Cooperativity
Encyclopedia
Cooperativity is a phenomenon displayed by enzyme
s or receptor
s that have multiple binding site
s where the affinity of the binding sites for a ligand is increased, positive cooperativity, or decreased, negative cooperativity, upon the binding of a ligand to a binding site. For example the affinity of hemoglobin's four binding sites for oxygen is increased above that of the unbound hemoglobin when the first oxygen molecule binds. This is referred to as cooperative binding
. We also see cooperativity in large chain molecules made of many identical (or nearly identical) subunits (such as DNA
, protein
s, and phospholipid
s), when such molecules undergo phase transitions such as melting, unfolding or unwinding. This is referred to as subunit cooperativity.
Ligands can either have non-cooperativity, positive cooperativity or negative cooperativity.
An example of positive cooperativity is the binding of oxygen
to hemoglobin
. One oxygen
molecule can bind to the ferrous iron of a heme molecule in each of the four chains of a hemoglobin
molecule. Deoxy-hemoglobin has a relatively low affinity for oxygen
, but when one molecule binds to a single heme, the oxygen
affinity increases, allowing the second molecule to bind more easily, and the third and fourth even more easily. The oxygen
affinity of 3-oxy-hemoglobin is ~300 times greater than that of deoxy-hemoglobin. This behavior leads the affinity curve of hemoglobin
to be sigmoidal
, rather than hyperbolic
as with the monomeric myoglobin
. By the same process, the ability for hemoglobin
to lose oxygen
increases as fewer oxygen molecules are bound. See also Oxygen-hemoglobin dissociation curve.
Negative cooperativity means that the opposite will be true; as ligand
s bind to the protein
, the protein
's affinity for the ligand will decrease. An example of this occurring is the relationship between glyceraldehyde-3-phosphate and the enzyme
glyceraldehyde-3-phosphate dehydrogenase.
Homotropic cooperativity refers to the fact that the molecule causing the cooperativity is the one that will be affected by it. Heterotropic cooperativity is where a third substance causes the change in affinity.
involves cooperativity. Portions of DNA must unwind in order for DNA to carry out replication
, transcription
and recombination
. Positive cooperativity among adjacent DNA nucleotide
s makes it easier to unwind a whole group of adjacent nucleotides than it is to unwind the same number of nucleotides spread out along the DNA chain. The cooperative unit size is the number of adjacent bases that tend to unwind as a single unit due to the effects of positive cooperativity. This phenomenon applies to other types of chain molecules as well, such as the folding and unfolding of proteins and in the "melting" of phospholipid
chains that make up the membranes of cells
. Subunit coorperativity is measured on the relative scale known as Hill's Constant.
plays a role. For example in the case of oxygen binding to hemoglobin
, the first oxygen has four different places where it can bind. This represents a state of higher entropy compared with binding the last oxygen which has only one place where it can bind. Thus, in going from the unbound to the bound state, the first oxygen must overcome a larger entropy change than the last oxygen. This entropy difference is the main reason for the positive cooperativity in binding oxygen to hemoglobin.
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
s or receptor
Receptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
s that have multiple binding site
Binding site
In biochemistry, a binding site is a region on a protein, DNA, or RNA to which specific other molecules and ions—in this context collectively called ligands—form a chemical bond...
s where the affinity of the binding sites for a ligand is increased, positive cooperativity, or decreased, negative cooperativity, upon the binding of a ligand to a binding site. For example the affinity of hemoglobin's four binding sites for oxygen is increased above that of the unbound hemoglobin when the first oxygen molecule binds. This is referred to as cooperative binding
Cooperative binding
In biochemistry, a macromolecule exhibits cooperative binding if its affinity for its ligand changes with the amount of ligand already bound.Cooperative binding is a special case of allostery. Cooperative binding requires that the macromolecule have more than one binding site, since cooperativity...
. We also see cooperativity in large chain molecules made of many identical (or nearly identical) subunits (such as DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
, protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
s, and phospholipid
Phospholipid
Phospholipids are a class of lipids that are a major component of all cell membranes as they can form lipid bilayers. Most phospholipids contain a diglyceride, a phosphate group, and a simple organic molecule such as choline; one exception to this rule is sphingomyelin, which is derived from...
s), when such molecules undergo phase transitions such as melting, unfolding or unwinding. This is referred to as subunit cooperativity.
Cooperative binding
When a substrate binds to one enzymatic subunit, the rest of the subunits are stimulated and become active.Ligands can either have non-cooperativity, positive cooperativity or negative cooperativity.
Oxygen
Oxygen is the element with atomic number 8 and represented by the symbol O. Its name derives from the Greek roots ὀξύς and -γενής , because at the time of naming, it was mistakenly thought that all acids required oxygen in their composition...
to hemoglobin
Hemoglobin
Hemoglobin is the iron-containing oxygen-transport metalloprotein in the red blood cells of all vertebrates, with the exception of the fish family Channichthyidae, as well as the tissues of some invertebrates...
. One oxygen
Oxygen
Oxygen is the element with atomic number 8 and represented by the symbol O. Its name derives from the Greek roots ὀξύς and -γενής , because at the time of naming, it was mistakenly thought that all acids required oxygen in their composition...
molecule can bind to the ferrous iron of a heme molecule in each of the four chains of a hemoglobin
Hemoglobin
Hemoglobin is the iron-containing oxygen-transport metalloprotein in the red blood cells of all vertebrates, with the exception of the fish family Channichthyidae, as well as the tissues of some invertebrates...
molecule. Deoxy-hemoglobin has a relatively low affinity for oxygen
Oxygen
Oxygen is the element with atomic number 8 and represented by the symbol O. Its name derives from the Greek roots ὀξύς and -γενής , because at the time of naming, it was mistakenly thought that all acids required oxygen in their composition...
, but when one molecule binds to a single heme, the oxygen
Oxygen
Oxygen is the element with atomic number 8 and represented by the symbol O. Its name derives from the Greek roots ὀξύς and -γενής , because at the time of naming, it was mistakenly thought that all acids required oxygen in their composition...
affinity increases, allowing the second molecule to bind more easily, and the third and fourth even more easily. The oxygen
Oxygen
Oxygen is the element with atomic number 8 and represented by the symbol O. Its name derives from the Greek roots ὀξύς and -γενής , because at the time of naming, it was mistakenly thought that all acids required oxygen in their composition...
affinity of 3-oxy-hemoglobin is ~300 times greater than that of deoxy-hemoglobin. This behavior leads the affinity curve of hemoglobin
Hemoglobin
Hemoglobin is the iron-containing oxygen-transport metalloprotein in the red blood cells of all vertebrates, with the exception of the fish family Channichthyidae, as well as the tissues of some invertebrates...
to be sigmoidal
Sigmoid function
Many natural processes, including those of complex system learning curves, exhibit a progression from small beginnings that accelerates and approaches a climax over time. When a detailed description is lacking, a sigmoid function is often used. A sigmoid curve is produced by a mathematical...
, rather than hyperbolic
Hyperbolic function
In mathematics, hyperbolic functions are analogs of the ordinary trigonometric, or circular, functions. The basic hyperbolic functions are the hyperbolic sine "sinh" , and the hyperbolic cosine "cosh" , from which are derived the hyperbolic tangent "tanh" and so on.Just as the points form a...
as with the monomeric myoglobin
Myoglobin
Myoglobin is an iron- and oxygen-binding protein found in the muscle tissue of vertebrates in general and in almost all mammals. It is related to hemoglobin, which is the iron- and oxygen-binding protein in blood, specifically in the red blood cells. The only time myoglobin is found in the...
. By the same process, the ability for hemoglobin
Hemoglobin
Hemoglobin is the iron-containing oxygen-transport metalloprotein in the red blood cells of all vertebrates, with the exception of the fish family Channichthyidae, as well as the tissues of some invertebrates...
to lose oxygen
Oxygen
Oxygen is the element with atomic number 8 and represented by the symbol O. Its name derives from the Greek roots ὀξύς and -γενής , because at the time of naming, it was mistakenly thought that all acids required oxygen in their composition...
increases as fewer oxygen molecules are bound. See also Oxygen-hemoglobin dissociation curve.
Negative cooperativity means that the opposite will be true; as ligand
Ligand
In coordination chemistry, a ligand is an ion or molecule that binds to a central metal atom to form a coordination complex. The bonding between metal and ligand generally involves formal donation of one or more of the ligand's electron pairs. The nature of metal-ligand bonding can range from...
s bind to the protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
, the protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
's affinity for the ligand will decrease. An example of this occurring is the relationship between glyceraldehyde-3-phosphate and the enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
glyceraldehyde-3-phosphate dehydrogenase.
Homotropic cooperativity refers to the fact that the molecule causing the cooperativity is the one that will be affected by it. Heterotropic cooperativity is where a third substance causes the change in affinity.
Subunit cooperativity
Cooperativity is not only a phenomenon of ligand binding, but applies as well any time energetic interactions make it easier or more difficult for something to happen involving multiple units as compared with single units. (That is, easier or more difficult compared with what might be expecting when only accounting for the addition of multiple units). For example, unwinding of DNADNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
involves cooperativity. Portions of DNA must unwind in order for DNA to carry out replication
DNA replication
DNA replication is a biological process that occurs in all living organisms and copies their DNA; it is the basis for biological inheritance. The process starts with one double-stranded DNA molecule and produces two identical copies of the molecule...
, transcription
Transcription (genetics)
Transcription is the process of creating a complementary RNA copy of a sequence of DNA. Both RNA and DNA are nucleic acids, which use base pairs of nucleotides as a complementary language that can be converted back and forth from DNA to RNA by the action of the correct enzymes...
and recombination
Genetic recombination
Genetic recombination is a process by which a molecule of nucleic acid is broken and then joined to a different one. Recombination can occur between similar molecules of DNA, as in homologous recombination, or dissimilar molecules, as in non-homologous end joining. Recombination is a common method...
. Positive cooperativity among adjacent DNA nucleotide
Nucleotide
Nucleotides are molecules that, when joined together, make up the structural units of RNA and DNA. In addition, nucleotides participate in cellular signaling , and are incorporated into important cofactors of enzymatic reactions...
s makes it easier to unwind a whole group of adjacent nucleotides than it is to unwind the same number of nucleotides spread out along the DNA chain. The cooperative unit size is the number of adjacent bases that tend to unwind as a single unit due to the effects of positive cooperativity. This phenomenon applies to other types of chain molecules as well, such as the folding and unfolding of proteins and in the "melting" of phospholipid
Phospholipid
Phospholipids are a class of lipids that are a major component of all cell membranes as they can form lipid bilayers. Most phospholipids contain a diglyceride, a phosphate group, and a simple organic molecule such as choline; one exception to this rule is sphingomyelin, which is derived from...
chains that make up the membranes of cells
Cell membrane
The cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...
. Subunit coorperativity is measured on the relative scale known as Hill's Constant.
Entropy and cooperativity
In all of the above types of cooperativity, entropyEntropy
Entropy is a thermodynamic property that can be used to determine the energy available for useful work in a thermodynamic process, such as in energy conversion devices, engines, or machines. Such devices can only be driven by convertible energy, and have a theoretical maximum efficiency when...
plays a role. For example in the case of oxygen binding to hemoglobin
Hemoglobin
Hemoglobin is the iron-containing oxygen-transport metalloprotein in the red blood cells of all vertebrates, with the exception of the fish family Channichthyidae, as well as the tissues of some invertebrates...
, the first oxygen has four different places where it can bind. This represents a state of higher entropy compared with binding the last oxygen which has only one place where it can bind. Thus, in going from the unbound to the bound state, the first oxygen must overcome a larger entropy change than the last oxygen. This entropy difference is the main reason for the positive cooperativity in binding oxygen to hemoglobin.