conformational ensembles
{{Main|Protein domain dynamics}}
{{short description|Computational models of intrinsically-disordered proteins}}
File:Modeling-Conformational-Ensembles-of-Slow-Functional-Motions-in-Pin1-WW-pcbi.1001015.s016.ogv
In protein chemistry, conformational ensembles, also known as structural ensembles, are models describing the structure of intrinsically unstructured proteins.{{cite journal | vauthors = Fisher CK, Stultz CM | title = Constructing ensembles for intrinsically disordered proteins | journal = Current Opinion in Structural Biology | volume = 21 | issue = 3 | pages = 426–31 | date = June 2011 | pmid = 21530234 | pmc = 3112268 | doi = 10.1016/j.sbi.2011.04.001 | series = (3) | url = http://dspace.mit.edu/bitstream/1721.1/99137/1/Stultz_Constructing%20ensembles.pdf | hdl = 1721.1/99137 }}{{cite journal | vauthors = Varadi M, Kosol S, Lebrun P, Valentini E, Blackledge M, Dunker AK, Felli IC, Forman-Kay JD, Kriwacki RW, Pierattelli R, Sussman J, Svergun DI, Uversky VN, Vendruscolo M, Wishart D, Wright PE, Tompa P | title = pE-DB: a database of structural ensembles of intrinsically disordered and of unfolded proteins | journal = Nucleic Acids Research | volume = 42 | issue = Database issue | pages = D326-35 | date = January 2014 | pmid = 24174539 | pmc = 3964940 | doi = 10.1093/nar/gkt960 }} Such proteins are flexible in nature and cannot be described by a single structural representation.{{cite journal|authorlink1=Jane Dyson | vauthors = Dyson HJ, Wright PE | title = Intrinsically unstructured proteins and their functions | journal = Nature Reviews. Molecular Cell Biology | volume = 6 | issue = 3 | pages = 197–208 | date = March 2005 | pmid = 15738986 | doi = 10.1038/nrm1589 | s2cid = 18068406 }} The techniques of ensemble calculation are relatively new on the field of structural biology, and are still facing certain limitations that need to be addressed before it will become comparable to classical structural description methods such as biological macromolecular crystallography.{{cite journal | vauthors = Tompa P | title = Unstructural biology coming of age | journal = Current Opinion in Structural Biology | volume = 21 | issue = 3 | pages = 419–25 | date = June 2011 | pmid = 21514142 | doi = 10.1016/j.sbi.2011.03.012 }}
Purpose
Ensembles are models consisting of a set of conformations that describe the structure of a flexible protein. Even though the degree of conformational freedom is extremely high, flexible/disordered protein generally differ from fully random coil structures.{{cite journal | vauthors = Communie G, Habchi J, Yabukarski F, Blocquel D, Schneider R, Tarbouriech N, Papageorgiou N, Ruigrok RW, Jamin M, Jensen MR, Longhi S, Blackledge M | title = Atomic resolution description of the interaction between the nucleoprotein and phosphoprotein of Hendra virus | journal = PLOS Pathogens | volume = 9 | issue = 9 | pages = e1003631 | year = 2013 | pmid = 24086133 | pmc = 3784471 | doi = 10.1371/journal.ppat.1003631 | doi-access = free }}{{cite journal | vauthors = Kurzbach D, Platzer G, Schwarz TC, Henen MA, Konrat R, Hinderberger D | title = Cooperative unfolding of compact conformations of the intrinsically disordered protein osteopontin | journal = Biochemistry | volume = 52 | issue = 31 | pages = 5167–75 | date = August 2013 | pmid = 23848319 | pmc = 3737600 | doi = 10.1021/bi400502c }} The main purpose of these models is to gain insights regarding the function of the flexible protein, extending the structure-function paradigm from folded proteins to intrinsically disordered proteins.
Calculation techniques
The calculation of ensembles rely on experimental measurements, mostly by Neutron spin echo spectroscopy, Nuclear Magnetic Resonance spectroscopy and Small-angle X-ray scattering. These measurements yield structural information.
= Short-range =
= Long-range =
- Paramagnetic Relaxation Enhancements (PREs)
- Nuclear Overhauser effects (NOEs)
- SAXS topological restraints.
= Constrained molecular dynamics simulations =
The structure of disordered proteins may be approximated by running constrained molecular dynamics (MD) simulations where the conformational sampling is being influenced by experimentally derived constraints.{{cite journal | vauthors = Allison JR, Varnai P, Dobson CM, Vendruscolo M | title = Determination of the free energy landscape of alpha-synuclein using spin label nuclear magnetic resonance measurements | journal = Journal of the American Chemical Society | volume = 131 | issue = 51 | pages = 18314–26 | date = December 2009 | pmid = 20028147 | doi = 10.1021/ja904716h }}
= Fitting experimental data =
Another approach uses selection algorithms such as ENSEMBLE and ASTEROIDS.{{cite journal | vauthors = Krzeminski M, Marsh JA, Neale C, Choy WY, Forman-Kay JD | title = Characterization of disordered proteins with ENSEMBLE | journal = Bioinformatics | volume = 29 | issue = 3 | pages = 398–9 | date = February 2013 | pmid = 23233655 | doi = 10.1093/bioinformatics/bts701 | doi-access = free }}{{cite journal | vauthors = Jensen MR, Salmon L, Nodet G, Blackledge M | title = Defining conformational ensembles of intrinsically disordered and partially folded proteins directly from chemical shifts | journal = Journal of the American Chemical Society | volume = 132 | issue = 4 | pages = 1270–2 | date = February 2010 | pmid = 20063887 | doi = 10.1021/ja909973n }} Calculation procedures first generate a pool of random conformers (initial pool) so that they sufficiently sample the conformation space. The selection algorithms start by choosing a smaller set of conformers (an ensemble) from the initial pool. Experimental parameters (NMR/SAXS) are calculated (usually by some theoretical prediction methods) for each conformer of chosen ensemble and averaged over ensemble. The difference between these calculated parameters and true experimental parameters is used to make an error function and the algorithm selects the final ensemble so that the error function is minimised.
Limitations
The determination of a structural ensemble for an IDP from NMR/SAXS experimental parameters involves generation of structures that agree with the parameters and their respective weights in the ensemble. Usually, the available experimental data is less compared to the number of variables required to determine making it an under-determined system. Due to this reason, several structurally very different ensembles may describe the experimental data equally well, and currently there are no exact methods to discriminate between ensembles of equally good fit. This problem has to be solved either by bringing in more experimental data or by improving the prediction methods by introducing rigorous computational methods.
References
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External links
- {{cite web | url = http://pedb.vib.be | title = PED3: Protein Ensemble Database | quote = Database of conformational ensembles describing flexible proteins | first = Mihaly | last = Varadi | name-list-style = vanc | work = Peter Tompa Lab | publisher = Vrije Universiteit Brussel | access-date = 2020-07-27 | archive-url = https://web.archive.org/web/20180310010556/http://pedb.vib.be/ | archive-date = 2018-03-10 | url-status = dead }}