Editing Protein structure (section)

==Protein dynamics and conformational ensembles==

{{Main|Protein dynamics}}

Proteins are not static objects, but rather populate ensembles of [[conformational change|conformational states]]. Transitions between these states typically occur on [[Nanoscopic scale|nanoscale]]s, and have been linked to functionally relevant phenomena such as [[Allosteric regulation|allosteric signaling]]<ref name="pmid21570668">{{cite book |vauthors=Bu Z, Callaway DJ |chapter=Proteins MOVE! Protein dynamics and long-range allostery in cell signaling |volume=83 |pages=163–221 |year=2011 |pmid=21570668 |doi=10.1016/B978-0-12-381262-9.00005-7 |chapter-url=http://linkinghub.elsevier.com/retrieve/pii/B978-0-12-381262-9.00005-7 |series=Advances in Protein Chemistry and Structural Biology |isbn=9780123812629|title=Protein Structure and Diseases |publisher=Academic Press }}</ref> and [[enzyme catalysis]].<ref>
{{cite journal | vauthors = Fraser JS, Clarkson MW, Degnan SC, Erion R, Kern D, Alber T | title = Hidden alternative structures of proline isomerase essential for catalysis | journal = Nature | volume = 462 | issue = 7273 | pages = 669–673 | date = December 2009 | pmid = 19956261 | pmc = 2805857 | doi = 10.1038/nature08615 | bibcode = 2009Natur.462..669F }}</ref>  [[Protein dynamics]]  and [[conformational change]]s allow proteins to function as nanoscale [[biological machine]]s  within cells, often in the form of [[Protein complex|multi-protein complexes]].<ref>{{Cite book|title=Biochemistry| vauthors = Voet D, Voet JG |date=2011|publisher=John Wiley & Sons |isbn=9780470570951|edition= 4th|location=Hoboken, NJ|oclc=690489261}}</ref> Examples include [[motor proteins]], such as [[myosin]], which is responsible for [[muscle]] contraction, [[kinesin]], which moves cargo inside cells away from the [[Cell nucleus|nucleus]] along [[microtubules]], and [[dynein]], which moves cargo inside cells towards the nucleus and produces the axonemal beating of [[cilia#Motile cilia|motile cilia]] and [[flagella]].  "[I]n effect, the [motile cilium] is a nanomachine composed of perhaps over 600 proteins in molecular complexes, many of which also function independently as nanomachines...[[Flexible linker]]s allow the [[Protein domain#Domains and protein flexibility|mobile protein domains]] connected by them to recruit their binding partners and induce long-range [[allostery]] via [[Protein dynamics#Global flexibility: multiple domains|protein domain dynamics]]. "<ref name="Satir2008">{{cite journal | vauthors = Satir P, Christensen ST | title = Structure and function of mammalian cilia | journal = Histochemistry and Cell Biology | volume = 129 | issue = 6 | pages = 687–693 | date = June 2008 | pmid = 18365235 | pmc = 2386530 | doi = 10.1007/s00418-008-0416-9 | id = 1432-119X }}</ref>

[[File:Schematic view of the two main ensemble modeling approaches.jpg|thumb|right|500px|Schematic view of the two main ensemble modeling approaches.<ref name=":2" />]]

Proteins are often thought of as relatively stable [[Protein tertiary structure|tertiary structures]] that experience conformational changes after being affected by interactions with other proteins or as a part of enzymatic activity. However, proteins may have varying degrees of stability, and some of the less stable variants are [[intrinsically disordered proteins]]. These proteins exist and function in a relatively 'disordered' state lacking a stable [[Protein tertiary structure|tertiary structure]]. As a result, they are difficult to describe by a single fixed [[Protein tertiary structure|tertiary structure]]. [[Conformational ensembles]] have been devised as a way to provide a more accurate and 'dynamic' representation of the conformational state of [[intrinsically disordered proteins]].<ref>[https://web.archive.org/web/20180310010556/http://pedb.vib.be/ Protein Ensemble Database]</ref><ref name=":2">{{cite journal | vauthors = Varadi M, Vranken W, Guharoy M, Tompa P | title = Computational approaches for inferring the functions of intrinsically disordered proteins | journal = Frontiers in Molecular Biosciences | volume = 2 | pages = 45 | date = 2015-01-01 | pmid = 26301226 | pmc = 4525029 | doi = 10.3389/fmolb.2015.00045 | doi-access = free }}</ref>

Protein [[Conformational ensembles|ensemble]] files are a representation of a protein that can be considered to have a flexible structure. Creating these files requires determining which of the various theoretically possible protein conformations actually exist. One approach is to apply computational algorithms to the protein data in order to try to determine the most likely set of conformations for an [[Conformational ensembles|ensemble]] file. There are multiple methods for preparing data for the [https://web.archive.org/web/20180310010556/http://pedb.vib.be/ Protein Ensemble Database] that fall into two general methodologies – pool and molecular dynamics (MD) approaches (diagrammed in the figure). The pool based approach uses the protein's amino acid sequence to create a massive pool of random conformations. This pool is then subjected to more computational processing that creates a set of theoretical parameters for each conformation based on the structure. Conformational subsets from this pool whose average theoretical parameters closely match known experimental data for this protein are selected. The alternative molecular dynamics approach takes multiple random conformations at a time and subjects all of them to experimental data. Here the experimental data is serving as limitations to be placed on the conformations (e.g. known distances between atoms). Only conformations that manage to remain within the limits set by the experimental data are accepted. This approach often applies large amounts of experimental data to the conformations which is a very computationally demanding task.<ref name=":2" />

The conformational ensembles were generated for a number of highly dynamic and partially unfolded proteins, such as [[Sic1]]/[[Cell division control protein 4|Cdc4]],<ref>{{cite journal | vauthors = Mittag T, Marsh J, Grishaev A, Orlicky S, Lin H, Sicheri F, Tyers M, Forman-Kay JD | display-authors = 6 | title = Structure/function implications in a dynamic complex of the intrinsically disordered Sic1 with the Cdc4 subunit of an SCF ubiquitin ligase | journal = Structure | volume = 18 | issue = 4 | pages = 494–506 | date = March 2010 | pmid = 20399186 | pmc = 2924144 | doi = 10.1016/j.str.2010.01.020 }}</ref> [[KIAA0101|p15 PAF]],<ref>{{cite journal | vauthors = De Biasio A, Ibáñez de Opakua A, Cordeiro TN, Villate M, Merino N, Sibille N, Lelli M, Diercks T, Bernadó P, Blanco FJ | display-authors = 6 | title = p15PAF is an intrinsically disordered protein with nonrandom structural preferences at sites of interaction with other proteins | journal = Biophysical Journal | volume = 106 | issue = 4 | pages = 865–874 | date = February 2014 | pmid = 24559989 | pmc = 3944474 | doi = 10.1016/j.bpj.2013.12.046 | bibcode = 2014BpJ...106..865D }}</ref> [[MAP2K7|MKK7]],<ref>{{cite journal | vauthors = Kragelj J, Palencia A, Nanao MH, Maurin D, Bouvignies G, Blackledge M, Jensen MR | title = Structure and dynamics of the MKK7-JNK signaling complex | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 112 | issue = 11 | pages = 3409–3414 | date = March 2015 | pmid = 25737554 | pmc = 4371970 | doi = 10.1073/pnas.1419528112 | doi-access = free | bibcode = 2015PNAS..112.3409K }}</ref> [[Beta-synuclein]]<ref>{{cite journal | vauthors = Allison JR, Rivers RC, Christodoulou JC, Vendruscolo M, Dobson CM | title = A relationship between the transient structure in the monomeric state and the aggregation propensities of α-synuclein and β-synuclein | journal = Biochemistry | volume = 53 | issue = 46 | pages = 7170–7183 | date = November 2014 | pmid = 25389903 | pmc = 4245978 | doi = 10.1021/bi5009326 }}</ref> and [[CDKN1B|P27]]<ref>{{cite journal | vauthors = Sivakolundu SG, Bashford D, Kriwacki RW | title = Disordered p27Kip1 exhibits intrinsic structure resembling the Cdk2/cyclin A-bound conformation | journal = Journal of Molecular Biology | volume = 353 | issue = 5 | pages = 1118–1128 | date = November 2005 | pmid = 16214166 | doi = 10.1016/j.jmb.2005.08.074 }}</ref>