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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 ligand binding to another subunit.
Two essential assumptions guide the KNF model:<ref name=":2">{{Cite book
# The protein exists in a single state of either low or high affinity for the ligand, when not bound to the ligand
# Upon ligation of a binding site, a conformational change is produced in that region of the protein. Changing this region of the protein may influence the conformation of nearby binding sites on the same protein, thus changing their affinity for the ligand. In negative cooperativity, affinity goes from high to low, while in positive cooperativity, affinity goes from low to high.
The KNF model characterizes enzymes that exhibit what was coined by Koshland and Hamadi in 2002 as i<sup>3</sup> cooperativity.<ref name=":0" /> This term is used merely to describe the structural nature of the sequential model, as the authors provide no other proposed descriptions or types of cooperativity.<ref>{{Cite book|url=https://books.google.com/
# the nature of the subunits of the multimeric protein are such that they are ''identical'' to each other
# ligand binding ''induces'' a conformational change in the protein
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=== Structural Differences ===
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, moving from T state to favoring the 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.<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|pmid=23523886}}</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.
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=== Functional Differences in Hemoglobin ===
[[Hemoglobin]], a tetrameric protein that transports four molecules of [[Molecular oxygen|oxygen]], is a highly biologically relevant protein that has been a subject of debate in allostery. It exhibits a sigmoidal binding curve, indicating cooperativity. While most scientific evidence points to concerted cooperativity,<ref name=":6">{{Cite journal|last=Cui|first=Qiang|last2=Karplus|first2=Martin|date=2017-03-25|title=Allostery and cooperativity revisited|journal=Protein Science|volume=17|issue=8|pages=1295–1307|doi=10.1110/ps.03259908|issn=0961-8368|pmc=2492820|pmid=18560010}}</ref><ref>{{Cite journal|last=Berg|first=Jeremy M.|last2=Tymoczko|first2=John L.|last3=Stryer|first3=Lubert|date=2002-01-01|title=Hemoglobin Transports Oxygen Efficiently by Binding Oxygen Cooperatively|url=https://www.ncbi.nlm.nih.gov/books/NBK22596/|language=en}}</ref> research into the affinities of specific heme subunits for oxygen has revealed that under certain physiological conditions, the subunits may display properties of sequential allostery.<ref name=":7">{{Cite journal|last=Lindstrom|first=Ted|year=1972|title=Functional nonequivalence of alpha and beta hemes in human adult hemoglobin|url=http://www.pnas.org/content/69/7/1707.full.pdf|journal=Proceedings of the National Academy of Sciences|volume=69|issue=7|pages=1707–1710|via=|doi=10.1073/pnas.69.7.1707|pmid=4505648|pmc=426783}}</ref>[[Nuclear magnetic resonance]] (NMR) studies show that in the presence of phosphate, deoxygenated human adult hemolglobin's alpha heme subunits display increased affinity for molecular oxygen, when compared to beta subunits. The results suggest either a modified concerted model, in which alpha subunits have a greater affinity for oxygen in the quaternary low-affinity T state, or a sequential model, in which phosphate binding creates a partially oligomerized state that stabilizes a low affinity form of the beta subunits, distinct from a T or R state.<ref name=":7" /> Thus, depending on physiological conditions, a combination of the MWC and KNF models appears to most comprehensively describe hemoglobin's binding characteristics.<ref name=":6" />
==References==
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