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Negative cooperativity is observed in a number of biologically significant molecules, including tyrosyl-tRNA synthetase and glyceraldehyde-3-phosphate dehydrogenase.<ref name=":5" /><ref name=":2" /> In fact, in a systematic literature review performed in 2002 by Koshland and Hamadani, the same literature review that coined i<sup>3</sup> cooperativity, 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" />
=== Functional
[[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|last1=Cui|first1=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|last1=Berg|first1=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|journal=Proceedings of the National Academy of Sciences|volume=69|issue=7|pages=1707–1710|doi=10.1073/pnas.69.7.1707|pmid=4505648|pmc=426783|bibcode=1972PNAS...69.1707L|doi-access=free}}</ref> [[Nuclear magnetic resonance]] (NMR) studies show that in the presence of phosphate, deoxygenated human adult hemoglobin'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" />
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