Editing Allosteric regulation (section)

== Models ==

[[File:Allosteric Regulation.svg|thumb|A – [[Active site]]<br/> B – Allosteric site<br/> C – [[Substrate (biochemistry)|Substrate]]<br/> D – [[Enzyme inhibitor|Inhibitor]]<br/> E – [[Enzyme]]<br/>This is a diagram of allosteric regulation of an enzyme.]]

Many allosteric effects can be explained by  the ''concerted'' [[MWC model]] put forth by [[Jacques Monod|Monod]], [[Jeffries Wyman (biologist)|Wyman]], and [[Jean-Pierre Changeux|Changeux]],<ref name="pmid14343300">{{cite journal | vauthors = Monod J, Wyman J, Changeux JP | title = On the nature of allosteric transitions:A plausible model | journal = Journal of Molecular Biology | volume = 12 | pages = 88–118 | date = May 1965 | pmid = 14343300 | doi = 10.1016/s0022-2836(65)80285-6}}</ref> or by the [[sequential model]] (also known as the KNF model) described by [[Daniel E. Koshland Jr.|Koshland]], Nemethy, and Filmer.<ref name="pmid5938952">{{cite journal | vauthors = Koshland DE, Némethy G, Filmer D | title = Comparison of experimental binding data and theoretical models in proteins containing subunits | journal = Biochemistry | volume = 5 | issue = 1 | pages = 365–85 | date = January 1966 | pmid = 5938952 | doi = 10.1021/bi00865a047}}</ref>  Both postulate that [[protein subunit]]s exist in one of two [[Protein structure|conformations]], tensed (T) or relaxed (R), and that relaxed subunits bind substrate more readily than those in the tense state. The two models differ most in their assumptions about subunit interaction and the preexistence of both states. For proteins in which [[Protein subunit|subunit]]s exist in more than two [[Protein structure|conformations]], the allostery landscape model described by Cuendet, Weinstein, and LeVine,<ref name="Cuendet_2016">{{cite journal | vauthors = Cuendet MA, Weinstein H, LeVine MV | title = The Allostery Landscape: Quantifying Thermodynamic Couplings in Biomolecular Systems | journal = Journal of Chemical Theory and Computation | volume = 12 | issue = 12 | pages = 5758–5767 | date = December 2016 | pmid = 27766843 | pmc = 5156960 | doi = 10.1021/acs.jctc.6b00841 }}</ref> can be used. Allosteric regulation may be facilitated by the evolution of large-scale, low-energy conformational changes, which enables long-range allosteric interaction between distant binding sites.<ref>{{Cite journal | vauthors = Eckmann JP, Rougemont J, Tlusty T |date=2019-07-30 |title=Colloquium : Proteins: The physics of amorphous evolving matter |url=https://link.aps.org/doi/10.1103/RevModPhys.91.031001 |journal=Reviews of Modern Physics |language=en |volume=91 |issue=3 |pages=031001 |doi=10.1103/RevModPhys.91.031001 |arxiv=1907.13371 |bibcode=2019RvMP...91c1001E |s2cid=199001124 |issn=0034-6861}}</ref>

=== Concerted model ===

The  concerted model of allostery, also referred to as the symmetry model or [[MWC model]], postulates that enzyme subunits are connected in such a way that a conformational change in one subunit is necessarily conferred to all other subunits. Thus, all subunits must exist in the same conformation. The model further holds that, in the absence of any ligand (substrate or otherwise), the equilibrium favors one of the conformational states, T or R.  The equilibrium can be shifted to the R or T state through the binding of one [[ligand (biochemistry)|ligand]] (the allosteric effector or ligand) to a site that is different from the active site

=== Sequential model ===

The sequential model of allosteric regulation holds that subunits are not connected in such a way that a conformational change in one induces a similar change in the others. Thus, all enzyme subunits do not necessitate the same conformation. Moreover, the sequential model dictates that molecules of a substrate bind via an [[induced fit]] protocol. While such an induced fit converts a subunit from the tensed state to relaxed state, it does not propagate the conformational change to adjacent subunits. Instead, substrate-binding at one subunit only slightly alters the structure of other subunits so that their binding sites are more receptive to substrate. To summarize:

* subunits need not exist in the same conformation
* molecules of substrate bind via induced-fit protocol
* conformational changes are not propagated to all subunits

=== Morpheein model ===

The [[morpheein]] model of allosteric regulation is a dissociative concerted model.<ref name=pmid16023348>{{cite journal | vauthors = Jaffe EK | title = Morpheeins--a new structural paradigm for allosteric regulation | journal = Trends in Biochemical Sciences | volume = 30 | issue = 9 | pages = 490–7 | date = September 2005 | pmid = 16023348 | doi = 10.1016/j.tibs.2005.07.003 }}</ref>

A morpheein is a homo-oligomeric structure that can exist as an ensemble of physiologically significant and functionally different alternate quaternary assemblies. Transitions between alternate morpheein assemblies involve oligomer dissociation, conformational change in the dissociated state, and reassembly to a different oligomer. The required oligomer disassembly step differentiates the morpheein model for allosteric regulation from the classic MWC and KNF models.

[[Porphobilinogen synthase]] (PBGS) is the prototype morpheein.

=== Ensemble models ===

Ensemble models of allosteric regulation enumerate an allosteric system's [[statistical ensemble]] as a function of its [[energy functional|potential energy function]], and then relate specific statistical measurements of allostery to specific energy terms in the energy function (such as an intermolecular salt bridge between two domains).<ref>{{cite journal | vauthors = Motlagh HN, Wrabl JO, Li J, Hilser VJ | title = The ensemble nature of allostery | journal = Nature | volume = 508 | issue = 7496 | pages = 331–9 | date = April 2014 | pmid = 24740064 | doi = 10.1038/nature13001 | pmc = 4224315 | bibcode = 2014Natur.508..331M }}</ref> Ensemble models like the ensemble allosteric model<ref>{{cite journal | vauthors = Hilser VJ, Wrabl JO, Motlagh HN | title = Structural and energetic basis of allostery | journal = Annual Review of Biophysics | volume = 41 | pages = 585–609 | year = 2012 | pmid = 22577828 | pmc = 3935618 | doi = 10.1146/annurev-biophys-050511-102319 }}</ref> and allosteric Ising model<ref>{{cite journal | vauthors = LeVine MV, Weinstein H | title = AIM for Allostery: Using the Ising Model to Understand Information Processing and Transmission in Allosteric Biomolecular Systems | journal = Entropy | volume = 17 | issue = 5 | pages = 2895–2918 | date = May 2015 | pmid = 26594108 | pmc = 4652859 | doi = 10.3390/e17052895 | bibcode = 2015Entrp..17.2895L | doi-access = free }}</ref>  assume that each domain of the system can adopt two states similar to the MWC model. The allostery landscape model introduced by Cuendet, Weinstein, and LeVine<ref name="Cuendet_2016"/>  allows for the domains to have any number of states and the contribution of a specific molecular interaction to a given allosteric coupling can be estimated using a rigorous set of rules. [[Molecular dynamics]] simulations can be used to estimate a system's statistical ensemble so that it can be analyzed with the allostery landscape model.