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The '''sequential model''' (also known as the '''KNF model''') is a theory that describes [[cooperativity]] of [[protein subunit]]s<ref name=":3">Koshland, D.E., Némethy, G. and Filmer, D. (1966) Comparison of experimental binding data and theoretical models in proteins containing subunits.
Biochemistry 5, 365–385. [http://pubs.acs.org/doi/abs/10.1021/bi00865a047 DOI: 10.1021/bi00865a047]</ref>. It postulates that a protein's conformation changes with each binding of a [[Ligand (biochemistry)|ligand]], thus sequentially changing its [[chemical affinity|affinity]] for the ligand at neighboring binding sites.
[[File:KNF_model.gif|thumb|Visual representation of the KNF model in a tetrameric protein.|433x433px]]
==Overview==
This model for [[allosteric regulation]] of [[enzyme]]s suggests that the [[Protein subunit|subunits]] of multimeric proteins have two conformational states.<ref name=":3" /> 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 [[Thermodynamic free energy|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.<ref name=":0">{{Cite journal|last=Koshland|first=Daniel E.|last2=Hamadani|first2=Kambiz|date=2002-12-06|title=Proteomics and Models for Enzyme Cooperativity|url=http://www.jbc.org/content/277/49/46841|journal=Journal of Biological Chemistry|language=en|volume=277|issue=49|pages=46841–46844|doi=10.1074/jbc.R200014200|issn=0021-9258|pmid=12189158}}</ref><ref name=":5">{{Cite journal|last=Henis|first=Y I|last2=Levitzki|first2=A|date=1980-09-01|title=Mechanism of negative cooperativity in glyceraldehyde-3-phosphate dehydrogenase deduced from ligand competition experiments.|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=77|issue=9|pages=5055–5059|issn=0027-8424|pmc=349994|pmid=6933545|doi=10.1073/pnas.77.9.5055}}</ref> It is named KNF after [[Daniel_E._Koshland_Jr.|Koshland]], Némethy and Filmer, who first suggested the model .<ref name=":3" />
== History ==
A multimeric protein's affinity for a ligand changes upon binding to a ligand, a process known as cooperativity. This phenomenon was first discovered by
The KNF model (or induced fit model or sequential model) arose to address the possibility of differential binding states.<ref name=":1">{{Cite news|url=http://bio.libretexts.org/Core/Biochemistry/Binding/MODEL_BINDING_SYSTEMS#Free_Energy_and_Cooperativity|title=Model Binding Systems|date=2013-11-21|newspaper=Biology LibreTexts|access-date=2017-02-21|language=en-US}}</ref> 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.<ref name=":4" />
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