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Cooperativity is a phenomenon displayed by enzymes or receptors that have multiple binding sites 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, proteins, and phospholipids), when such molecules undergo phase transitions such as melting, unfolding or unwinding. This is referred to as subunit cooperativity.
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.
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 ligands 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.
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 DNA involves cooperativity. Portions of DNA must unwind in order for DNA to carry out replication, transcription and recombination. Positive cooperativity among adjacent DNA nucleotides 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 cooperativity is measured on the relative scale known as Hill's Constant.
Entropy and cooperativity
In all of the above types of cooperativity, entropy 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.
- Whitford, David: Proteins: structure and function, 2005, John Wiley & Sons, pages 66-74