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Negative cooperativity is a phenomenon in which the binding of a first ligand or substrate molecule decreases the rate of subsequent binding. This definition is not exclusive to ligand-receptor binding, it holds whenever two or more molecules undergo two successive binding events.

Negative CooperativityEdit An example of negative cooperativity is the decrease in binding affinity once one of the sites is bound. As ligands bind to the protein, the protein's affinity for the ligand decreases.

If the change in shape of the first subunit makes easier the binding of substrate to the second subunit, the effect is called positive cooperativity. In negative cooperativity, the binding of a molecule to the first subunit makes more difficult the binding of substrate to the second.

Negative cooperativity has been observed in CTP synthetase, an allosteric enzyme which contains a regulatory site. Thus, the same enzyme exhibits negative cooperativity for GTP (an effector) and glutamine (a substrate) and positive cooperativity for ATP and UTP (both substrates).

Half-site reactivity is an enzyme characteristic in which the active sites of a multimeric enzyme “fire” alternately, which means that one-half of the identical subunits is active at any one time (1).

If the first binding event increases the affinity of the second site, there is positive cooperativity. If the first binding event decreases the affinity of the second site, there is negative cooperativity.

Many enzymes consisting of tetramers or higher order multimers are made from two or more pairs of such coupled sites. These enzymes can then also display positive cooperativity towards the same ligand.