Editing Protein folding (section)

{{short description|Change of a linear protein chain to a 3D structure}}
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[[Image:Protein folding.png|thumb|right|360px|Protein before and after folding]]
[[File:Protein structure.png|right|360px|thumb|Results of protein folding]]
'''Protein folding''' is the [[physical process]] by which a [[protein]], after [[Protein biosynthesis|synthesis]] by a [[ribosome]] as a linear chain of [[Amino acid|amino acids]], changes from an unstable [[random coil]] into a more ordered [[protein tertiary structure|three-dimensional structure]]. This structure permits the protein to become biologically functional or active.<ref name=Alberts>{{cite book | last1 = Alberts | first1 = Bruce | first2 = Alexander | last2 = Johnson | first3 = Julian | last3 = Lewis | first4 = Martin | last4 = Raff | first5 = Keith | last5 = Roberts | first6 = Peter | last6 = Walters | name-list-style = vanc | title = Molecular Biology of the Cell; Fourth Edition | publisher = Garland Science| year = 2002 | location = New York and London | chapter = The Shape and Structure of Proteins | chapter-url = https://www.ncbi.nlm.nih.gov/books/NBK26830/ | isbn = 978-0-8153-3218-3 | author-link1 = Bruce Alberts}}</ref>

The folding of many proteins begins even during the translation of the polypeptide chain. The amino acids interact with each other to produce a well-defined three-dimensional structure, known as the protein's [[native state]]. This structure is determined by the amino-acid sequence or [[primary structure]].<ref name="Anfinsen">{{cite journal | vauthors = Anfinsen CB | title = The formation and stabilization of protein structure | journal = The Biochemical Journal | volume = 128 | issue = 4 | pages = 737–49 | date = July 1972 | pmid = 4565129 | pmc = 1173893 | doi = 10.1042/bj1280737 }}</ref>

The correct three-dimensional structure is essential to function, although some parts of functional proteins [[Intrinsically unstructured proteins|may remain unfolded]],<ref>{{cite book | first1 = Jeremy M. | last1 = Berg | first2 = John L. | last2 = Tymoczko | first3 = Lubert | last3 = Stryer | author-link3 = Lubert Stryer | name-list-style = vanc | title = Biochemistry | publisher = W. H. Freeman | location = San Francisco | year = 2002 | isbn = 978-0-7167-4684-3 | chapter = 3. Protein Structure and Function | chapter-url = https://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Search&db=books&doptcmdl=GenBookHL&term=stryer%5Bbook%5D+AND+215168%5Buid%5D&rid=stryer.chapter.280}}</ref> indicating that [[protein dynamics]] are important. Failure to fold into a native structure generally produces inactive proteins, but in some instances, misfolded proteins have modified or toxic functionality. Several [[neurodegenerative]] and other [[disease]]s are believed to result from the accumulation of [[amyloid]] [[fibrils]] formed by misfolded proteins, the infectious varieties of which are known as [[Prion|prions]].<ref name="Selkoe:03">{{cite journal | vauthors = Selkoe DJ | title = Folding proteins in fatal ways | journal = Nature | volume = 426 | issue = 6968 | pages = 900–4 | date = December 2003 | pmid = 14685251 | doi = 10.1038/nature02264 | bibcode = 2003Natur.426..900S | s2cid = 6451881 }}</ref> Many [[Protein allergy|allergies]] are caused by the incorrect folding of some proteins because the [[immune system]] does not produce the [[antibodies]] for certain protein structures.<ref>{{cite book | last1 = Alberts | first1 = Bruce | first2 = Dennis | last2 = Bray | first3 = Karen | last3 = Hopkin | first4 = Alexander | last4 = Johnson | first5 = Julian | last5 = Lewis | first6 = Martin | last6 = Raff | first7 = Keith | last7 = Roberts | first8 = Peter | last8 = Walter | name-list-style = vanc | title = Essential cell biology | date = 2010 | publisher = Garland Science | location = New York, NY | isbn = 978-0-8153-4454-4 | pages = 120–70 | edition = Third | chapter = Protein Structure and Function}}</ref>

[[Denaturation (biochemistry)|Denaturation]] of proteins is a process of transition from a folded to an [[Random coil|unfolded state]]. It happens in [[cooking]], [[burn]]s, [[proteinopathy|proteinopathies]], and other contexts.  Residual structure present, if any, in the supposedly unfolded state may form a folding initiation site and guide the subsequent folding reactions. <ref>{{cite journal | vauthors = Yagi-Utsumi M, Chandak MS, Yanaka S, Hiranyakorn M, Nakamura T, Kato K, Kuwajima K| title = Residual Structure of Unfolded Ubiquitin as Revealed by Hydrogen/Deuterium-Exchange 2D NMR | journal = Biophysical Journal | volume = 119 | issue = 10 | pages = 2029–38 | date = November 2020 | pmid = 33142107 | doi = 10.1016/j.bpj.2020.10.003 | pmc = 7732725 | bibcode = 2020BpJ...119.2029Y }}</ref>

The duration of the folding process varies dramatically depending on the protein of interest. When studied [[in vitro|outside the cell]], the slowest folding proteins require many minutes or hours to fold, primarily due to [[Proline#Cis-trans isomerization|proline isomerization]], and must pass through a number of intermediate states, like checkpoints, before the process is complete.<ref>{{cite journal | vauthors = Kim PS, Baldwin RL | title = Intermediates in the folding reactions of small proteins | journal = Annual Review of Biochemistry | volume = 59 | pages = 631–60 | year = 1990 | pmid = 2197986 | doi = 10.1146/annurev.bi.59.070190.003215 }}</ref> On the other hand, very small single-[[protein domain|domain]] proteins with lengths of up to a hundred amino acids typically fold in a single step.<ref>{{cite journal | vauthors = Jackson SE | title = How do small single-domain proteins fold? | journal = Folding & Design | volume = 3 | issue = 4 | pages = R81-91 | year = 1998 | pmid = 9710577 | doi = 10.1016/S1359-0278(98)00033-9 | doi-access =  }}</ref> Time scales of milliseconds are the norm, and the fastest known protein folding reactions are complete within a few microseconds.<ref>{{cite journal | vauthors = Kubelka J, Hofrichter J, Eaton WA | title = The protein folding 'speed limit' | journal = Current Opinion in Structural Biology | volume = 14 | issue = 1 | pages = 76–88 | date = February 2004 | pmid = 15102453 | doi = 10.1016/j.sbi.2004.01.013 | url = https://zenodo.org/record/1259347 }} </ref> The folding time scale of a protein depends on its size, [[contact order]], and [[circuit topology]].<ref>{{Cite journal | url=https://pubs.rsc.org/en/content/articlelanding/2021/cp/d1cp03390e | doi=10.1039/D1CP03390E | title=Topological principles of protein folding | year=2021 | last1=Scalvini | first1=Barbara | last2=Sheikhhassani | first2=Vahid | last3=Mashaghi | first3=Alireza | journal=Physical Chemistry Chemical Physics | volume=23 | issue=37 | pages=21316–21328 | pmid=34545868 | bibcode=2021PCCP...2321316S | hdl=1887/3277889 | s2cid=237583577 | hdl-access=free }}</ref>

Understanding and simulating the protein folding process has been an important challenge for [[computational biology]] since the late 1960s.