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{{Short description|Molecule-specific coordinate bonding area in biological systems}} [[File:Glucose_binding_Hexokinase.png|thumb|Glucose binds to hexokinase in the active site at the beginning of glycolysis.]] In biochemistry and molecular biology, a '''binding site''' is a region on a [[macromolecule]] such as a [[protein]] that binds to another molecule with [[Chemical specificity|specificity]].<ref name = "MeSH_Bind_Site">{{cite web | title = Binding site | quote = The parts of a macromolecule that directly participate in its specific combination with another molecule. | url = https://meshb.nlm.nih.gov/record/ui?name=Binding%20Sites | work = Medical Subject Headings (MeSH) | publisher = U.S. National Library of Medicine}}</ref> The binding partner of the macromolecule is often referred to as a [[Ligand (biochemistry)|ligand]].<ref name = "MeSH_Ligand">{{cite web | title = Ligands | quote = A molecule that binds to another molecule, used especially to refer to a small molecule that binds specifically to a larger molecule. | url = https://meshb.nlm.nih.gov/record/ui?name=Binding%20Sites | work = Medical Subject Headings (MeSH) | publisher = U.S. National Library of Medicine}}</ref> Ligands may include other proteins (resulting in a [[protein–protein interaction]]),<ref name="Amos-Binks_2011">{{cite journal | vauthors = Amos-Binks A, Patulea C, Pitre S, Schoenrock A, Gui Y, Green JR, Golshani A, Dehne F | title = Binding site prediction for protein-protein interactions and novel motif discovery using re-occurring polypeptide sequences | journal = BMC Bioinformatics | volume = 12 | pages = 225 | date = June 2011 | pmid = 21635751 | pmc = 3120708 | doi = 10.1186/1471-2105-12-225 | doi-access = free }}</ref> [[enzyme substrate]]s,<ref name="Hardin_2013">{{cite book | chapter = Chapter 8: Enzymes |title=Biochemistry - Essential Concepts | vauthors = Hardin CC, Knopp JA |publisher=Oxford University Press |year=2013 |isbn=978-1-62870-176-0 |location= New York |pages=51–69}}</ref> [[second messenger system|second messengers]], [[hormone]]s, or [[allosteric modulator]]s.<ref name = "Kenakin_2016">{{cite book | vauthors = Kenakin TP | veditors = Bowery NG | chapter = Characteristics of Allosterism in Drug Action | chapter-url = https://books.google.com/books?id=WRfgvOKfZMcC&pg=PA26 | title = Allosteric Receptor Modulation in Drug Targeting | publisher = CRC Press | date = April 2016 | isbn = 978-1-4200-1618-5 | page = 26 }}</ref> The binding event is often, but not always, accompanied by a [[conformational change]] that alters the protein's [[Protein#Cellular functions|function]].<ref name=":12">{{cite journal | vauthors = Spitzer R, Cleves AE, Varela R, Jain AN | title = Protein function annotation by local binding site surface similarity | journal = Proteins | volume = 82 | issue = 4 | pages = 679–94 | date = April 2014 | pmid = 24166661 | pmc = 3949165 | doi = 10.1002/prot.24450 }}</ref> Binding to protein binding sites is most often reversible (transient and [[non-covalent]]), but can also be covalent reversible<ref name="pmid27599186">{{cite journal | vauthors = Bandyopadhyay A, Gao J | title = Targeting biomolecules with reversible covalent chemistry | journal = Current Opinion in Chemical Biology | volume = 34 | pages = 110–116 | date = October 2016 | pmid = 27599186 | pmc = 5107367 | doi = 10.1016/j.cbpa.2016.08.011 }}</ref> or irreversible.<ref>{{cite book | vauthors = Bellelli A, Carey J | chapter = Reversible Ligand Binding | chapter-url = https://books.google.com/books?id=gPw6DwAAQBAJ | title = Reversible Ligand Binding: Theory and Experiment | publisher = John Wiley & Sons | date = January 2018 | isbn = 978-1-119-23848-5 | page = 278 }}</ref><ref>{{cite journal |last1=Nazem |first1=Fatemeh |last2=Ghasemi |first2=Fahimeh |last3=Fassihi |first3=Afshin |last4=Mehri Dehnavi |first4=Alireza |title=3D U-Net: A Voxel-based method in binding site prediction of protein structure|journal=Journal of Bioinformatics and Computational Biology |date=2021 |volume=19 |issue=2 |doi= 10.1142/S0219720021500062 |pmid=33866960 }}</ref> == Function == Binding of a ligand to a binding site on protein often triggers a change in conformation in the protein and results in altered cellular function. Hence binding site on protein are critical parts of [[signal transduction]] pathways.<ref name=":0">{{cite journal | vauthors = Xu D, Jalal SI, Sledge GW, Meroueh SO | title = Small-molecule binding sites to explore protein-protein interactions in the cancer proteome | journal = Molecular BioSystems | volume = 12 | issue = 10 | pages = 3067–87 | date = October 2016 | pmid = 27452673 | pmc = 5030169 | doi = 10.1039/c6mb00231e }}</ref> Types of ligands include [[neurotransmitter]]s, [[toxin]]s, [[neuropeptide]]s, and [[steroid hormone]]s.<ref name="Wilson_2010">{{cite book | vauthors = Wilson K |date=March 2010 |title =Principles and Techniques of Biochemistry and Molecular Biology |pages=581–624 |publisher=Cambridge University Press |doi=10.1017/cbo9780511841477.016 |isbn=9780511841477 }}</ref> Binding sites incur functional changes in a number of contexts, including enzyme catalysis, molecular pathway signaling, homeostatic regulation, and physiological function. [[Electric charge]], steric shape and geometry of the site selectively allow for highly specific ligands to bind, activating a particular cascade of cellular interactions the protein is responsible for.<ref name=":03">{{Cite book|title=Biochemistry Free For All| vauthors = Ahern K |publisher=Oregon State University|year=2015|pages=110–141}}</ref><ref name=":4">{{cite journal | vauthors = Kumar AP, Lukman S | title = Allosteric binding sites in Rab11 for potential drug candidates | journal = PLOS ONE | volume = 13 | issue = 6 | pages = e0198632 | date = 2018-06-06 | pmid = 29874286 | pmc = 5991966 | doi = 10.1371/journal.pone.0198632 | bibcode = 2018PLoSO..1398632K | doi-access = free }}</ref><ref>{{cite journal |last1=Nazem |first1=Fatemeh |last2=Ghasemi |first2=Fahimeh |last3=Fassihi |first3=Afshin |last4=Mehri Dehnavi |first4=Alireza |title=Deep attention network for identifying ligand-protein binding sites |journal= Journal of Computational Science|date=2024 |volume=81 |doi= 10.1016/j.jocs.2024.102368 }}</ref> === Catalysis === [[File:ActivationEnergyInt.svg|thumb|[[Activation energy]] is decreased in the presence of an enzyme to catalyze the reaction.]] Enzymes incur catalysis by binding more strongly to [[transition state]]s than substrates and products. At the catalytic binding site, several different interactions may act upon the substrate. These range from electric catalysis, acid and base catalysis, covalent catalysis, and metal ion catalysis.<ref name="Wilson_2010" /> These interactions decrease the activation energy of a chemical reaction by providing favorable interactions to stabilize the high energy molecule. Enzyme binding allows for closer proximity and exclusion of substances irrelevant to the reaction. Side reactions are also discouraged by this specific binding.<ref name=":52">{{Cite book | vauthors = Dobson JA, Gerrard AJ, Pratt JA |title=Foundations of chemical biology |date=2008|publisher=Oxford University Press|isbn=9780199248995|oclc=487962823}}</ref><ref name="Wilson_2010" /> Types of enzymes that can perform these actions include oxidoreductases, transferases, hydrolases, lyases, isomerases, and ligases.<ref>{{cite book | vauthors = Azzaroni O, Szleifer I |date=2017-12-04|title=Polymer and Biopolymer Brushes |doi=10.1002/9781119455042 | isbn = 978-1-119-45501-1 }}</ref> For instance, the transferase hexokinase catalyzes the phosphorylation of glucose to make glucose-6-phosphate. Active site residues of hexokinase allow for stabilization of the glucose molecule in the active site and spur the onset of an alternative pathway of favorable interactions, decreasing the activation energy.<ref>{{Cite book|title=Dictionary of Food Science and Technology|publisher=International Food Information Service|year=2009|isbn=978-1-4051-8740-4|edition=2nd}}</ref> === Inhibition === Protein inhibition by inhibitor binding may induce obstruction in pathway regulation, homeostatic regulation and physiological function. [[Competitive inhibition|Competitive inhibitors]] compete with substrate to bind to free enzymes at active sites and thus impede the production of the enzyme-substrate complex upon binding. For example, carbon monoxide poisoning is caused by the competitive binding of carbon monoxide as opposed to oxygen in hemoglobin. [[Uncompetitive inhibitor]]s, alternatively, bind concurrently with substrate at active sites. Upon binding to an enzyme substrate (ES) complex, an enzyme substrate inhibitor (ESI) complex is formed. Similar to competitive inhibitors, the rate at product formation is decreased also.<ref name="Hardin_2013" /> Lastly, mixed inhibitors are able to bind to both the free enzyme and the enzyme-substrate complex. However, in contrast to competitive and uncompetitive inhibitors, mixed inhibitors bind to the allosteric site. Allosteric binding induces conformational changes that may increase the protein's affinity for substrate. This phenomenon is called positive modulation. Conversely, allosteric binding that decreases the protein's affinity for substrate is negative modulation.<ref>{{cite book | vauthors = Clarke KG |date=2013 |title=Bioprocess engineering |publisher=Woodhead Publishing |pages=79–84 |doi=10.1533/9781782421689 |isbn=978-1-78242-167-2 }}</ref> == Types == === Active site === {{Main|Active site}} At the active site, a substrate binds to an enzyme to induce a chemical reaction.<ref name=":3">{{cite book | vauthors = Wilson K |chapter=Enzymes|date=March 2010|chapter-url=https://www.cambridge.org/core/books/principles-and-techniques-of-biochemistry-and-molecular-biology/enzymes/10382334B13C92480C86AA1E10F9DABD|pages=581–624|publisher=Cambridge University Press|language=en|doi=10.1017/cbo9780511841477.016|isbn=9780511841477|access-date=2018-11-01|title=Principles and Techniques of Biochemistry and Molecular Biology| veditors = Wilson K, Walker J }}</ref><ref>{{Cite book|title=Dictionary of Chemical Engineering| vauthors = Schaschke C |publisher=Oxford University Press|year=2014|isbn=978-1-62870-844-8}}</ref> Substrates, transition states, and products can bind to the active site, as well as any competitive inhibitors.<ref name=":3" /> For example, in the context of protein function, the binding of calcium to troponin in muscle cells can induce a conformational change in troponin. This allows for tropomyosin to expose the actin-myosin binding site to which the myosin head binds to form a [[Sliding filament theory|cross-bridge]] and induce a [[muscle contraction]].<ref>{{Cite book|title=Biology How Life Works| vauthors = Morris J | publisher= W.H. Freeman and Company|year=2016|isbn=978-1-4641-2609-3|location=United States of America|pages=787–792}}</ref> In the context of the blood, an example of competitive binding is carbon monoxide which competes with oxygen for the active site on [[heme]]. Carbon monoxide's high affinity may outcompete oxygen in the presence of low oxygen concentration. In these circumstances, the binding of carbon monoxide induces a conformation change that discourages heme from binding to oxygen, resulting in carbon monoxide poisoning.<ref name="Hardin_2013" /> [[File:Enzyme inhibition.png|thumb|Competitive and noncompetitive enzyme binding at active and regulatory (allosteric) site respectively.]] === Allosteric site === At the regulatory site, the binding of a ligand may elicit amplified or inhibited protein function.<ref name="Hardin_2013" /><ref name="Konc_2014">{{cite journal | vauthors = Konc J, Janežič D | title = Binding site comparison for function prediction and pharmaceutical discovery | journal = Current Opinion in Structural Biology | volume = 25 | pages = 34–9 | date = April 2014 | pmid = 24878342 | doi = 10.1016/j.sbi.2013.11.012 }}</ref> The binding of a ligand to an allosteric site of a multimeric enzyme often induces positive cooperativity, that is the binding of one substrate induces a favorable conformation change and increases the enzyme's likelihood to bind to a second substrate.<ref name = "Fuqua_2004">{{cite book | vauthors = Fuqua C, White D |chapter=Prokaryotic Intercellular Signalling |date=2004 |title=Cell Signalling in Prokaryotes and Lower Metazoa |pages=27–71 |publisher=Springer Netherlands |isbn=9789048164837 | doi = 10.1007/978-94-017-0998-9_2}}</ref> Regulatory site ligands can involve [[Allosteric regulation#Types|homotropic]] and [[Allosteric regulation#Types|heterotropic]] ligands, in which single or multiple types of molecule affects enzyme activity respectively.<ref name="Creighton_2010">{{cite book|title=The Biophysical Chemistry of Nucleic Acids & Proteins| vauthors = Creighton TE |date=2010|publisher=Helvetian Press |isbn=978-0956478115|oclc=760830351}}</ref> Enzymes that are highly regulated are often essential in metabolic pathways. For example, [[phosphofructokinase]] (PFK), which phosphorylates fructose in glycolysis, is largely regulated by ATP. Its regulation in glycolysis is imperative because it is the committing and rate limiting step of the pathway. PFK also controls the amount of glucose designated to form ATP through the [[Catabolism|catabolic]] pathway. Therefore, at sufficient levels of ATP, PFK is allosterically inhibited by ATP. This regulation efficiently conserves glucose reserves, which may be needed for other pathways. Citrate, an intermediate of the citric acid cycle, also works as an allosteric regulator of PFK.<ref name="Creighton_2010" /><ref name = "Currell_1997">{{Cite book | vauthors = Currell BR, van Dam-Mieras MC |title=Biotechnological Innovations in Chemical Synthesis |publisher= Butterworth-Heinemann |location=Oxford |year=1997 |isbn=978-0-7506-0561-8 |pages=125–128 }}</ref> === Single- and multi-chain binding sites === Binding sites can be characterized also by their structural features. Single-chain sites (of “monodesmic” ligands, μόνος: single, δεσμός: binding) are formed by a single protein chain, while multi-chain sites (of "polydesmic” ligands, πολοί: many)<ref name="pmid31306664">{{cite journal | vauthors = Abrusan G, Marsh JA | title = Ligand Binding Site Structure Shapes Folding, Assembly and Degradation of Homomeric Protein Complexes. | journal = Journal of Molecular Biology | volume = 431 | issue = 19 | pages = 3871–3888 | date = 2019 | pmid = 31306664 | pmc = 6739599 | doi = 10.1016/j.jmb.2019.07.014 }}</ref> are frequent in protein complexes, and are formed by ligands that bind more than one protein chain, typically in or near protein interfaces. Recent research shows that binding site structure has profound consequences for the biology of protein complexes (evolution of function, allostery).<ref name="pmid29562182">{{cite journal | vauthors = Abrusan G, Marsh JA | title = Ligand Binding Site Structure Influences the Evolution of Protein Complex Function and Topology. | journal = Cell Reports | volume = 22 | issue = 12 | pages = 3265–3276 | date = 2018 | pmid = 29562182 | pmc = 5873459 | doi = 10.1016/j.celrep.2018.02.085 }}</ref><ref name="pmid31004156">{{cite journal | vauthors = Abrusan G, Marsh JA | title = Ligand-Binding-Site Structure Shapes Allosteric Signal Transduction and the Evolution of Allostery in Protein Complexes. | journal = Molecular Biology and Evolution | volume = 36 | issue = 8 | pages = 1711–1727 | date = 2019 | pmid = 31004156 | pmc = 6657754 | doi = 10.1093/molbev/msz093 }}</ref> === Cryptic binding sites === Cryptic binding sites are the binding sites that are transiently formed in an apo form or that are induced by ligand binding. Considering the cryptic binding sites increases the size of the potentially “[[Druggability|druggable]]” human proteome from ~40% to ~78% of disease-associated proteins.<ref name=":1">{{cite journal | vauthors = Cimermancic P, Weinkam P, Rettenmaier TJ, Bichmann L, Keedy DA, Woldeyes RA, Schneidman-Duhovny D, Demerdash ON, Mitchell JC, Wells JA, Fraser JS, Sali A | display-authors = 6 | title = CryptoSite: Expanding the Druggable Proteome by Characterization and Prediction of Cryptic Binding Sites | journal = Journal of Molecular Biology | volume = 428 | issue = 4 | pages = 709–719 | date = February 2016 | pmid = 26854760 | doi = 10.1016/j.jmb.2016.01.029 | pmc = 4794384 | doi-access = free }}</ref> The binding sites have been investigated by: [[Support-vector machine|support vector machine]] applied to "CryptoSite" data set,<ref name=":1" /> Extension of "CryptoSite" data set,<ref>{{cite journal | vauthors = Beglov D, Hall DR, Wakefield AE, Luo L, Allen KN, Kozakov D, Whitty A, Vajda S | display-authors = 6 | title = Exploring the structural origins of cryptic sites on proteins | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 115 | issue = 15 | pages = E3416–E3425 | date = April 2018 | pmid = 29581267 | doi = 10.1073/pnas.1711490115 | pmc = 5899430 | bibcode = 2018PNAS..115E3416B | doi-access = free }}</ref> long timescale [[Molecular dynamics|molecular dynamics simulation]] with Markov state model and with biophysical experiments,<ref>{{cite journal | vauthors = Bowman GR, Bolin ER, Hart KM, Maguire BC, Marqusee S | title = Discovery of multiple hidden allosteric sites by combining Markov state models and experiments | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 112 | issue = 9 | pages = 2734–9 | date = March 2015 | pmid = 25730859 | pmc = 4352775 | doi = 10.1073/pnas.1417811112 | bibcode = 2015PNAS..112.2734B | doi-access = free }}</ref> and cryptic-site index that is based on relative [[accessible surface area]].<ref>{{cite journal | vauthors = Iida S, Nakamura HK, Mashimo T, Fukunishi Y | title = Structural Fluctuations of Aromatic Residues in an Apo-Form Reveal Cryptic Binding Sites: Implications for Fragment-Based Drug Design | journal = The Journal of Physical Chemistry B | volume = 124 | issue = 45 | pages = 9977–9986 | date = November 2020 | pmid = 33140952 | doi = 10.1021/acs.jpcb.0c04963 | s2cid = 226244554 }}</ref> == Binding curves == [[File:HillEquation.svg|thumb|Sigmoidal versus hyperbolic binding patterns demonstrate cooperative and noncooperative character of enzymes.]] Binding curves describe the binding behavior of ligand to a protein. Curves can be characterized by their shape, [[Sigmoid function|sigmoidal]] or hyperbolic, which reflect whether or not the protein exhibits [[Cooperative binding|cooperative]] or noncooperative binding behavior respectively.<ref>{{cite journal | vauthors = Ahern K | title = Teaching biochemistry online at Oregon State University | journal = Biochemistry and Molecular Biology Education | volume = 45 | issue = 1 | pages = 25–30 | date = January 2017 | pmid = 27228905 | doi = 10.1002/bmb.20979 | doi-access = free }}</ref> Typically, the x-axis describes the concentration of ligand and the y-axis describes the fractional saturation of ligands bound to all available binding sites.<ref name="Hardin_2013" /> The Michaelis Menten equation is usually used when determining the shape of the curve. The Michaelis Menten equation is derived based on steady-state conditions and accounts for the enzyme reactions taking place in a solution. However, when the reaction takes place while the enzyme is bound to a substrate, the kinetics play out differently.<ref>{{cite journal | vauthors = Anne A, Demaille C | title = Kinetics of enzyme action on surface-attached substrates: a practical guide to progress curve analysis in any kinetic situation | journal = Langmuir | volume = 28 | issue = 41 | pages = 14665–71 | date = October 2012 | pmid = 22978617 | doi = 10.1021/la3030827 }}</ref> Modeling with binding curves are useful when evaluating the binding affinities of oxygen to [[hemoglobin]] and [[myoglobin]] in the blood. Hemoglobin, which has four heme groups, exhibits [[cooperative binding]]. This means that the binding of oxygen to a heme group on hemoglobin induces a favorable conformation change that allows for increased binding favorability of oxygen for the next heme groups. In these circumstances, the binding curve of hemoglobin will be sigmoidal due to its increased binding favorability for oxygen. Since myoglobin has only one heme group, it exhibits noncooperative binding which is hyperbolic on a binding curve.<ref>{{cite book |title=Biology: how life works | vauthors = Morris JR, Hartl DL, Knoll AH | date = 19 November 2015 |isbn=9781464126093 |edition= Second|location=New York, NY|oclc=937824456}}</ref> == Applications == Biochemical differences between different organisms and humans are useful for [[drug development]]. For instance, [[penicillin]] kills bacteria by inhibiting the bacterial enzyme [[DD-Transpeptidase|<small>DD</small>-transpeptidase]], destroying the development of the bacterial cell wall and inducing cell death. Thus, the study of binding sites is relevant to many fields of research, including cancer mechanisms,<ref>{{cite journal | vauthors = Spitzer R, Cleves AE, Varela R, Jain AN | title = Protein function annotation by local binding site surface similarity | journal = Proteins | volume = 82 | issue = 4 | pages = 679–94 | date = April 2014 | pmid = 24166661 | doi = 10.1002/prot.24450 | pmc = 3949165 }}</ref> drug formulation,<ref>{{cite journal | vauthors = Peng J, Li XP | title = Apolipoprotein A-IV: A potential therapeutic target for atherosclerosis | journal = Prostaglandins & Other Lipid Mediators | volume = 139 | pages = 87–92 | date = November 2018 | pmid = 30352313 | doi = 10.1016/j.prostaglandins.2018.10.004 | s2cid = 53023273 }}</ref> and physiological regulation.<ref>{{cite journal | vauthors = McNamara JW, Sadayappan S | title = Skeletal myosin binding protein-C: An increasingly important regulator of striated muscle physiology | journal = Archives of Biochemistry and Biophysics | volume = 660 | pages = 121–128 | date = December 2018 | pmid = 30339776 | pmc = 6289839 | doi = 10.1016/j.abb.2018.10.007 }}</ref> The formulation of an inhibitor to mute a protein's function is a common form of pharmaceutical therapy.<ref name=":2">{{cite journal | vauthors = Widemann BC, Adamson PC | title = Understanding and managing methotrexate nephrotoxicity | journal = The Oncologist | volume = 11 | issue = 6 | pages = 694–703 | date = June 2006 | pmid = 16794248 | doi = 10.1634/theoncologist.11-6-694 | doi-access = free }}</ref> [[File:DHFR methotrexate inhibitor.png|thumb|Methotrexate inhibits dihydrofolate reductase by outcompeting the substrate folic acid. Binding site in blue, inhibitor in green, and substrate in black.]] In the scope of cancer, ligands that are edited to have a similar appearance to the natural ligand are used to inhibit tumor growth. For example, [[Methotrexate]], a [[Chemotherapy|chemotherapeutic]], acts as a competitive inhibitor at the [[dihydrofolate reductase]] active site.<ref name="Rajagopalan 13481–13486">{{cite journal | vauthors = Rajagopalan PT, Zhang Z, McCourt L, Dwyer M, Benkovic SJ, Hammes GG | title = Interaction of dihydrofolate reductase with methotrexate: ensemble and single-molecule kinetics | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 99 | issue = 21 | pages = 13481–6 | date = October 2002 | pmid = 12359872 | doi = 10.1073/pnas.172501499 | pmc = 129699 | bibcode = 2002PNAS...9913481R | doi-access = free }}</ref> This interaction inhibits the synthesis of [[Tetrahydrofolic acid|tetrahydrofolate]], shutting off production of DNA, RNA and proteins.<ref name="Rajagopalan 13481–13486"/> Inhibition of this function represses [[Neoplasm|neoplastic growth]] and improves severe [[psoriasis]] and adult [[rheumatoid arthritis]].<ref name=":2" /> In cardiovascular illnesses, drugs such as beta blockers are used to treat patients with hypertension. [[Beta blocker]]s (β-Blockers) are antihypertensive agents that block the binding of the hormones adrenaline and noradrenaline to β1 and β2 receptors in the heart and blood vessels. These receptors normally mediate the sympathetic "fight or flight" response, causing constriction of the blood vessels.<ref>{{Cite book |date=2000| veditors = Frishman WH, Cheng-Lai A, Chen J |title=Current Cardiovascular Drugs |doi=10.1007/978-1-4615-6767-7|isbn=978-1-57340-135-7| s2cid = 38187984 }}</ref> Competitive inhibitors are also largely found commercially. [[Botulinum toxin]], known commercially as Botox, is a [[neurotoxin]] that causes flaccid paralysis in the muscle due to binding to acetylcholine dependent nerves. This interaction inhibits muscle contractions, giving the appearance of smooth muscle.<ref>{{cite journal | vauthors = Montecucco C, Molgó J | title = Botulinal neurotoxins: revival of an old killer | journal = Current Opinion in Pharmacology | volume = 5 | issue = 3 | pages = 274–9 | date = June 2005 | pmid = 15907915 | doi = 10.1016/j.coph.2004.12.006 }}</ref> A number of computational tools have been developed for the prediction of the location of binding sites on proteins.<ref name="Konc_2014" /><ref name="pmid26694353">{{cite journal | vauthors = Roche DB, Brackenridge DA, McGuffin LJ | title = Proteins and Their Interacting Partners: An Introduction to Protein-Ligand Binding Site Prediction Methods | journal = International Journal of Molecular Sciences | volume = 16 | issue = 12 | pages = 29829–42 | date = December 2015 | pmid = 26694353 | pmc = 4691145 | doi = 10.3390/ijms161226202 | doi-access = free }}</ref><ref name="Broomhead_2017">{{cite journal | vauthors = Broomhead NK, Soliman ME | title = Can We Rely on Computational Predictions To Correctly Identify Ligand Binding Sites on Novel Protein Drug Targets? Assessment of Binding Site Prediction Methods and a Protocol for Validation of Predicted Binding Sites | journal = Cell Biochemistry and Biophysics | volume = 75 | issue = 1 | pages = 15–23 | date = March 2017 | pmid = 27796788 | doi = 10.1007/s12013-016-0769-y | s2cid = 6705144 }}</ref><ref name="Sestak_2023">{{cite journal | vauthors = Sestak F, Schneckenreiter L, Hochreiter S, Mayr A, Klambauer G | title = VN-EGNN: Equivariant Graph Neural Networks with Virtual Nodes Enhance Protein Binding Site Identification | journal = NeurIPS 2023 Workshop: New Frontiers in Graph Learning }}</ref> These can be broadly classified into sequence based or structure based.<ref name="Broomhead_2017" /> Sequence based methods rely on the assumption that the sequences of functionally conserved portions of proteins such as binding site are conserved. Structure based methods require the 3D structure of the protein. These methods in turn can be subdivided into template and pocket based methods.<ref name="Broomhead_2017" /> Template based methods search for 3D similarities between the target protein and proteins with known binding sites. The pocket based methods search for concave surfaces or buried pockets in the target protein that possess features such as [[hydrophobicity]] and [[hydrogen bonding]] capacity that would allow them to bind ligands with high affinity.<ref name="Broomhead_2017" /> Even though the term pocket is used here, similar methods can be used to predict binding sites used in protein-protein interactions that are usually more planar, not in pockets.<ref>{{cite journal | vauthors = Jones S, Thornton JM | title = Analysis of protein-protein interaction sites using surface patches | journal = Journal of Molecular Biology | volume = 272 | issue = 1 | pages = 121–32 | date = September 1997 | pmid = 9299342 | doi = 10.1006/jmbi.1997.1234 }}</ref> == References == {{Reflist}} == External links == * {{MeSH name|Binding Sites}} *[https://huggingface.co/spaces/ml-jku/vnegnn Finding the binding site of a protein with an online tool] *[https://web.archive.org/web/20070514191455/http://www.proteincrystallography.org/programs/Pocket/ Drawing the active site of an enzyme] {{Enzymes}} {{DEFAULTSORT:Binding Site}} [[Category:Chemical bonding]] [[Category:Structural biology]] [[Category:Protein structure]]
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