biology Molecular biology is the branch of biology Biology is the natural science that studies life and living organisms, including their anatomy ...
). The correct three-dimensional structure is essential to function, although some parts of functional proteins may remain unfolded, so that
protein dynamics Proteins are generally thought to adopt unique structures determined by their amino acid sequences. However, proteins are not strictly static objects, but rather populate ensembles of (sometimes similar) conformations. Transitions between these stat ...
is important. Failure to fold into native structure generally produces inactive proteins, but in some instances misfolded proteins have modified or toxic functionality. Several
neurodegenerative A neurodegenerative disease is caused by the progressive loss of structure or function of neuron A neuron or nerve cell is an electrically excitable cell Cell most often refers to: * Cell (biology), the functional basic unit of life Cell ...
and other
disease A disease is a particular abnormal condition that negatively affects the structure A structure is an arrangement and organization of interrelated elements in a material object or system A system is a group of Interaction, interactin ...
s are believed to result from the accumulation of
amyloid Amyloids are aggregates of proteins characterised by a Fibril, fibrillar morphology of 7–13 Nanometer, nm in diameter, a β-sheet Secondary structure of proteins, secondary structure (known as cross-β) and ability to be Histological stain, st ...
fibrils Fibrils (from the Latin Latin (, or , ) is a classical language belonging to the Italic languages, Italic branch of the Indo-European languages. Latin was originally spoken in the area around Rome, known as Latium. Through the power of the R ...
formed by misfolded proteins, infectious varieties of which are known as
prions Prions are misfolded protein Protein folding is the physical process Physical changes are changes affecting the form of a chemical substance A chemical substance is a form of matter In classical physics and general chemistry, matte ...

prions
. Many
allergies Allergies, also known as allergic diseases, are a number of conditions caused by hypersensitivity Hypersensitivity (also called hypersensitivity reaction or intolerance) refers to undesirable reactions produced by the normal immune system, ...
are caused by incorrect folding of some proteins, because the
immune system The immune system is a network of biological processes that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as Tumor immunology, cancer cells and objects such ...
does not produce
antibodies An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and Viral disease, viruses. The antibody recognizes a unique mo ...

antibodies
for certain protein structures. Denaturation of proteins is a process of transition from the folded to the unfolded state. It happens in
cooking Cooking, cookery, or culinary arts is the art, science, and craft of using heat In thermodynamics Thermodynamics is a branch of physics that deals with heat, Work (thermodynamics), work, and temperature, and their relation to energy ...

cooking
, in
burn A burn is a type of injury Injury, also known as physical trauma, is damage Damage is any change in a thing, often a physical object, that degrades it away from its initial state. It can broadly be defined as "changes introduced into a ...

burn
s, in proteinopathies, and in other contexts. The duration of the folding process varies dramatically depending on the protein of interest. When studied
outside the cell
outside the cell
, the slowest folding proteins require many minutes or hours to fold primarily due to
proline isomerization
proline isomerization
, and must pass through a number of intermediate states, like checkpoints, before the process is complete. On the other hand, very small single-
domain Domain may refer to: Mathematics *Domain of a function In mathematics, the domain of a Function (mathematics), function is the Set (mathematics), set of inputs accepted by the function. It is sometimes denoted by \operatorname(f), where is th ...
proteins with lengths of up to a hundred amino acids typically fold in a single step. Time scales of milliseconds are the norm and the very fastest known protein folding reactions are complete within a few microseconds. Understanding and simulating the protein folding process has been an important challenge for
computational biology Computational biology involves the development and application of data-analytical and theoretical methods, mathematical modelling A mathematical model is a description of a system A system is a group of Interaction, interacting or interrelat ...

computational biology
since the late 1960s.


Process of protein folding


Primary structure

The
primary structure of a protein
primary structure of a protein
, its linear amino-acid sequence, determines its native conformation. The specific amino acid residues and their position in the polypeptide chain are the determining factors for which portions of the protein fold closely together and form its three-dimensional conformation. The amino acid composition is not as important as the sequence. 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 nearly 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.


Secondary structure

Formation of a
secondary structure Biomolecular structure is the intricate folded, three-dimensional shape that is formed by a molecule A scanning tunneling microscopy image of pentacene molecules, which consist of linear chains of five carbon rings. A molecule is an elect ...
is the first step in the folding process that a protein takes to assume its native structure. Characteristic of secondary structure are the structures known as
alpha helices The alpha helix (α-helix) is a common motif in the secondary structure Biomolecular structure is the intricate folded, three-dimensional shape that is formed by a molecule File:Pentacene on Ni(111) STM.jpg, A scanning tunneling microscopy i ...

alpha helices
and
beta sheet The beta sheet, (β-sheet) (also β-pleated sheet) is a common motif Motif may refer to: General concepts * Motif (chess composition), an element of a move in the consideration of its purpose * Motif (folkloristics), a recurring element that cre ...
s that fold rapidly because they are stabilized by intramolecular
hydrogen bond A hydrogen bond (or H-bond) is a primarily electrostatic Electrostatics is a branch of physics Physics is the that studies , its , its and behavior through , and the related entities of and . "Physical science is that department ...

hydrogen bond
s, as was first characterized by
Linus Pauling Linus Carl Pauling (; February 28, 1901 – August 19, 1994) was an American chemist, biochemist, chemical engineer, peace activist, author, and educator. He published more than 1,200 papers and books, of which about 850 dealt with scientific t ...

Linus Pauling
. Formation of intramolecular hydrogen bonds provides another important contribution to protein stability. α-helices are formed by hydrogen bonding of the
backbone The backbone is the vertebral column of a vertebrate. Arts, entertainment, and media Film * Backbone (1923 film), ''Backbone'' (1923 film), 1923 lost silent film starring Alfred Lunt * Backbone (1975 film), ''Backbone'' (1975 film), 1975 Yugoslav ...
to form a spiral shape (refer to figure on the right). The β pleated sheet is a structure that forms with the backbone bending over itself to form the hydrogen bonds (as displayed in the figure to the left). The hydrogen bonds are between the amide hydrogen and carbonyl oxygen of the
peptide bond In organic chemistry Organic chemistry is a branch of chemistry Chemistry is the study of the properties and behavior of . It is a that covers the that make up matter to the composed of s, s and s: their composition, structure, pro ...

peptide bond
. There exists anti-parallel β pleated sheets and parallel β pleated sheets where the stability of the hydrogen bonds is stronger in the anti-parallel β sheet as it hydrogen bonds with the ideal 180 degree angle compared to the slanted hydrogen bonds formed by parallel sheets.


Tertiary structure

The alpha helices and beta pleated sheets can be
amphipathic An amphiphile (a.k.a. amphipath; from the Greek#REDIRECT Greek Greek may refer to: Greece Anything of, from, or related to Greece Greece ( el, Ελλάδα, , ), officially the Hellenic Republic, is a country located in Southeast Europe. ...
in nature, or contain a hydrophilic portion and a hydrophobic portion. This property of secondary structures aids in the
tertiary structure of a protein Tertiary ( ) is a widely used but obsolete term for the Period (geology), geologic period from 66 million to 2.6 million years ago. The period began with the demise of the non-bird, avian dinosaurs in the Cretaceous–Paleogene extinct ...
in which the folding occurs so that the hydrophilic sides are facing the
aqueous An aqueous solution is a solution Solution may refer to: * Solution (chemistry) Image:SaltInWaterSolutionLiquid.jpg, upMaking a saline water solution by dissolving Salt, table salt (sodium chloride, NaCl) in water. The salt is the solute an ...
environment surrounding the protein and the hydrophobic sides are facing the hydrophobic core of the protein. Secondary structure hierarchically gives way to tertiary structure formation. Once the protein's tertiary structure is formed and stabilized by the hydrophobic interactions, there may also be
covalent bond A covalent bond is a chemical bond that involves the sharing of electron pairs between atoms. These electron pairs are known as shared pairs or bonding pairs, and the stable balance of attractive and repulsive forces between atoms, when they s ...
ing in the form of
disulfide bridges In biochemistry Biochemistry or biological chemistry, is the study of chemical process In a scientific Science () is a systematic enterprise that Scientific method, builds and organizes knowledge in the form of Testability, testable ex ...
formed between two
cysteine Cysteine (symbol Cys or C; ) is a semiessential proteinogenic amino acid with the chemical formula, formula HOOC-CH-(NH2)-CH2-SH. The thiol side chain in cysteine often participates in enzymatic reactions as a nucleophile. The thiol is suscepti ...

cysteine
residues. Tertiary structure of a protein involves a single polypeptide chain; however, additional interactions of folded polypeptide chains give rise to quaternary structure formation.


Quaternary structure

Tertiary structure may give way to the formation of
quaternary structure Biomolecular structure is the intricate folded, three-dimensional shape that is formed by a molecule File:Pentacene on Ni(111) STM.jpg, A scanning tunneling microscopy image of pentacene molecules, which consist of linear chains of five carbon ...
in some proteins, which usually involves the "assembly" or "coassembly" of subunits that have already folded; in other words, multiple polypeptide chains could interact to form a fully functional quaternary protein.


Driving forces of protein folding

Folding is a
spontaneous process In thermodynamics Thermodynamics is a branch of physics that deals with heat, Work (thermodynamics), work, and temperature, and their relation to energy, entropy, and the physical properties of matter and radiation. The behavior of these quanti ...

spontaneous process
that is mainly guided by hydrophobic interactions, formation of intramolecular
hydrogen bond A hydrogen bond (or H-bond) is a primarily electrostatic Electrostatics is a branch of physics Physics is the that studies , its , its and behavior through , and the related entities of and . "Physical science is that department ...

hydrogen bond
s,
van der Waals forces In molecular physics Molecular physics is the study of the physical properties of molecule File:Pentacene on Ni(111) STM.jpg, A scanning tunneling microscopy image of pentacene molecules, which consist of linear chains of five carbon rings ...
, and it is opposed by
conformational entropy Conformational entropy is the entropy Entropy is a scientific concept as well as a measurable physical property that is most commonly associated with a state of disorder, randomness, or uncertainty. The term and the concept are used in dive ...
. The process of folding often begins co-translationally, so that the
N-terminus The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein Proteins are large biomolecule , showing alpha helices, represented by ribbons. This poten was the first to hav ...

N-terminus
of the protein begins to fold while the
C-terminal The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid Amino acids are organic compound In , organic compounds are generally any s that contain ...

C-terminal
portion of the protein is still being
synthesized Synthesis or synthesize may also refer to: Science Chemistry and biochemistry *Chemical synthesis, the execution of chemical reactions to form a more complex molecule from chemical precursors **Organic synthesis, the chemical synthesis of or ...
by the
ribosome Ribosomes ( ), also called Palade granules, are molecular machine, macromolecular machines, found within all cell (biology), cells, that perform Translation (biology), biological protein synthesis (mRNA translation). Ribosomes link amino acids ...

ribosome
; however, a protein molecule may fold spontaneously during or after
biosynthesis Biosynthesis is a multi-step, enzyme Enzymes () are proteins that act as biological catalysts (biocatalysts). Catalysts accelerate chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and ...
. While these
macromolecule A macromolecule is a very large molecule A molecule is an electrically Electricity is the set of physical phenomena associated with the presence and motion Image:Leaving Yongsan Station.jpg, 300px, Motion involves a change in ...
s may be regarded as "", the process also depends on the
solvent A solvent (from the Latin Latin (, or , ) is a classical language belonging to the Italic languages, Italic branch of the Indo-European languages. Latin was originally spoken in the area around Rome, known as Latium. Through the power of the ...

solvent
(
water Water (chemical formula H2O) is an Inorganic compound, inorganic, transparent, tasteless, odorless, and Color of water, nearly colorless chemical substance, which is the main constituent of Earth's hydrosphere and the fluids of all known li ...

water
or
lipid bilayer The lipid bilayer (or phospholipid bilayer) is a thin polar membrane A polarized membrane is a lipid bilayer, lipid membrane that has a positive electrical charge on one side and a negative charge on another side, which produces the resting pot ...
), the concentration of
salts In chemistry Chemistry is the study of the properties and behavior of . It is a that covers the that make up matter to the composed of s, s and s: their composition, structure, properties, behavior and the changes they undergo during ...
, the , the
temperature Temperature ( ) is a physical quantity that expresses hot and cold. It is the manifestation of thermal energy Thermal radiation in visible light can be seen on this hot metalwork. Thermal energy refers to several distinct physical concept ...

temperature
, the possible presence of cofactors and of molecular chaperones. Proteins will have limitations on their folding abilities by the restricted bending angles or conformations that are possible. These allowable angles of protein folding are described with a two-dimensional plot known as the
Ramachandran plot In biochemistry, a Ramachandran plot (also known as a Rama plot, a Ramachandran diagram or a plot), originally developed in 1963 by Gopalasamudram Narayana Ramachandran, G. N. Ramachandran, C. Ramakrishnan, and V. Sasisekharan, is a way to ...
, depicted with psi and phi angles of allowable rotation.


Hydrophobic effect

Protein folding must be thermodynamically favorable within a cell in order for it to be a spontaneous reaction. Since it is known that protein folding is a spontaneous reaction, then it must assume a negative
Gibbs free energy In thermodynamics Thermodynamics is a branch of physics that deals with heat, Work (thermodynamics), work, and temperature, and their relation to energy, entropy, and the physical properties of matter and radiation. The behavior of these qua ...
value. Gibbs free energy in protein folding is directly related to
enthalpy Enthalpy , a property of a thermodynamic system, is the sum of the system's internal energy and the product of its pressure and volume. It is a state function used in many measurements in chemical, biological, and physical systems at a constant p ...

enthalpy
and
entropy Entropy is a scientific concept as well as a measurable physical property that is most commonly associated with a state of disorder, randomness, or uncertainty. The term and the concept are used in diverse fields, from classical thermodynamic ...

entropy
. For a negative delta G to arise and for protein folding to become thermodynamically favorable, then either enthalpy, entropy, or both terms must be favorable. Minimizing the number of hydrophobic side-chains exposed to water is an important driving force behind the folding process. The hydrophobic effect is the phenomenon in which the hydrophobic chains of a protein collapse into the core of the protein (away from the hydrophilic environment). In an aqueous environment, the water molecules tend to aggregate around the hydrophobic regions or side chains of the protein, creating water shells of ordered water molecules. An ordering of water molecules around a hydrophobic region increases order in a system and therefore contributes a negative change in entropy (less entropy in the system). The water molecules are fixed in these water cages which drives the
hydrophobic collapse Hydrophobic collapse is a proposed process for the production of the Protein structure, 3-D conformation adopted by Peptide, polypeptides and other molecules in polar solvents. The theory states that the nascent polypeptide forms initial Protein se ...
, or the inward folding of the hydrophobic groups. The hydrophobic collapse introduces entropy back to the system via the breaking of the water cages which frees the ordered water molecules. The multitude of hydrophobic groups interacting within the core of the globular folded protein contributes a significant amount to protein stability after folding, because of the vastly accumulated van der Waals forces (specifically
London Dispersion forces London dispersion forces (LDF, also known as dispersion forces, London forces, instantaneous dipole–induced dipole forces, Fluctuating Induced Dipole Bonds or loosely as van der Waals forces) are a type of force acting between atom An at ...
). The
hydrophobic effect The hydrophobic effect is the observed tendency of nonpolar In chemistry Chemistry is the science, scientific study of the properties and behavior of matter. It is a natural science that covers the Chemical element, elements that make u ...
exists as a driving force in thermodynamics only if there is the presence of an aqueous medium with an
amphiphilic An amphiphile (a.k.a. amphipath; from the Greek#REDIRECT Greek Greek may refer to: Greece Anything of, from, or related to Greece Greece ( el, Ελλάδα, , ), officially the Hellenic Republic, is a country located in Southeast Europe. ...
molecule containing a large hydrophobic region. The strength of hydrogen bonds depends on their environment; thus, H-bonds enveloped in a hydrophobic core contribute more than H-bonds exposed to the aqueous environment to the stability of the native state. In proteins with globular folds, hydrophobic amino acids tend to be interspersed along the primary sequence, rather than randomly distributed or clustered together. However, proteins that have recently been born
de novo In general usage, ''de novo'' (literally 'of new') is Latin expression used in English to mean 'from the beginning', 'anew'. De novo may also refer to: Biology * ''De novo'', mutation, an alteration in a gene that is present for the first time i ...
, which tend to be intrinsically disordered, show the opposite pattern of hydrophobic amino acid clustering along the primary sequence.


Chaperones

Molecular chaperones Chaperone proteins participate in the folding of over half of all mammalian proteins. In molecular biology Molecular biology is the branch of biology Biology is the natural science that studies life and living organisms, including their ...
are a class of proteins that aid in the correct folding of other proteins ''
in vivo Studies Study or studies may refer to: General * Education **Higher education * Clinical trial * Experiment * Observational study * Research * Study skills, abilities and approaches applied to learning Other * Study (art), a drawing or series ...
''. Chaperones exist in all cellular compartments and interact with the polypeptide chain in order to allow the native three-dimensional conformation of the protein to form; however, chaperones themselves are not included in the final structure of the protein they are assisting in. Chaperones may assist in folding even when the nascent polypeptide is being synthesized by the ribosome. Molecular chaperones operate by binding to stabilize an otherwise unstable structure of a protein in its folding pathway, but chaperones do not contain the necessary information to know the correct native structure of the protein they are aiding; rather, chaperones work by preventing incorrect folding conformations. In this way, chaperones do not actually increase the rate of individual steps involved in the folding pathway toward the native structure; instead, they work by reducing possible unwanted aggregations of the polypeptide chain that might otherwise slow down the search for the proper intermediate and they provide a more efficient pathway for the polypeptide chain to assume the correct conformations. Chaperones are not to be confused with folding
catalyst Catalysis () is the process of increasing the rate of a chemical reaction A chemical reaction is a process that leads to the chemical transformation of one set of chemical substance A chemical substance is a form of matter In cla ...

catalyst
proteins, which catalyze chemical reactions responsible for slow steps in folding pathways. Examples of folding catalysts are protein disulfide isomerases and peptidyl-prolyl isomerases that may be involved in formation of
disulfide bond In biochemistry Biochemistry or biological chemistry, is the study of chemical process In a scientific Science () is a systematic enterprise that Scientific method, builds and organizes knowledge in the form of Testability, testable ex ...
s or interconversion between cis and trans stereoisomers of peptide group. Chaperones are shown to be critical in the process of protein folding ''in vivo'' because they provide the protein with the aid needed to assume its proper alignments and conformations efficiently enough to become "biologically relevant". This means that the polypeptide chain could theoretically fold into its native structure without the aid of chaperones, as demonstrated by protein folding experiments conducted ''
in vitro ''In vitro'' (meaning in glass, or ''in the glass'') studies Study or studies may refer to: General * Education **Higher education * Clinical trial * Experiment * Observational study * Research * Study skills, abilities and approaches applie ...

in vitro
''; however, this process proves to be too inefficient or too slow to exist in biological systems; therefore, chaperones are necessary for protein folding ''in vivo.'' Along with its role in aiding native structure formation, chaperones are shown to be involved in various roles such as protein transport, degradation, and even allow denatured proteins exposed to certain external denaturant factors an opportunity to refold into their correct native structures. A fully denatured protein lacks both tertiary and secondary structure, and exists as a so-called
random coil A random coil is a polymer A polymer (; Greek ''wikt:poly-, poly-'', "many" + ''wikt:-mer, -mer'', "part") is a Chemical substance, substance or material consisting of very large molecules, or macromolecules, composed of many Repeat unit, repe ...
. Under certain conditions some proteins can refold; however, in many cases, denaturation is irreversible. Cells sometimes protect their proteins against the denaturing influence of heat with
enzyme Enzymes () are proteins that act as biological catalysts (biocatalysts). Catalysts accelerate chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates in ...

enzyme
s known as
heat shock protein Heat shock proteins (HSP) are a family of protein, proteins that are produced by cell (biology), cells in response to exposure to Stress (biology), stressful conditions. They were first described in relation to heat shock#Heat shock, heat shock, but ...
s (a type of chaperone), which assist other proteins both in folding and in remaining folded.
Heat shock protein Heat shock proteins (HSP) are a family of protein, proteins that are produced by cell (biology), cells in response to exposure to Stress (biology), stressful conditions. They were first described in relation to heat shock#Heat shock, heat shock, but ...
s have been found in all species examined, from
bacteria Bacteria (; common noun bacteria, singular bacterium) are ubiquitous, mostly free-living organisms often consisting of one Cell (biology), biological cell. They constitute a large domain (biology), domain of prokaryotic microorganisms. Typ ...

bacteria
to humans, suggesting that they evolved very early and have an important function. Some proteins never fold in cells at all except with the assistance of chaperones which either isolate individual proteins so that their folding is not interrupted by interactions with other proteins or help to unfold misfolded proteins, allowing them to refold into the correct native structure. This function is crucial to prevent the risk of
precipitation In meteorology Meteorology is a branch of the (which include and ), with a major focus on . The study of meteorology dates back , though significant progress in meteorology did not begin until the 18th century. The 19th century saw mod ...
into
insoluble In chemistry Chemistry is the scientific Science () is a systematic enterprise that builds and organizes knowledge Knowledge is a familiarity or awareness, of someone or something, such as facts A fact is an occurrence i ...
amorphous aggregates. The external factors involved in protein denaturation or disruption of the native state include temperature, external fields (electric, magnetic), molecular crowding, and even the limitation of space (i.e. confinement), which can have a big influence on the folding of proteins. High concentrations of
solutes In chemistry Chemistry is the scientific Science () is a systematic enterprise that builds and organizes knowledge Knowledge is a familiarity or awareness, of someone or something, such as facts A fact is an occurrence i ...
, extremes of , mechanical forces, and the presence of chemical denaturants can contribute to protein denaturation, as well. These individual factors are categorized together as stresses. Chaperones are shown to exist in increasing concentrations during times of cellular stress and help the proper folding of emerging proteins as well as denatured or misfolded ones. Under some conditions proteins will not fold into their biochemically functional forms. Temperatures above or below the range that cells tend to live in will cause thermally unstable proteins to unfold or denature (this is why boiling makes an
egg white Egg white is the clear liquid (also called the albumen or the glair/glaire) contained within an egg An egg is the organic vessel containing the in which an develops until it can survive on its own, at which point the animal hatches. An ...
turn opaque). Protein thermal stability is far from constant, however; for example, hyperthermophilic bacteria have been found that grow at temperatures as high as 122 °C, which of course requires that their full complement of vital proteins and protein assemblies be stable at that temperature or above. The bacterium ''
E. coli ''Escherichia coli'' (),Wells, J. C. (2000) Longman Pronunciation Dictionary. Harlow ngland Pearson Education Ltd. also known as ''E. coli'' (), is a Gram-negative Gram-negative bacteria are bacteria Bacteria (; common noun bacteri ...

E. coli
'' is the host for
bacteriophage T4 Escherichia virus T4 is a species of bacteriophages that infect ''Escherichia coli'' bacteria. It is a double-stranded DNA virus in the subfamily ''Tevenvirinae'' from the family Myoviridae. T4 is capable of undergoing only a lytic, lytic life ...
, and the phage encoded gp31 protein () appears to be structurally and functionally homologous to ''E. coli''
chaperone protein Chaperone proteins participate in the folding of over half of all mammalian proteins. In molecular biology Molecular biology is the branch of biology Biology is the natural science that studies life and living organisms, including their a ...
GroES Heat shock 10 kDa protein 1 (Hsp10), also known as chaperonin 10 (cpn10) or early-pregnancy factor (EPF), is a protein Proteins are large biomolecule , showing alpha helices, represented by ribbons. This poten was the first to have its s ...
and able to substitute for it in the assembly of bacteriophage T4
virus A virus is a submicroscopic infectious agent In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular biology, molecu ...

virus
particles during infection.Marusich EI, Kurochkina LP, Mesyanzhinov VV. Chaperones in bacteriophage T4 assembly. Biochemistry (Mosc). 1998;63(4):399-406 Like GroES, gp31 forms a stable complex with
GroEL GroEL is a protein which belongs to the family of , and is found in many bacteria. It is required for the proper of many proteins. To function properly, GroEL requires the lid-like cochaperonin protein complex . In the proteins Hsp60 and Hsp1 ...

GroEL
chaperonin that is absolutely necessary for the folding and assembly in vivo of the bacteriophage T4 major capsid protein gp23.


Fold switching

Some proteins have multiple native structures, and change their fold based on some external factors. For example, the KaiB protein switches fold throughout the day, acting as a clock for cyanobacteria. It has been estimated that around 0.5–4% of PDB (
Protein Data Bank The Protein Data Bank (PDB) is a database In computing, a database is an organized collection of Data (computing), data stored and accessed electronically from a computer system. Where databases are more complex they are often developed using ...

Protein Data Bank
) proteins switch folds.


Protein misfolding and neurodegenerative disease

A protein is considered to be misfolded if it cannot achieve its normal native state. This can be due to mutations in the amino acid sequence or a disruption of the normal folding process by external factors. The misfolded protein typically contains
β-sheets The beta sheet, (β-sheet) (also β-pleated sheet) is a common motif of the regular protein secondary structure. Beta sheets consist of beta strands (β-strands) connected laterally by at least two or three backbone hydrogen bonds, forming a ge ...
that are organized in a supramolecular arrangement known as a cross-β structure. These β-sheet-rich assemblies are very stable, very insoluble, and generally resistant to proteolysis. The structural stability of these fibrillar assemblies is caused by extensive interactions between the protein monomers, formed by backbone hydrogen bonds between their β-strands. The misfolding of proteins can trigger the further misfolding and accumulation of other proteins into aggregates or oligomers. The increased levels of aggregated proteins in the cell leads to formation of
amyloid Amyloids are aggregates of proteins characterised by a Fibril, fibrillar morphology of 7–13 Nanometer, nm in diameter, a β-sheet Secondary structure of proteins, secondary structure (known as cross-β) and ability to be Histological stain, st ...
-like structures which can cause degenerative disorders and cell death. The amyloids are fibrillary structures that contain intermolecular hydrogen bonds which are highly insoluble and made from converted protein aggregates. Therefore, the proteasome pathway may not be efficient enough to degrade the misfolded proteins prior to aggregation. Misfolded proteins can interact with one another and form structured aggregates and gain toxicity through intermolecular interactions. Aggregated proteins are associated with
prion Prions are misfolded protein Protein folding is the physical process Physical changes are changes affecting the form of a chemical substance A chemical substance is a form of matter In classical physics and general chemistry, matte ...

prion
-related illnesses such as
Creutzfeldt–Jakob disease Creutzfeldt–Jakob disease (CJD), also known as subacute spongiform encephalopathy or neurocognitive disorder due to prion disease, is a fatal neurodegeneration, degenerative brain disorder. Early symptoms include memory problems, behavioral ch ...
,
bovine spongiform encephalopathy Bovine spongiform encephalopathy (BSE), commonly known as mad cow disease, is a neurodegenerative disease A neurodegenerative disease is caused by the progressive loss of structure or function of neuron A neuron or nerve cell is an membr ...
(mad cow disease), amyloid-related illnesses such as
Alzheimer's disease Alzheimer's disease (AD), also referred to simply as Alzheimer's, is a neurodegenerative disease A neurodegenerative disease is caused by the progressive loss of structure or function of neuron A neuron or nerve cell is an membrane p ...
and
familial amyloid cardiomyopathy Familial amyloid cardiomyopathy (FAC), or transthyretin amyloid cardiomyopathy (ATTR-CM) results from the aggregation and deposition of mutant and wild-type transthyretin (TTR) protein in the heart. TTR amyloid fibrils infiltrate the myocardium, le ...
or
polyneuropathy Polyneuropathy (poly- Poly, from the Greek :wikt:πολύς, πολύς meaning "many" or "much", may refer to: Businesses * China Poly Group Corporation, a Chinese business group, and its subsidiaries: ** Poly Property, a Hong Kong incorporated ...
, as well as intracellular aggregation diseases such as
Huntington's Huntington's disease (HD), also known as Huntington's chorea, is a neurodegenerative disease A neurodegenerative disease is caused by the progressive loss of structure or function of neuron A neuron or nerve cell is an membrane potentia ...
and
Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a chronic condition, long-term neurodegeneration, degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disea ...
. These age onset degenerative diseases are associated with the aggregation of misfolded proteins into insoluble, extracellular aggregates and/or intracellular inclusions including cross-β
amyloid Amyloids are aggregates of proteins characterised by a Fibril, fibrillar morphology of 7–13 Nanometer, nm in diameter, a β-sheet Secondary structure of proteins, secondary structure (known as cross-β) and ability to be Histological stain, st ...
fibril Fibrils (from the Latin Latin (, or , ) is a classical language belonging to the Italic languages, Italic branch of the Indo-European languages. Latin was originally spoken in the area around Rome, known as Latium. Through the power of the R ...
s. It is not completely clear whether the aggregates are the cause or merely a reflection of the loss of protein homeostasis, the balance between synthesis, folding, aggregation and protein turnover. Recently the
European Medicines Agency The European Medicines Agency (EMA) is an agency of the European Union An agency of the European Union is a decentralised body of the European Union The European Union (EU) is a political and economic union of Member state of the Eu ...
approved the use of
Tafamidis Tafamidis, sold under the brand names Vyndaqel and Vyndamax, is a medication used to delay disease progression in adults with certain forms of transthyretin amyloidosis. It can be used to treat both hereditary forms, familial amyloid cardiomyopa ...

Tafamidis
or Vyndaqel (a kinetic stabilizer of tetrameric transthyretin) for the treatment of transthyretin amyloid diseases. This suggests that the process of amyloid fibril formation (and not the fibrils themselves) causes the degeneration of post-mitotic tissue in human amyloid diseases. Misfolding and excessive degradation instead of folding and function leads to a number of
proteopathy In medicine Medicine is the science Science () is a systematic enterprise that builds and organizes knowledge Knowledge is a familiarity, awareness, or understanding of someone or something, such as facts ( descriptive knowledge), ...
diseases such as
antitrypsin Alpha-1 antitrypsin or α1-antitrypsin (A1AT, α1AT, A1A, or AAT) is a protein belonging to the serpin superfamily. It is encoded in humans by the ''SERPINA1'' gene. A protease inhibitor (biology), protease inhibitor, it is also known as alpha1 ...
-associated
emphysema Emphysema, or pulmonary emphysema, is a lower respiratory tract disease, characterised by air-filled spaces ( pneumatoses) in the lung The lungs are the primary organs An organ is a group of tissues with similar functions. Plant lif ...
,
cystic fibrosis Cystic fibrosis (CF) is a genetic disorder A genetic disorder is a health problem caused by one or more abnormalities in the genome In the fields of molecular biology and genetics, a genome is all genetic information of an organis ...
and the
lysosomal storage diseases Lysosomal storage diseases (LSDs; ) are a group of over 70 rare inherited metabolic disorders A metabolic disorder is a disorder that negatively alters the body's processing and distribution of macronutrients A nutrient is a substance Substance ...
, where loss of function is the origin of the disorder. While protein replacement therapy has historically been used to correct the latter disorders, an emerging approach is to use pharmaceutical chaperones to fold mutated proteins to render them functional.


Experimental techniques for studying protein folding

While inferences about protein folding can be made through Phi value analysis, mutation studies, typically, experimental techniques for studying protein folding rely on the Equilibrium unfolding, gradual unfolding or folding of proteins and observing conformational changes using standard non-crystallographic techniques.


X-ray crystallography

X-ray crystallography is one of the more efficient and important methods for attempting to decipher the three dimensional configuration of a folded protein. To be able to conduct X-ray crystallography, the protein under investigation must be located inside a crystal lattice. To place a protein inside a crystal lattice, one must have a suitable solvent for crystallization, obtain a pure protein at supersaturated levels in solution, and precipitate the crystals in solution. Once a protein is crystallized, X-ray beams can be concentrated through the crystal lattice which would diffract the beams or shoot them outwards in various directions. These exiting beams are correlated to the specific three-dimensional configuration of the protein enclosed within. The X-rays specifically interact with the electron clouds surrounding the individual atoms within the protein crystal lattice and produce a discernible diffraction pattern. Only by relating the electron density clouds with the amplitude of the X-rays can this pattern be read and lead to assumptions of the phases or phase angles involved that complicate this method. Without the relation established through a mathematical basis known as Fourier transform, the "phase problem" would render predicting the diffraction patterns very difficult. Emerging methods like multiple isomorphous replacement use the presence of a heavy metal ion to diffract the X-rays into a more predictable manner, reducing the number of variables involved and resolving the phase problem.


Fluorescence spectroscopy

Fluorescence spectroscopy is a highly sensitive method for studying the folding state of proteins. Three amino acids, phenylalanine (Phe), tyrosine (Tyr) and tryptophan (Trp), have intrinsic fluorescence properties, but only Tyr and Trp are used experimentally because their quantum yields are high enough to give good fluorescence signals. Both Trp and Tyr are excited by a wavelength of 280 nm, whereas only Trp is excited by a wavelength of 295 nm. Because of their aromatic character, Trp and Tyr residues are often found fully or partially buried in the hydrophobic core of proteins, at the interface between two protein domains, or at the interface between subunits of oligomeric proteins. In this apolar environment, they have high quantum yields and therefore high fluorescence intensities. Upon disruption of the protein's tertiary or quaternary structure, these side chains become more exposed to the hydrophilic environment of the solvent, and their quantum yields decrease, leading to low fluorescence intensities. For Trp residues, the wavelength of their maximal fluorescence emission also depend on their environment. Fluorescence spectroscopy can be used to characterize the equilibrium unfolding of proteins by measuring the variation in the intensity of fluorescence emission or in the wavelength of maximal emission as functions of a denaturant value. The denaturant can be a chemical molecule (urea, guanidinium hydrochloride), temperature, pH, pressure, etc. The equilibrium between the different but discrete protein states, i.e. native state, intermediate states, unfolded state, depends on the denaturant value; therefore, the global fluorescence signal of their equilibrium mixture also depends on this value. One thus obtains a profile relating the global protein signal to the denaturant value. The profile of equilibrium unfolding may enable one to detect and identify intermediates of unfolding. General equations have been developed by Hugues Bedouelle to obtain the thermodynamic parameters that characterize the unfolding equilibria for homomeric or heteromeric proteins, up to trimers and potentially tetramers, from such profiles. Fluorescence spectroscopy can be combined with fast-mixing devices such as stopped flow, to measure protein folding kinetics, generate a chevron plot and derive a Phi value analysis.


Circular dichroism

Circular dichroism is one of the most general and basic tools to study protein folding. Circular dichroism spectroscopy measures the absorption of circular polarization, circularly polarized light. In proteins, structures such as
alpha helices The alpha helix (α-helix) is a common motif in the secondary structure Biomolecular structure is the intricate folded, three-dimensional shape that is formed by a molecule File:Pentacene on Ni(111) STM.jpg, A scanning tunneling microscopy i ...

alpha helices
and beta sheets are chiral, and thus absorb such light. The absorption of this light acts as a marker of the degree of foldedness of the protein ensemble. This technique has been used to measure equilibrium unfolding of the protein by measuring the change in this absorption as a function of denaturant concentration or
temperature Temperature ( ) is a physical quantity that expresses hot and cold. It is the manifestation of thermal energy Thermal radiation in visible light can be seen on this hot metalwork. Thermal energy refers to several distinct physical concept ...

temperature
. A denaturant melt measures the Thermodynamic free energy, free energy of unfolding as well as the protein's m value, or denaturant dependence. A temperature melt measures the Denaturation midpoint, denaturation temperature (Tm) of the protein. As for fluorescence spectroscopy, circular-dichroism spectroscopy can be combined with fast-mixing devices such as stopped flow to measure protein folding Chemical kinetics, kinetics and to generate chevron plots.


Vibrational circular dichroism of proteins

The more recent developments of vibrational circular dichroism (VCD) techniques for proteins, currently involving Fourier transform (FT) instruments, provide powerful means for determining protein conformations in solution even for very large protein molecules. Such VCD studies of proteins can be combined with X-ray diffraction data for protein crystals, FT-IR data for protein solutions in heavy water (D2O), or Quantum chemistry, quantum computations.


Protein nuclear magnetic resonance spectroscopy

Protein nuclear magnetic resonance (NMR) is able to collect protein structural data by inducing a magnet field through samples of concentrated protein. In NMR, depending on the chemical environment, certain nuclei will absorb specific radio-frequencies. Because protein structural changes operate on a time scale from ns to ms, NMR is especially equipped to study intermediate structures in timescales of ps to s. Some of the main techniques for studying proteins structure and non-folding protein structural changes include Two-dimensional nuclear magnetic resonance spectroscopy, COSY, Two-dimensional nuclear magnetic resonance spectroscopy, TOCSY, Heteronuclear single quantum coherence spectroscopy, HSQC, Relaxation (NMR), time relaxation (T1 & T2), and Nuclear Overhauser effect, NOE. NOE is especially useful because magnetization transfers can be observed between spatially proximal hydrogens are observed. Different NMR experiments have varying degrees of timescale sensitivity that are appropriate for different protein structural changes. NOE can pick up bond vibrations or side chain rotations, however, NOE is too sensitive to pick up protein folding because it occurs at larger timescale. Because protein folding takes place in about 50 to 3000 s−1 CPMG Relaxation dispersion and Magnetization transfer, chemical exchange saturation transfer have become some of the primary techniques for NMR analysis of folding. In addition, both techniques are used to uncover excited intermediate states in the protein folding landscape. To do this, CPMG Relaxation dispersion takes advantage of the spin echo phenomenon. This technique exposes the target nuclei to a 90 pulse followed by one or more 180 pulses. As the nuclei refocus, a broad distribution indicates the target nuclei is involved in an intermediate excited state. By looking at Relaxation dispersion plots the data collect information on the thermodynamics and kinetics between the excited and ground. Saturation Transfer measures changes in signal from the ground state as excited states become perturbed. It uses weak radio frequency irradiation to saturate the excited state of a particular nuclei which transfers its saturation to the ground state. This signal is amplified by decreasing the magnetization (and the signal) of the ground state. The main limitations in NMR is that its resolution decreases with proteins that are larger than 25 kDa and is not as detailed as X-ray crystallography. Additionally, protein NMR analysis is quite difficult and can propose multiple solutions from the same NMR spectrum. In a study focused on the folding of an amyotrophic lateral sclerosis involved protein SOD1, excited intermediates were studied with relaxation dispersion and Saturation transfer. SOD1 had been previously tied to many disease causing mutants which were assumed to be involved in protein aggregation, however the mechanism was still unknown. By using Relaxation Dispersion and Saturation Transfer experiments many excited intermediate states were uncovered misfolding in the SOD1 mutants.


Dual-polarization interferometry

Dual polarisation interferometry is a surface-based technique for measuring the optical properties of molecular layers. When used to characterize protein folding, it measures the protein conformation, conformation by determining the overall size of a monolayer of the protein and its density in real time at sub-Angstrom resolution, although real-time measurement of the kinetics of protein folding are limited to processes that occur slower than ~10 Hz. Similar to circular dichroism, the stimulus for folding can be a denaturant or
temperature Temperature ( ) is a physical quantity that expresses hot and cold. It is the manifestation of thermal energy Thermal radiation in visible light can be seen on this hot metalwork. Thermal energy refers to several distinct physical concept ...

temperature
.


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. Experimenters rapidly trigger the folding of a sample of unfolded protein and observe the resulting protein dynamics, dynamics. Fast techniques in use include neutron scattering, ultrafast mixing of solutions, photochemical methods, and Temperature jump, laser temperature jump spectroscopy. Among the many scientists who have contributed to the development of these techniques are Jeremy Cook, Heinrich Roder, Harry Gray (chemist), Harry Gray, Martin Gruebele, Brian Dyer, William Eaton, Sheena Radford, Chris Dobson, Alan Fersht, Bengt Nölting and Lars Konermann.


Proteolysis

Proteolysis is routinely used to probe the fraction unfolded under a wide range of solution conditions (e.g. fast parallel proteolysis (FASTpp).


Single-molecule force spectroscopy

Single molecule techniques such as optical tweezers and AFM have been used to understand protein folding mechanisms of isolated proteins as well as proteins with chaperones. Optical tweezers have been used to stretch single protein molecules from their C- and N-termini and unfold them to allow study of the subsequent refolding. The technique allows one to measure folding rates at single-molecule level; for example, optical tweezers have been recently applied to study folding and unfolding of proteins involved in blood coagulation. von Willebrand factor (vWF) is a protein with an essential role in blood clot formation process. It discovered – using single molecule optical tweezers measurement – that calcium-bound vWF acts as a shear force sensor in the blood. Shear force leads to unfolding of the A2 domain of vWF, whose refolding rate is dramatically enhanced in the presence of calcium. Recently, it was also shown that the simple src SH3 domain accesses multiple unfolding pathways under force.


Biotin painting

Biotin painting enables condition-specific cellular snapshots of (un)folded proteins. Biotin 'painting' shows a bias towards predicted Intrinsically disordered proteins.


Computational studies of protein folding

Computational studies of protein folding includes three main aspects related to the prediction of protein stability, kinetics, and structure. A recent review summarizes the available computational methods for protein folding.


Levinthal's paradox

In 1969, Cyrus Levinthal noted that, because of the very large number of degrees of freedom in an unfolded polypeptide chain, the molecule has an astronomical number of possible conformations. An estimate of 3300 or 10143 was made in one of his papers. Levinthal's paradox is a thought experiment based on the observation that if a protein were folded by sequential sampling of 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, and the protein must, therefore, fold through a series of meta-stable Reaction intermediate, intermediate states.


Energy landscape of protein folding

The Configuration space (physics), configuration space of a protein during folding can be visualized as an energy landscape. According to Joseph Bryngelson and Peter Wolynes, proteins follow the ''principle of minimal frustration'' meaning that naturally evolved proteins have optimized their folding energy landscapes, and that nature has chosen amino acid sequences so that the folded state of the protein is sufficiently stable. In addition, the acquisition of the folded state had to become a sufficiently fast process. Even though nature has reduced the level of ''frustration'' in proteins, some degree of it remains up to now as can be observed in the presence of local minima in the energy landscape of proteins. 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 toward 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 lattice protein, computational simulations of model proteins and experimental studies, and it has been used to improve methods for protein structure prediction and protein design, design. The description of protein folding by the leveling free-energy landscape is also consistent with the 2nd law of thermodynamics. Physically, thinking of landscapes in terms of visualizable potential or total energy surfaces simply with maxima, saddle points, minima, and funnels, rather like geographic landscapes, is perhaps a little misleading. The relevant description is really a high-dimensional phase space in which manifolds might take a variety of more complicated topological forms. The unfolded polypeptide chain begins at the top of the funnel where it may assume the largest number of unfolded variations and is in its highest energy state. Energy landscapes such as these indicate that there are a large number of initial possibilities, but only a single native state is possible; however, it does not reveal the numerous folding pathways that are possible. A different molecule of the same exact protein may be able to follow marginally different folding pathways, seeking different lower energy intermediates, as long as the same native structure is reached. Different pathways may have different frequencies of utilization depending on the thermodynamic favorability of each pathway. This means that if one pathway is found to be more thermodynamically favorable than another, it is likely to be used more frequently in the pursuit of the native structure. As the protein begins to fold and assume its various conformations, it always seeks a more thermodynamically favorable structure than before and thus continues through the energy funnel. Formation of secondary structures is a strong indication of increased stability within the protein, and only one combination of secondary structures assumed by the polypeptide backbone will have the lowest energy and therefore be present in the native state of the protein. Among the first structures to form once the polypeptide begins to fold are alpha helices and beta turns, where alpha helices can form in as little as 100 nanoseconds and beta turns in 1 microsecond. There exists a saddle point in the energy funnel landscape where the transition state for a particular protein is found. The transition state in the energy funnel diagram is the conformation that must be assumed by every molecule of that protein if the protein wishes to finally assume the native structure. No protein may assume the native structure without first passing through the transition state. The transition state can be referred to as a variant or premature form of the native state rather than just another intermediary step. The folding of the transition state is shown to be rate-determining, and even though it exists in a higher energy state than the native fold, it greatly resembles the native structure. Within the transition state, there exists a nucleus around which the protein is able to fold, formed by a process referred to as "nucleation condensation" where the structure begins to collapse onto the nucleus.


Modeling of protein folding

''wiktionary:de novo, De novo'' or ''ab initio'' techniques for computational protein structure prediction can be used for simulating various aspects of protein folding. Molecular Dynamics (MD) was used in simulations of protein folding and dynamics in silico. First equilibrium folding simulations were done using implicit solvent model and umbrella sampling. 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. Long-time folding processes (beyond about 1 millisecond), like folding of small-size proteins (about 50 residues) or larger, can be accessed using Coarse-grained modeling, coarse-grained models. Several large-scale computational projects, such as Rosetta@home, Folding@home and Foldit,FoldIt - Folding Protein Game
/ref> target protein folding. Long continuous-trajectory simulations have been performed on Anton (computer), Anton, a massively parallel supercomputer designed and built around custom ASICs and interconnects by D. E. Shaw Research. The longest published result of a simulation performed using Anton is a 2.936 millisecond simulation of NTL9 at 355 K.


See also

* Chevron plot * Denaturation midpoint * Downhill folding * Folding (chemistry) * Phi value analysis * Potential energy of protein * Protein dynamics * Protein misfolding cyclic amplification * Protein structure prediction software * Proteopathy * Time-resolved mass spectrometry


References


External links


Human Proteome Folding Project
{{Authority control Protein folding, Protein structure