Sequential model

The sequential model (also known as the KNF model ) is a theory that describes cooperativity of protein subunits It postulates that a protein's conformation changes with each binding of a ligand, thus sequentially changing its affinity for the ligand at neighboring binding sites.

This model for allosteric regulation of enzymes suggests that the subunits of multimeric proteins have two conformational states. The binding of the ligand causes conformational change in the other subunits of the multimeric protein. Although the subunits go through conformational changes independently (as opposed to in the MWC model), the switch of one subunit makes the other subunits more likely to change, by reducing the energy needed for subsequent subunits to undergo the same conformational change. In elaboration, the binding of a ligand to one subunit changes the protein's shape, thereby making it more thermodynamically favorable for the other subunits to switch conformation to the high affinity state. Ligand binding may also result in negative cooperativity, or a reduced affinity for the ligand at the next binding site, a feature that makes the KNF model distinct from the MWC model, which suggests only positive cooperativity. It is named KNF after Koshland, Némethy and Filmer, who first suggested the model .

A multimeric protiein's affinity for a ligand changes upon binding to a ligand, a process known as cooperativity. This phenomenon was first discovered by C. Bohr's analysis of hemoglobin, whose binding affinity for molecular oxygen increases as oxygen binds its subunits.^[1] The concerted model (or MWC model or symmetry model) provides a theoretical basis for understanding this phenomenon. The model proposes that multimeric proteins exist in two separate states, T and R. Upon ligand binding, equilibrium between the two states shifts towards the R state, thought to result from protein conformation changes due to ligand binding. The model is useful in describing hemoglobin's sigmoidal binding curve.

The KNF model (or induced fit model or sequential model) arose to address the possibility of differential binding states. Developed by Koshland, Némethy and Filmer in 1966, the KNF model describes cooperativity as a sequential process, where ligand binding alters the conformation, and thus the affinity, of proximal subunits of the protein, resulting in several different conformations that have varying affinities for a given ligand. This model suggests that the MWC model oversimplifies cooperativity in that it does not account for conformational changes of individual binding sites, opting instead to suggest a single, whole-protein conformational change.

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