Protein tertiary structure is the three-dimensional shape of a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

. The tertiary structure will have a single

polypeptide Peptides are short chains of amino acids linked by peptide bonds. A polypeptide is a longer, continuous, unbranched peptide chain. Polypeptides that have a molecular mass of 10,000 Da or more are called proteins. Chains of fewer than twenty ...

chain "backbone" with one or more

protein secondary structure Protein secondary structure is the local spatial conformation of the polypeptide backbone excluding the side chains. The two most common secondary structural elements are alpha helices and beta sheets, though beta turns and omega loops occu ...

s, the

protein domain In molecular biology, a protein domain is a region of a protein's Peptide, polypeptide chain that is self-stabilizing and that Protein folding, folds independently from the rest. Each domain forms a compact folded Protein tertiary structure, thre ...

Amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...

side chain In organic chemistry and biochemistry, a side chain is a substituent, chemical group that is attached to a core part of the molecule called the "main chain" or backbone chain, backbone. The side chain is a hydrocarbon branching element of a mo ...

s and the backbone may interact and bond in a number of ways. The interactions and bonds of side chains within a particular protein determine its tertiary structure. The protein tertiary structure is defined by its

atom Atoms are the basic particles of the chemical elements. An atom consists of a atomic nucleus, nucleus of protons and generally neutrons, surrounded by an electromagnetically bound swarm of electrons. The chemical elements are distinguished fr ...

ic coordinates. These coordinates may refer either to a protein domain or to the entire tertiary structure. A number of these structures may bind to each other, forming a

quaternary structure Protein quaternary structure is the fourth (and highest) classification level of protein structure. Protein quaternary structure refers to the structure of proteins which are themselves composed of two or more smaller protein chains (also refe ...

History

The science of the tertiary structure of proteins has progressed from one of

hypothesis A hypothesis (: hypotheses) is a proposed explanation for a phenomenon. A scientific hypothesis must be based on observations and make a testable and reproducible prediction about reality, in a process beginning with an educated guess o ...

to one of detailed definition. Although

Emil Fischer Hermann Emil Louis Fischer (; 9 October 1852 – 15 July 1919) was a German chemist and List of Nobel laureates in Chemistry, 1902 recipient of the Nobel Prize in Chemistry. He discovered the Fischer esterification. He also developed the Fisch ...

had suggested proteins were made of

polypeptide chain Peptides are short chains of amino acids linked by peptide bonds. A polypeptide is a longer, continuous, unbranched peptide chain. Polypeptides that have a molecular mass of 10,000 Da or more are called proteins. Chains of fewer than twenty ami ...

s and amino acid side chains, it was Dorothy Maud Wrinch who incorporated

geometry Geometry (; ) is a branch of mathematics concerned with properties of space such as the distance, shape, size, and relative position of figures. Geometry is, along with arithmetic, one of the oldest branches of mathematics. A mathematician w ...

into the prediction of

protein structure Protein structure is the three-dimensional arrangement of atoms in an amino acid-chain molecule. Proteins are polymers specifically polypeptides formed from sequences of amino acids, which are the monomers of the polymer. A single amino acid ...

s. Wrinch demonstrated this with the ''Cyclol'' model, the first prediction of the structure of a

globular protein In biochemistry, globular proteins or spheroproteins are spherical ("globe-like") proteins and are one of the common protein types (the others being fibrous, disordered and membrane proteins). Globular proteins are somewhat water-soluble (form ...

. Contemporary methods are able to determine, without prediction, tertiary structures to within 5 Å (0.5 nm) for small proteins (<120 residues) and, under favorable conditions, confident

secondary structure Protein secondary structure is the local spatial conformation of the polypeptide backbone excluding the side chains. The two most common Protein structure#Secondary structure, secondary structural elements are alpha helix, alpha helices and beta ...

predictions.

Determinants

Stability of native states

A protein folded into its

native state In biochemistry, the native state of a protein or nucleic acid is its properly Protein folding, folded and/or assembled form, which is operative and functional. The native state of a biomolecule may possess all four levels of biomolecular structu ...

or native conformation typically has a lower

Gibbs free energy In thermodynamics, the Gibbs free energy (or Gibbs energy as the recommended name; symbol is a thermodynamic potential that can be used to calculate the maximum amount of Work (thermodynamics), work, other than Work (thermodynamics)#Pressure–v ...

(a combination of

enthalpy Enthalpy () is the sum of a thermodynamic system's internal energy and the product of its pressure and volume. It is a state function in thermodynamics used in many measurements in chemical, biological, and physical systems at a constant extern ...

and

entropy Entropy is a scientific concept, most commonly associated with states of disorder, randomness, or uncertainty. The term and the concept are used in diverse fields, from classical thermodynamics, where it was first recognized, to the micros ...

) than the unfolded conformation. A protein will tend towards low-energy conformations, which will determine the protein's fold in the cellular environment. Because many similar conformations will have similar energies, protein structures are dynamic, fluctuating between these similar structures.

Globular protein In biochemistry, globular proteins or spheroproteins are spherical ("globe-like") proteins and are one of the common protein types (the others being fibrous, disordered and membrane proteins). Globular proteins are somewhat water-soluble (form ...

s have a core of

hydrophobic In chemistry, hydrophobicity is the chemical property of a molecule (called a hydrophobe) that is seemingly repelled from a mass of water. In contrast, hydrophiles are attracted to water. Hydrophobic molecules tend to be nonpolar and, thu ...

amino acid residues and a surface region of

water Water is an inorganic compound with the chemical formula . It is a transparent, tasteless, odorless, and Color of water, nearly colorless chemical substance. It is the main constituent of Earth's hydrosphere and the fluids of all known liv ...

-exposed, charged,

hydrophilic A hydrophile is a molecule or other molecular entity that is attracted to water molecules and tends to be dissolved by water.Liddell, H.G. & Scott, R. (1940). ''A Greek-English Lexicon'' Oxford: Clarendon Press. In contrast, hydrophobes are n ...

residues. This arrangement may stabilize interactions within the tertiary structure. For example, in

secrete Secretion is the movement of material from one point to another, such as a secreted chemical substance from a cell or gland. In contrast, excretion is the removal of certain substances or waste products from a cell or organism. The classical mec ...

d proteins, which are not bathed in

cytoplasm The cytoplasm describes all the material within a eukaryotic or prokaryotic cell, enclosed by the cell membrane, including the organelles and excluding the nucleus in eukaryotic cells. The material inside the nucleus of a eukaryotic cell a ...

disulfide bond In chemistry, a disulfide (or disulphide in British English) is a compound containing a functional group or the anion. The linkage is also called an SS-bond or sometimes a disulfide bridge and usually derived from two thiol groups. In inor ...

s between

cysteine Cysteine (; symbol Cys or C) is a semiessential proteinogenic amino acid with the chemical formula, formula . The thiol side chain in cysteine enables the formation of Disulfide, disulfide bonds, and often participates in enzymatic reactions as ...

residues help to maintain the tertiary structure. There is a commonality of stable tertiary structures seen in proteins of diverse function and diverse

evolution Evolution is the change in the heritable Phenotypic trait, characteristics of biological populations over successive generations. It occurs when evolutionary processes such as natural selection and genetic drift act on genetic variation, re ...

. For example, the

TIM barrel The TIM barrel (triose-phosphate isomerase), also known as an alpha/beta barrel, is a conserved protein fold consisting of eight alpha helices (α-helices) and eight parallel beta strands (β-strands) that alternate along the peptide backbone. ...

, named for the enzyme

triosephosphateisomerase Triose-phosphate isomerase (TPI or TIM) is an enzyme () that catalyzes the reversible interconversion of the triose phosphate isomers dihydroxyacetone phosphate and D-glyceraldehyde 3-phosphate. TPI plays an important role in glycolysis and i ...

, is a common tertiary structure as is the highly stable, dimeric,

coiled coil A coiled coil is a structural motif in proteins in which two to seven alpha-helices are coiled together like the strands of a rope. ( Dimers and trimers are the most common types.) They have been found in roughly 5-10% of proteins and have a ...

structure. Hence, proteins may be classified by the structures they hold. Databases of proteins which use such a classification include ''

SCOP A ( or ) was a poet as represented in Old English poetry. The scop is the Old English counterpart of the Old Norse ', with the important difference that "skald" was applied to historical persons, and scop is used, for the most part, to designat ...

'' and ''

CATH Cath may refer to: __NOTOC__ People * Cath Bishop (born 1971), British former rower and 2003 world champion * Cath Carroll (born 1960), British musician and music journalist * Cath Coffey (), one of the earliest members of British rap band Stereo ...

''. Folding kinetics may trap a protein in a high-

energy Energy () is the physical quantity, quantitative physical property, property that is transferred to a physical body, body or to a physical system, recognizable in the performance of Work (thermodynamics), work and in the form of heat and l ...

conformation, i.e. a high-energy intermediate conformation blocks access to the lowest-energy conformation. The high-energy conformation may contribute to the function of the protein. For example, the

influenza Influenza, commonly known as the flu, is an infectious disease caused by influenza viruses. Symptoms range from mild to severe and often include fever, runny nose, sore throat, muscle pain, headache, coughing, and fatigue. These sympto ...

hemagglutinin The term hemagglutinin (alternatively spelt ''haemagglutinin'', from the Greek , 'blood' + Latin , 'glue') refers to any protein that can cause red blood cells (erythrocytes) to clump together (" agglutinate") ''in vitro''. They do this by bindin ...

protein is a single polypeptide chain which when activated, is proteolytically cleaved to form two polypeptide chains. The two chains are held in a high-energy conformation. When the local pH drops, the protein undergoes an energetically favorable conformational rearrangement that enables it to penetrate the host

cell membrane The cell membrane (also known as the plasma membrane or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of a cell from the outside environment (the extr ...

. Some tertiary protein structures may exist in long-lived states that are not the expected most stable state. For example, many serpins (serine protease inhibitors) show this

metastability In chemistry and physics, metastability is an intermediate energetic state within a dynamical system other than the system's state of least energy. A ball resting in a hollow on a slope is a simple example of metastability. If the ball is onl ...

. They undergo a

conformational change In biochemistry, a conformational change is a change in the shape of a macromolecule, often induced by environmental factors. A macromolecule is usually flexible and dynamic. Its shape can change in response to changes in its environment or othe ...

when a loop of the protein is cut by a

protease A protease (also called a peptidase, proteinase, or proteolytic enzyme) is an enzyme that catalysis, catalyzes proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the formation of new protein products ...

Chaperone proteins

It is commonly assumed that the native state of a protein is also the most thermodynamically stable and that a protein will reach its native state, given its

chemical kinetics Chemical kinetics, also known as reaction kinetics, is the branch of physical chemistry that is concerned with understanding the rates of chemical reactions. It is different from chemical thermodynamics, which deals with the direction in which a ...

, before it 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 ...

. Protein chaperones within the cytoplasm of a cell assist a newly synthesised polypeptide to attain its native state. Some chaperone proteins are highly specific in their function, for example,

protein disulfide isomerase Protein disulfide isomerase (), or PDI, is an enzyme in the endoplasmic reticulum (ER) in eukaryotes and the periplasm of bacteria that catalyzes the formation and breakage of disulfide bonds between cysteine residues within proteins as the ...

; others are general in their function and may assist most globular proteins, for example, the

prokaryotic A prokaryote (; less commonly spelled procaryote) is a single-celled organism whose cell lacks a nucleus and other membrane-bound organelles. The word ''prokaryote'' comes from the Ancient Greek (), meaning 'before', and (), meaning 'nut' ...

GroEL GroEL is a protein which belongs to the chaperonin family of Chaperone (protein), molecular chaperones, and is found in many bacteria. It is required for the proper protein folding, folding of many proteins. To function properly, GroEL requires ...

GroES Heat shock 10 kDa protein 1 (Hsp10), also known as chaperonin 10 (cpn10) or early-pregnancy factor (EPF), is a protein that in humans is encoded by the ''HSPE1'' gene. The homolog in ''Escherichia coli, E. coli'' is GroES that is a chaperonin ...

system of proteins and the homologous

eukaryotic The eukaryotes ( ) constitute the Domain (biology), domain of Eukaryota or Eukarya, organisms whose Cell (biology), cells have a membrane-bound cell nucleus, nucleus. All animals, plants, Fungus, fungi, seaweeds, and many unicellular organisms ...

heat shock protein Heat shock proteins (HSPs) are a family of proteins produced by cells in response to exposure to stressful conditions. They were first described in relation to heat shock, but are now known to also be expressed during other stresses including ex ...

s (the Hsp60/Hsp10 system).

Cytoplasmic environment

Prediction of protein tertiary structure relies on knowing the protein's

primary structure Protein primary structure is the linear sequence of amino acids in a peptide or protein. By convention, the primary structure of a protein is reported starting from the amino-terminal (N) end to the carboxyl-terminal (C) end. Protein biosynthe ...

and comparing the possible predicted tertiary structure with known tertiary structures in

protein data bank The Protein Data Bank (PDB) is a database for the three-dimensional structural data of large biological molecules such as proteins and nucleic acids, which is overseen by the Worldwide Protein Data Bank (wwPDB). This structural data is obtained a ...

s. This only takes into account the cytoplasmic environment present at the time of

protein synthesis Protein biosynthesis, or protein synthesis, is a core biological process, occurring inside cells, balancing the loss of cellular proteins (via degradation or export) through the production of new proteins. Proteins perform a number of critica ...

to the extent that a similar cytoplasmic environment may also have influenced the structure of the proteins recorded in the protein data bank.

Ligand binding

The structure of a protein, such as an

enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...

, may change upon binding of its natural ligands, for example a cofactor. In this case, the structure of the protein bound to the ligand is known as holo structure, while the unbound protein has an apo structure. Structure stabilized by the formation of weak bonds between amino acid side chains - Determined by the folding of the polypeptide chain on itself (nonpolar residues are located inside the protein, while polar residues are mainly located outside) - Envelopment of the protein brings the protein closer and relates a-to located in distant regions of the sequence - Acquisition of the tertiary structure leads to the formation of pockets and sites suitable for the recognition and the binding of specific molecules (biospecificity).

Determination

The knowledge of the tertiary structure of soluble

s is more advanced than that of

membrane protein Membrane proteins are common proteins that are part of, or interact with, biological membranes. Membrane proteins fall into several broad categories depending on their location. Integral membrane proteins are a permanent part of a cell membrane ...

s because the former are easier to study with available technology.

X-ray crystallography

X-ray crystallography X-ray crystallography is the experimental science of determining the atomic and molecular structure of a crystal, in which the crystalline structure causes a beam of incident X-rays to Diffraction, diffract in specific directions. By measuring th ...

is the most common tool used to determine

. It provides high resolution of the structure but it does not give information about protein's conformational flexibility.

NMR

Protein NMR Nuclear magnetic resonance spectroscopy of proteins (usually abbreviated protein NMR) is a field of structural biology in which NMR spectroscopy is used to obtain information about the structure and dynamics of proteins, and also nucleic acids, and ...

gives comparatively lower resolution of protein structure. It is limited to smaller proteins. However, it can provide information about conformational changes of a protein in solution.

Cryogenic electron microscopy

Cryogenic electron microscopy Cryogenic electron microscopy (cryo-EM) is a transmission electron microscopy technique applied to samples cooled to cryogenic temperatures. For biological specimens, the structure is preserved by embedding in an environment of vitreous ice. An ...

(cryo-EM) can give information about both a protein's tertiary and quaternary structure. It is particularly well-suited to large proteins and symmetrical complexes of

protein subunit In structural biology, a protein subunit is a polypeptide chain or single protein molecule that assembles (or "''coassembles''") with others to form a protein complex. Large assemblies of proteins such as viruses often use a small number of t ...

Dual polarisation interferometry

Dual polarisation interferometry Dual-polarization interferometry (DPI) is an analytical technique that probes molecular layers adsorbed to the surface of a waveguide using the evanescent wave of a laser beam. It is used to measure the conformational change in proteins, or o ...

provides complementary information about surface captured proteins. It assists in determining structure and conformation changes over time.

Prediction algorithm

The

Folding@home Folding@home (FAH or F@h) is a distributed computing project aimed to help scientists develop new therapeutics for a variety of diseases by the means of simulating protein dynamics. This includes the process of protein folding and the movements ...

project at the

University of Pennsylvania The University of Pennsylvania (Penn or UPenn) is a Private university, private Ivy League research university in Philadelphia, Pennsylvania, United States. One of nine colonial colleges, it was chartered in 1755 through the efforts of f ...

is a

distributed computing Distributed computing is a field of computer science that studies distributed systems, defined as computer systems whose inter-communicating components are located on different networked computers. The components of a distributed system commu ...

research effort which uses approximately 5

petaFLOPS Floating point operations per second (FLOPS, flops or flop/s) is a measure of computer performance in computing, useful in fields of scientific computations that require floating-point calculations. For such cases, it is a more accurate measu ...

(≈10 x86 petaFLOPS) of available computing. It aims to find an

algorithm In mathematics and computer science, an algorithm () is a finite sequence of Rigour#Mathematics, mathematically rigorous instructions, typically used to solve a class of specific Computational problem, problems or to perform a computation. Algo ...

which will consistently predict protein tertiary and quaternary structures given the protein's amino acid sequence and its cellular conditions. A list of software for protein tertiary structure prediction can be found at

List of protein structure prediction software This list of protein structure prediction software summarizes notable used software tools in protein structure prediction, including homology modeling, protein threading, ''ab initio'' methods, secondary structure prediction, and transmembrane ...

References

External links

Protein Data Bank

Display, analyse and superimpose protein 3D structures

Display, analyse and superimpose protein 3D structures

WWW-based course teaching elementary protein bioinformatics

Critical Assessment of Structure Prediction (CASP)

Structural Classification of Proteins (SCOP)

CATH Protein Structure Classification

DALI/FSSP software and database of superposed protein structures

TOPOFIT-DB Invariant Structural Cores between proteins
* PDBWiki �
PDBWiki Home Page
– a website for community annotation of PDB structures. {{DEFAULTSORT:Tertiary Structure Protein structure 3