Editing Protein (section)

==History and etymology==

{{further|History of molecular biology}}

=== Discovery and early studies ===

Proteins have been studied and recognized since the 1700s by [[Antoine François, comte de Fourcroy|Antoine Fourcroy]] and others,<ref name="Osborne-1909">{{cite book |author-link1=Thomas Burr Osborne (chemist) |title=The Vegetable Proteins |vauthors=Osborne TB |date=1909 |pages=1–6 |chapter=History |chapter-url=https://archive.org/details/vegetableprotein00osbouoft}}</ref><ref name="Reynolds2003" /> who often collectively called them "[[albumin]]s", or "albuminous materials" (''Eiweisskörper'', in German).<ref name="Reynolds2003" /> [[Gluten]], for example, was first separated from wheat in published research around 1747, and later determined to exist in many plants.<ref name="Osborne-1909" /> In 1789, Antoine Fourcroy recognized three distinct varieties of animal proteins: [[albumin]], [[fibrin]], and [[gelatin]].<ref>{{Cite book |last=Tanford |first=Charles |url=http://archive.org/details/naturesrobotshis0000tanf |title=Nature's robots: a history of proteins |date=2001 |publisher=Oxford; Toronto: Oxford University Press |others=Internet Archive |isbn=978-0-19-850466-5}}</ref> Vegetable (plant) proteins studied in the late 1700s and early 1800s included [[gluten]], [[Albumin|plant albumin]], [[gliadin]], and [[legumin]].<ref name="Osborne-1909" />

Proteins were first described by the Dutch chemist [[Gerardus Johannes Mulder]] and named by the Swedish chemist [[Jöns Jacob Berzelius]] in 1838.<ref name="Mulder1938">{{cite journal | vauthors = Mulder GJ | year = 1838 | url = https://archive.org/stream/bulletindesscien00leyd#page/104/mode/2up | title = Sur la composition de quelques substances animales | journal = Bulletin des Sciences Physiques et Naturelles en Néerlande | pages = 104 }}</ref><ref name="Hartley">{{cite journal | vauthors = Hartley H | title = Origin of the word 'protein' | journal = Nature | volume = 168 | issue = 4267 | pages = 244 | date = August 1951 | pmid = 14875059 | doi = 10.1038/168244a0 | s2cid = 4271525 | doi-access = free | bibcode = 1951Natur.168..244H }}</ref> Mulder carried out [[elemental analysis]] of common proteins and found that nearly all proteins had the same [[empirical formula]], C<sub>400</sub>H<sub>620</sub>N<sub>100</sub>O<sub>120</sub>P<sub>1</sub>S<sub>1</sub>.<ref name=Perrett2007/> He came to the erroneous conclusion that they might be composed of a single type of (very large) molecule. The term "protein" to describe these molecules was proposed by Mulder's associate Berzelius; protein is derived from the [[Greek language|Greek]] word {{lang|el|πρώτειος|italic=no}} ({{transliteration|el|proteios|italic=yes}}), meaning "primary",<ref>{{cite encyclopedia | encyclopedia = Oxford English Dictionary | title = Protein (n.) | date = July 2023 | doi = 10.1093/OED/5657543824 }}</ref> "in the lead", or "standing in front",<ref name=Reynolds2003/> + ''[[wikt:-in#Suffix|-in]]''. Mulder went on to identify the products of protein degradation such as the [[amino acid]] [[leucine]] for which he found a (nearly correct) molecular weight of 131 [[atomic mass unit|Da]].<ref name=Perrett2007/>

Early nutritional scientists such as the German [[Carl von Voit]] believed that protein was the most important nutrient for maintaining the structure of the body, because it was generally believed that "flesh makes flesh."<ref name=Bischoff1860/> Around 1862, [[Karl Heinrich Ritthausen]] isolated the amino acid [[glutamic acid]].<ref>{{cite journal |last1=Osborne |first1=Thomas B. |date=April 1913 |title=In Memoriam Heinrich Ritthausen |url=https://www.biodiversitylibrary.org/ia/blumenzeitung09hssl#page/400/mode/2up |journal=Biochemical Bulletin |publisher=[[Columbia University]] Biochemical Association |volume=II |page=338 |authorlink1=Thomas Burr Osborne (chemist) |accessdate=1 January 2016 |number=7}}, archived at the [[Biodiversity Heritage Library]]</ref> [[Thomas Burr Osborne (chemist)|Thomas Burr Osborne]] compiled a detailed review of the vegetable proteins at the [[Connecticut Agricultural Experiment Station]]. Osborne, alongside [[Lafayette Mendel]], established several [[essential amino acid|nutritionally essential amino acids]] in feeding experiments with laboratory rats.<ref>{{Cite journal |last1=Simoni |first1=Robert D. |last2=Hill |first2=Robert L. |last3=Vaughan |first3=Martha |date=2002-05-03 |title=Nutritional Biochemistry and the Amino Acid Composition of Proteins: The early years of protein chemistry, the Work of Thomas B. Osborne and Lafayette B. Mendel |journal=Journal of Biological Chemistry |volume=277 |issue=18 |pages=14–15 |doi=10.1016/S0021-9258(19)35800-4 |doi-access=free }}</ref> Diets lacking an essential amino acid stunts the rats' growth, consistent with [[Liebig's law of the minimum]].<ref>{{Cite journal |last1=Osborne |first1=Thomas B. |last2=Mendel |first2=Lafayette B. |last3=Ferry |first3=Edna L. |last4=Wakeman |first4=Alfred J. |date=1916 |title=The Amino-Acid Minimum for Maintenance and Growth, as Exemplified by Further Experiments with Lysine and Tryptophane |journal=Journal of Biological Chemistry |volume=25 |issue=1 |pages=1–12 |doi=10.1016/S0021-9258(18)87509-3 |doi-access=free }}</ref> The final essential amino acid to be discovered, [[threonine]], was identified by [[William Cumming Rose]].<ref>{{Cite journal |last1=Simoni |first1=Robert D. |last2=Hill |first2=Robert L. |last3=Vaughan |first3=Martha |date=2002-09-13 |title=The Discovery of the Amino Acid Threonine: the Work of William C. Rose |journal=Journal of Biological Chemistry |volume=277 |issue=37 |pages=56–58 |doi=10.1016/S0021-9258(20)74369-3 |doi-access=free }}</ref>

The difficulty in purifying proteins impeded work by early protein biochemists. Proteins could be obtained in large quantities from blood, egg whites, and [[keratin]], but individual proteins were unavailable.  In the 1950s, the [[Armour and Company|Armour Hot Dog Company]] purified 1&nbsp;kg of bovine pancreatic [[ribonuclease A]] and made it freely available to scientists.  This gesture helped ribonuclease A become a major target for biochemical study for the following decades.<ref name="Perrett2007" />

=== Polypeptides ===

[[File:Peptide bond.jpg|thumb|polypeptide]]

The understanding of proteins as [[polypeptide]]s, or chains of amino acids, came through the work of [[Franz Hofmeister]] and [[Hermann Emil Fischer]] in 1902.<ref>{{cite web|url=http://www.encyclopedia.com/science/dictionaries-thesauruses-pictures-and-press-releases/hofmeister-franz|title=Hofmeister, Franz|publisher=encyclopedia.com|access-date=4 April 2017|archive-url=https://web.archive.org/web/20170405073423/http://www.encyclopedia.com/science/dictionaries-thesauruses-pictures-and-press-releases/hofmeister-franz|archive-date=5 April 2017|url-status=live}}</ref><ref>{{cite web | vauthors = Koshland DE, Haurowitz F |url=https://www.britannica.com/science/protein/Conformation-of-proteins-in-interfaces#ref593795|title=Protein, section: Classification of protein|publisher=britannica.com|access-date=4 April 2017|archive-url=https://web.archive.org/web/20170404225132/https://www.britannica.com/science/protein/Conformation-of-proteins-in-interfaces#ref593795|archive-date=4 April 2017|url-status=live}}</ref> The central role of proteins as [[enzyme]]s in living organisms that catalyzed reactions was not fully appreciated until 1926, when [[James B. Sumner]] showed that the enzyme [[urease]] was in fact a protein.<ref name="Sumner1926" />

[[Linus Pauling]] is credited with the successful prediction of regular protein [[secondary structure]]s based on [[hydrogen bonding]], an idea first put forth by [[William Astbury]] in 1933.<ref name="Pauling1951" /> Later work by [[Walter Kauzmann]] on [[Denaturation (biochemistry)|denaturation]],<ref name="Kauzmann1956" /><ref name="Kauzmann1959" /> based partly on previous studies by [[Kaj Ulrik Linderstrøm-Lang|Kaj Linderstrøm-Lang]],<ref name="Kalman1955" /> contributed an understanding of [[protein folding]] and structure mediated by [[hydrophobic core|hydrophobic interactions]].<ref>{{Cite journal |last=Dill |first=Ken A. |date=1990 |title=Dominant forces in protein folding |url=https://pubs.acs.org/doi/abs/10.1021/bi00483a001 |journal=Biochemistry |volume=29 |issue=31 |pages=7133–7155 |doi=10.1021/bi00483a001|pmid=2207096 |url-access=subscription }}</ref>

The first protein to have its amino acid chain [[protein sequencing|sequenced]] was [[insulin]], by [[Frederick Sanger]], in 1949. Sanger correctly determined the amino acid sequence of insulin, thus conclusively demonstrating that proteins consisted of linear polymers of amino acids rather than branched chains, [[colloid]]s, or [[cyclol]]s.<ref name=Sanger1949/> He won the Nobel Prize for this achievement in 1958.<ref name="Lecture 1958"/> [[Christian Anfinsen]]'s studies of the [[oxidative folding]] process of ribonuclease A, for which he won the nobel prize in 1972, solidified the [[thermodynamic hypothesis]] of protein folding, according to which the folded form of a protein represents its [[Free energy (thermodynamics)|free energy]] minimum.<ref name="pmid17754377">{{cite journal |vauthors=Richards FM |year=1972 |title=The 1972 nobel prize for chemistry |journal=Science |volume=178 |issue=4060 |pages=492–3 |bibcode=1972Sci...178..492R |doi=10.1126/science.178.4060.492 |pmid=17754377}}</ref><ref name="marshall">{{Cite journal |last1=Marshall |first1=G. R. |last2=Feng |first2=J. A. |last3=Kuster |first3=D. J. |year=2008 |title=Back to the future: Ribonuclease A |journal=Biopolymers |volume=90 |issue=3 |pages=259–77 |doi=10.1002/bip.20845 |pmid=17868092 |doi-access=free}}</ref>

=== Structure ===

[[File:KendrewMyoglobin.jpg|thumb|upright=1.15|[[John Kendrew]] with model of myoglobin in progress]]

With the development of [[X-ray crystallography]], it became possible to determine protein structures as well as their sequences.<ref name="Stoddart">{{cite journal | vauthors = Stoddart C |title=Structural biology: How proteins got their close-up |journal=Knowable Magazine |date=1 March 2022 |doi=10.1146/knowable-022822-1 |doi-access=free }}</ref> The first [[protein structure]]s to be solved were [[hemoglobin]] by [[Max Perutz]] and [[myoglobin]] by [[John Kendrew]], in 1958.<ref name=Muirhead1963/><ref name=Kendrew1958/> The use of computers and increasing computing power has supported the sequencing of complex proteins. In 1999, [[Roger Kornberg]] sequenced the highly complex structure of [[RNA polymerase]] using high intensity X-rays from [[synchrotrons]].<ref name="Stoddart"/>

Since then, [[cryo-electron microscopy]] (cryo-EM) of large [[Macromolecular Assembly|macromolecular assemblies]]<ref name=Zhou2008/> has been developed. Cryo-EM uses protein samples that are frozen rather than crystals, and [[electron microscopy|beams of electrons]] rather than X-rays. It causes less damage to the sample, allowing scientists to obtain more information and analyze larger structures.<ref name="Stoddart"/> Computational [[protein structure prediction]] of small protein [[structural domain]]s<ref name=Keskin2008/> has helped researchers to approach atomic-level resolution of protein structures.
{{As of|April 2024}}, the [[Protein Data Bank]] contains 181,018 X-ray, 19,809 [[Cryogenic electron microscopy|EM]] and 12,697 [[Protein nuclear magnetic resonance spectroscopy|NMR]] protein structures.<ref>{{cite web |url=https://www.rcsb.org/stats/summary |title=Summary Statistics |website=RCSB PDB |access-date=2024-04-20}}</ref>