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The '''sequential model''' (also known as the '''[[Induced fit#Induced fit model|KNF model]] ''') is a theory that describes co-operativity 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, thus sequentially changing its 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 enzymes 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 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 only offers 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> It is named KNF after Koshland, Némethy and Filmer.<ref name=":3" />
== History ==
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.<sup>[1]</sup> The [[Monod-Wyman-Changeux model|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 chemistry|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.<ref name=":4">{{Cite journal|last=Marzen|first=Sarah|last2=Garcia|first2=Hernan G.|last3=Phillips|first3=Rob|date=2013-05-13|title=Statistical mechanics of Monod-Wyman-Changeux (MWC) models
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" />
== Rules Guiding the KNF Model ==
The KNF model follows the structural theory of the induced fit model of substrate binding to an enzyme.<ref name=":1" /> A slight change in the conformation of an enzyme improves its binding affinity to the transition state of the ligand, thus catalyzing a reaction. This follows the KNF model, which models cooperativity as the changing conformation of the ligand binding site upon binding to another subunit.
Two essential assumptions guide the KNF model:<ref name=":2">{{Cite book|url=https://www.worldcat.org/oclc/837581840|title=Structure and mechanism in protein science : a guide to enzyme catalysis and protein folding|last=Alan|first=Fersht,|publisher=Freeman|isbn=9780716732686|oclc=837581840}}</ref>
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The primary differentiating feature between the MWC model and KNF model lies in the scale of conformational changes.<ref name=":2" /> While both suggest that a protein's affinity for a given ligand changes upon binding of the ligand, the MWC model suggests that this occurs by a quaternary conformational change that involves the entire protein, i.e. moving from T state to R state. On the other hand, the KNF model suggests these conformational changes occur on the level of tertiary structure within the protein, as neighboring subunits change conformation with successive ligand binding, resulting in a fixed quaternary state.<ref>{{Cite journal|last=Ronda|first=Luca|last2=Bruno|first2=Stefano|last3=Bettati|first3=Stefano|date=2013-09-01|title=Tertiary and quaternary effects in the allosteric regulation of animal hemoglobins|url=http://www.sciencedirect.com/science/article/pii/S157096391300126X|journal=Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics|series=Oxygen Binding and Sensing Proteins|volume=1834|issue=9|pages=1860–1872|doi=10.1016/j.bbapap.2013.03.013}}</ref>
Unlike the MWC model, the KNF model offers the possibility of "negative cooperativity".<ref name=":0" /><ref name=":2" /> This term describes a reduction in the affinity of the other binding sites of a protein for a ligand after the binding of one or more of the ligand to its subunits. The MWC model only allows for positive cooperativity, where a single conformational switch from the T to R states results in an increase in affinity for the ligand at unligated binding sites. Ligand binding to the T state thus cannot increase the amount of the protein in the T, or low-affinity, state.
Negative cooperativity is observed in a number of biologically significant molecules, including tyrosyl-tRNA synthetase and glyceraldehyde-3-phosphate dehydrogenase.<ref name=":2" /> In fact, in a systematic literature review performed in 2002, negatively cooperating proteins are seen to compose slightly less than 50% of scientifically studied proteins that exhibit cooperativity, while positively cooperating proteins compose the other, slightly greater than 50%.<ref name=":0" /> Positive cooperativity is seen to thus have a slight evolutionary advantage over negative cooperativity.
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[[Category:Protein structure]]
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