582:
296:
individual proteins and regulated protein turnover. Often, post-translational modifications such as phosphorylation tune the affinity (not rarely by several orders of magnitude) of individual linear motifs for specific interactions. Relatively rapid evolution and a relatively small number of structural restraints for establishing novel (low-affinity) interfaces make it particularly challenging to detect linear motifs but their widespread biological roles and the fact that many viruses mimick/hijack linear motifs to efficiently recode infected cells underlines the timely urgency of research on this very challenging and exciting topic.
634:
characterized as disorder-promoting amino acids, while order-promoting amino acids W, C, F, I, Y, V, L, and N are hydrophobic and uncharged. The remaining amino acids H, M, T and D are ambiguous, found in both ordered and unstructured regions. A more recent analysis ranked amino acids by their propensity to form disordered regions as follows (order promoting to disorder promoting): W, F, Y, I, M, L, V, N, C, T, A, G, R, D, H, Q, K, S, E, P. As it can be seen from the list, small, charged, hydrophilic residues often promote disorder, while large and hydrophobic residues promote order.
317:). The coupled folding and binding may be local, involving only a few interacting residues, or it might involve an entire protein domain. It was recently shown that the coupled folding and binding allows the burial of a large surface area that would be possible only for fully structured proteins if they were much larger. Moreover, certain disordered regions might serve as "molecular switches" in regulating certain biological function by switching to ordered conformation upon molecular recognition like small molecule-binding, DNA/RNA binding, ion interactions etc.
389:). Many disordered proteins reveal regions without any regular secondary structure. These regions can be termed as flexible, compared to structured loops. While the latter are rigid and contain only one set of Ramachandran angles, IDPs involve multiple sets of angles. The term flexibility is also used for well-structured proteins, but describes a different phenomenon in the context of disordered proteins. Flexibility in structured proteins is bound to an equilibrium state, while it is not so in IDPs. Many disordered proteins also reveal
728:
for accurate representation of these ensembles by computer simulations. All-atom molecular dynamic simulations can be used for this purpose but their use is limited by the accuracy of current force-fields in representing disordered proteins. Nevertheless, some force-fields have been explicitly developed for studying disordered proteins by optimising force-field parameters using available NMR data for disordered proteins. (examples are CHARMM 22*, CHARMM 32, Amber ff03* etc.)
31:
146:
653:
the expense of IDP determination. In order to overcome this obstacle, computer-based methods are created for predicting protein structure and function. It is one of the main goals of bioinformatics to derive knowledge by prediction. Predictors for IDP function are also being developed, but mainly use structural information such as
716:
255:, thus it has been proposed that the flexibility of disordered proteins facilitates the different conformational requirements for binding the modifying enzymes as well as their receptors. Intrinsic disorder is particularly enriched in proteins implicated in cell signaling and transcription, as well as
701:
is thought to be responsible. The structural flexibility of this protein together with its susceptibility to modification in the cell leads to misfolding and aggregation. Genetics, oxidative and nitrative stress as well as mitochondrial impairment impact the structural flexibility of the unstructured
664:
Many computational methods exploit sequence information to predict whether a protein is disordered. Notable examples of such software include IUPRED and
Disopred. Different methods may use different definitions of disorder. Meta-predictors show a new concept, combining different primary predictors to
178:
suggested that the systematic conformational search of a long polypeptide is unlikely to yield a single folded protein structure on biologically relevant timescales (i.e. microseconds to minutes). Curiously, for many (small) proteins or protein domains, relatively rapid and efficient refolding can be
727:
Owing to high structural heterogeneity, NMR/SAXS experimental parameters obtained will be an average over a large number of highly diverse and disordered states (an ensemble of disordered states). Hence, to understand the structural implications of these experimental parameters, there is a necessity
652:
Determining disordered regions from biochemical methods is very costly and time-consuming. Due to the variable nature of IDPs, only certain aspects of their structure can be detected, so that a full characterization requires a large number of different methods and experiments. This further increases
376:
Therefore, their structures are strongly function-related. However, only few proteins are fully disordered in their native state. Disorder is mostly found in intrinsically disordered regions (IDRs) within an otherwise well-structured protein. The term intrinsically disordered protein (IDP) therefore
637:
This information is the basis of most sequence-based predictors. Regions with little to no secondary structure, also known as NORS (NO Regular
Secondary structure) regions, and low-complexity regions can easily be detected. However, not all disordered proteins contain such low complexity sequences.
304:
Unlike globular proteins, IDPs do not have spatially-disposed active pockets. Fascinatingly, 80% of target-unbound IDPs (~4 dozens) subjected to detailed structural characterization by NMR possess linear motifs termed PresMos (pre-structured motifs) that are transient secondary structural elements
633:
Separating disordered from ordered proteins is essential for disorder prediction. One of the first steps to find a factor that distinguishes IDPs from non-IDPs is to specify biases within the amino acid composition. The following hydrophilic, charged amino acids A, R, G, Q, S, P, E and K have been
364:
of the complex is modulated via post-translational modifications or protein interactions. Specificity of DNA binding proteins often depends on the length of fuzzy regions, which is varied by alternative splicing. Some fuzzy complexes may exhibit high binding affinity, although other studies showed
696:
and toxicity as those proteins start binding to each other randomly and can lead to cancer or cardiovascular diseases. Thereby, misfolding can happen spontaneously because millions of copies of proteins are made during the lifetime of an organism. The aggregation of the intrinsically unstructured
173:
in that the amino acid sequence of a protein determines its structure which, in turn, determines its function. In 1950, Karush wrote about 'Configurational
Adaptability' contradicting this assumption. He was convinced that proteins have more than one configuration at the same energy level and can
549:
for visualising molecular interactions and conformational transitions, x-ray crystallography to highlight more mobile regions in otherwise rigid protein crystals, cryo-EM to reveal less fixed parts of proteins, light scattering to monitor size distributions of IDPs or their aggregation kinetics,
533:
have been introduced, which allow to determine the fraction folded/disordered without the need for purification. Even subtle differences in the stability of missense mutations, protein partner binding and (self)polymerisation-induced folding of (e.g.) coiled-coils can be detected using FASTpp as
706:
have large intrinsically unstructured regions, for example p53 and BRCA1. These regions of the proteins are responsible for mediating many of their interactions. Taking the cell's native defense mechanisms as a model drugs can be developed, trying to block the place of noxious substrates and
384:
amino acids and a high proportion of polar and charged amino acids, usually referred to as low hydrophobicity. This property leads to good interactions with water. Furthermore, high net charges promote disorder because of electrostatic repulsion resulting from equally charged residues. Thus
295:
Linear motifs are short disordered segments of proteins that mediate functional interactions with other proteins or other biomolecules (RNA, DNA, sugars etc.). Many roles of linear motifs are associated with cell regulation, for instance in control of cell shape, subcellular localisation of
215:
It is now generally accepted that proteins exist as an ensemble of similar structures with some regions more constrained than others. IDPs occupy the extreme end of this spectrum of flexibility and include proteins of considerable local structure tendency or flexible multidomain assemblies.
183:
from 1973, the fixed 3D structure of these proteins is uniquely encoded in its primary structure (the amino acid sequence), is kinetically accessible and stable under a range of (near) physiological conditions, and can therefore be considered as the native state of such "ordered" proteins.
731:
MD simulations restrained by experimental parameters (restrained-MD) have also been used to characterise disordered proteins. In principle, one can sample the whole conformational space given an MD simulation (with accurate Force-field) is run long enough. Because of very high structural
607:
can predict
Intrinsic Disorder (ID) propensity with high accuracy (approaching around 80%) based on primary sequence composition, similarity to unassigned segments in protein x-ray datasets, flexible regions in NMR studies and physico-chemical properties of amino acids.
1283:
Dunker AK, Lawson JD, Brown CJ, Williams RM, Romero P, Oh JS, Oldfield CJ, Campen AM, Ratliff CM, Hipps KW, Ausio J, Nissen MS, Reeves R, Kang C, Kissinger CR, Bailey RW, Griswold MD, Chiu W, Garner EC, Obradovic Z (2001-01-01). "Intrinsically disordered protein".
385:
disordered sequences cannot sufficiently bury a hydrophobic core to fold into stable globular proteins. In some cases, hydrophobic clusters in disordered sequences provide the clues for identifying the regions that undergo coupled folding and binding (refer to
859:
Dunker AK, Lawson JD, Brown CJ, Williams RM, Romero P, Oh JS, Oldfield CJ, Campen AM, Ratliff CM, Hipps KW, Ausio J, Nissen MS, Reeves R, Kang C, Kissinger CR, Bailey RW, Griswold MD, Chiu W, Garner EC, Obradovic Z (2001). "Intrinsically disordered protein".
534:
recently demonstrated using the tropomyosin-troponin protein interaction. Fully unstructured protein regions can be experimentally validated by their hypersusceptibility to proteolysis using short digestion times and low protease concentrations.
198:
In 2001, Dunker questioned whether the newly found information was ignored for 50 years with more quantitative analyses becoming available in the 2000s. In the 2010s it became clear that IDPs are common among disease-related proteins, such as
305:
primed for target recognition. In several cases it has been demonstrated that these transient structures become full and stable secondary structures, e.g., helices, upon target binding. Hence, PresMos are the putative active sites in IDPs.
568:
for high-resolution insights into the ensembles of IDPs and their oligomers or aggregates, nanopores to reveal global shape distributions of IDPs, magnetic tweezers to study structural transitions for long times at low forces, high-speed
42:). The central part shows relatively ordered structure. Conversely, the N- and C-terminal regions (left and right, respectively) show βintrinsic disorderβ, although a short helical region persists in the N-terminal tail. Ten alternative
397:. While low complexity sequences are a strong indication of disorder, the reverse is not necessarily true, that is, not all disordered proteins have low complexity sequences. Disordered proteins have a low content of predicted
753:
Moreover, various protocols and methods of analyzing IDPs, such as studies based on quantitative analysis of GC content in genes and their respective chromosomal bands, have been used to understand functional IDP segments.
3718:
Iida S, Kawabata T, Kasahara K, Nakamura H, Higo J (April 2019). "Multimodal
Structural Distribution of the p53 C-Terminal Domain upon Binding to S100B via a Generalized Ensemble Method: From Disorder to Extradisorder".
133:. Many IDPs can also adopt a fixed three-dimensional structure after binding to other macromolecules. Overall, IDPs are different from structured proteins in many ways and tend to have distinctive function, structure,
3625:
Zerze GH, Miller CM, Granata D, Mittal J (June 2015). "Free energy surface of an intrinsically disordered protein: comparison between temperature replica exchange molecular dynamics and bias-exchange metadynamics".
408:
has been applied to track the dynamics of disordered protein domains. By employing a topological approach, one can categorize motifs according to their topological buildup and the timescale of their formation.
624:
is a database combining experimentally curated disorder annotations (e.g. from DisProt) with data derived from missing residues in X-ray crystallographic structures and flexible regions in NMR structures.
2867:
Japrung D, Dogan J, Freedman KJ, Nadzeyka A, Bauerdick S, Albrecht T, Kim MJ, Jemth P, Edel JB (February 2013). "Single-molecule studies of intrinsically disordered proteins using solid-state nanopores".
732:
heterogeneity, the time scales that needs to be run for this purpose are very large and are limited by computational power. However, other computational techniques such as accelerated-MD simulations,
235:. Based on DISOPRED2 prediction, long (>30 residue) disordered segments occur in 2.0% of archaean, 4.2% of eubacterial and 33.0% of eukaryotic proteins, including certain disease-related proteins.
417:
IDPs can be validated in several contexts. Most approaches for experimental validation of IDPs are restricted to extracted or purified proteins while some new experimental strategies aim to explore
2960:
Miyagi A, Tsunaka Y, Uchihashi T, Mayanagi K, Hirose S, Morikawa K, Ando T (September 2008). "Visualization of intrinsically disordered regions of proteins by high-speed atomic force microscopy".
356:
Intrinsically disordered proteins can retain their conformational freedom even when they bind specifically to other proteins. The structural disorder in bound state can be static or dynamic. In
723:. The globular thioredoxin fold is depicted in blue, while the disordered N-tail in green. According to the MD results, the disordered tail can be modulating the dynamics of the binding pocket.
4056:
117:
IDPs are a very large and functionally important class of proteins and their discovery has disproved the idea that three-dimensional structures of proteins must be fixed to accomplish their
462:
Intrinsically unfolded proteins, once purified, can be identified by various experimental methods. The primary method to obtain information on disordered regions of a protein is
3257:
Balatti GE, Barletta GP, Parisi G, Tosatto SC, Bellanda M, Fernandez-Alberti S (December 2021). "Intrinsically
Disordered Region Modulates Ligand Binding in Glutaredoxin 1 from
187:
During the subsequent decades, however, many large protein regions could not be assigned in x-ray datasets, indicating that they occupy multiple positions, which average out in
192:
43:
3848:
Garaizar A, Espinosa JR (September 2021). "Salt dependent phase behavior of intrinsically disordered proteins from a coarse-grained model with explicit water and ions".
3572:
Apicella A, Marascio M, Colangelo V, Soncini M, Gautieri A, Plummer CJ (June 2017). "Molecular dynamics simulations of the intrinsically disordered protein amelogenin".
1332:
Ward JJ, Sodhi JS, McGuffin LJ, Buxton BF, Jones DT (March 2004). "Prediction and functional analysis of native disorder in proteins from the three kingdoms of life".
271:
Disordered regions are often found as flexible linkers or loops connecting domains. Linker sequences vary greatly in length but are typically rich in polar uncharged
2241:
Borgia A, Borgia MB, Bugge K, Kissling VM, Heidarsson PO, Fernandes CB, Sottini A, Soranno A, Buholzer KJ, Nettels D, Kragelund BB, Best RB, Schuler B (March 2018).
320:
The ability of disordered proteins to bind, and thus to exert a function, shows that stability is not a required condition. Many short functional sites, for example
2679:
Robaszkiewicz K, Ostrowska Z, Cyranka-Czaja A, Moraczewska J (May 2015). "Impaired tropomyosin-troponin interactions reduce activation of the actin thin filament".
1917:
Lee SH, Kim DH, Han JJ, Cha EJ, Lim JE, Cho YJ, Lee C, Han KH (February 2012). "Understanding pre-structured motifs (PresMos) in intrinsically unfolded proteins".
404:
Due to the disordered nature of these proteins, topological approaches have been developed to search for conformational patterns in their dynamics. For instance,
3762:
Kurcinski M, Kolinski A, Kmiecik S (June 2014). "Mechanism of
Folding and Binding of an Intrinsically Disordered Protein As Revealed by ab Initio Simulations".
3306:"Optimization of the additive CHARMM all-atom protein force field targeting improved sampling of the backbone Ο, Ο and side-chain Ο(1) and Ο(2) dihedral angles"
373:
Intrinsically disordered proteins adapt many different structures in vivo according to the cell's conditions, creating a structural or conformational ensemble.
2431:
Scalvini B. et al., Circuit
Topology Approach for the Comparative Analysis of Intrinsically Disordered Proteins. J. Chem. Inf. Model. 63, 8, 2586β2602 (2023)
1952:
Mohan A, Oldfield CJ, Radivojac P, Vacic V, Cortese MS, Dunker AK, Uversky VN (October 2006). "Analysis of molecular recognition features (MoRFs)".
444:
persistence of intrinsic disorder has been achieved by in-cell NMR upon electroporation of a purified IDP and recovery of cells to an intact state.
2114:
Atkinson SC, Audsley MD, Lieu KG, Marsh GA, Thomas DR, Heaton SM, Paxman JJ, Wagstaff KM, Buckle AM, Moseley GW, Jans DA, Borg NA (January 2018).
1621:
Iakoucheva LM, Brown CJ, Lawson JD, ObradoviΔ Z, Dunker AK (October 2002). "Intrinsic disorder in cell-signaling and cancer-associated proteins".
1571:"Phosphoproteomic analysis of the mouse brain cytosol reveals a predominance of protein phosphorylation in regions of intrinsic sequence disorder"
3044:
Schlessinger A, Schaefer C, Vicedo E, Schmidberger M, Punta M, Rost B (June 2011). "Protein disorder--a breakthrough invention of evolution?".
380:
The existence and kind of protein disorder is encoded in its amino acid sequence. In general, IDPs are characterized by a low content of bulky
2636:
Park C, Marqusee S (March 2005). "Pulse proteolysis: a simple method for quantitative determination of protein stability and ligand binding".
344:. This enables such viruses to overcome their informationally limited genomes by facilitating binding, and manipulation of, a large number of
1987:
Gunasekaran K, Tsai CJ, Kumar S, Zanuy D, Nussinov R (February 2003). "Extended disordered proteins: targeting function with less scaffold".
564:
Single-molecule methods to study IDPs include spFRET to study conformational flexibility of IDPs and the kinetics of structural transitions,
3159:"Structures of the E46K mutant-type Ξ±-synuclein protein and impact of E46K mutation on the structures of the wild-type Ξ±-synuclein protein"
647:
604:
581:
2300:"Binding Affinity and Function of the Extremely Disordered Protein Complex Containing Human Linker Histone H1.0 and Its Chaperone ProTΞ±"
668:
Due to the different approaches of predicting disordered proteins, estimating their relative accuracy is fairly difficult. For example,
490:
530:
390:
170:
1439:
836:
2442:
Theillet FX, Binolfi A, Bekei B, Martorana A, Rose HM, Stuiver M, Verzini S, Lorenz D, van Rossum M, Goldfarb D, Selenko P (2016).
750:
representation with implicit and explicit solvents have been used to sample broader conformational space in smaller time scales.
1038:
Mir M, Stadler MR, Ortiz SA, Hannon CE, Harrison MM, Darzacq X, Eisen MB (December 2018). Singer RH, Struhl K, Crocker J (eds.).
4042:
620:
database contains a collection of manually curated protein segments which have been experimentally determined to be disordered.
677:
595:, human growth hormone bound to receptor). Compilation of screenshots from PDB database and molecule representation via
252:
1382:
Uversky VN, Oldfield CJ, Dunker AK (2008). "Intrinsically disordered proteins in human diseases: introducing the D2 concept".
4098:
486:
421:
conformations and structural variations of IDPs inside intact living cells and systematic comparisons between their dynamics
341:
360:
structural multiplicity is required for function and the manipulation of the bound disordered region changes activity. The
324:
are over-represented in disordered proteins. Disordered proteins and short linear motifs are particularly abundant in many
2716:"Large extent of disorder in Adenomatous Polyposis Coli offers a strategy to guard Wnt signalling against point mutations"
482:
191:
maps. The lack of fixed, unique positions relative to the crystal lattice suggested that these regions were "disordered".
954:
Dunker AK, Silman I, Uversky VN, Sussman JL (December 2008). "Function and structure of inherently disordered proteins".
529:. (Folded proteins typically show dispersions as large as 5 ppm for the amide protons.) Recently, new methods including
813:
676:
experiment that is designed to test methods according accuracy in finding regions with missing 3D structure (marked in
3799:"Modeling of Disordered Protein Structures Using Monte Carlo Simulations and Knowledge-Based Statistical Force Fields"
3114:
Ferron F, Longhi S, Canard B, Karlin D (October 2006). "A practical overview of protein disorder prediction methods".
518:
287:. The flexible linker of FBP25 which connects two domains of FKBP25 is important for the binding of FKBP25 with DNA.
4103:
3353:
Best RB (February 2017). "Computational and theoretical advances in studies of intrinsically disordered proteins".
232:
75:
2905:"Mechanical unzipping and rezipping of a single SNARE complex reveals hysteresis as a force-generating mechanism"
2396:
Oldfield CJ, Dunker AK (2014). "Intrinsically disordered proteins and intrinsically disordered protein regions".
669:
658:
603:
Intrinsic disorder can be either annotated from experimental information or predicted with specialized software.
596:
275:. Flexible linkers allow the connecting domains to freely twist and rotate to recruit their binding partners via
134:
361:
150:
2528:"Biotin proximity tagging favours unfolded proteins and enables the study of intrinsically disordered regions"
1193:"Micelle-induced folding of spinach thylakoid soluble phosphoprotein of 9 kDa and its functional implications"
263:
tend to have higher disorder. In animals, genes with high disorder are lost at higher rates during evolution.
2773:
Brucale M, Schuler B, Samorì B (March 2014). "Single-molecule studies of intrinsically disordered proteins".
153:
of NMR structures of the
Thylakoid soluble phosphoprotein TSP9, which shows a largely flexible protein chain.
747:
743:
570:
162:
1870:"Structural basis of nucleic acid recognition by FK506-binding protein 25 (FKBP25), a nuclear immunophilin"
243:
Highly dynamic disordered regions of proteins have been linked to functionally important phenomena such as
169:
might be generally required to mediate biological functions of proteins. These publications solidified the
3663:"The inverted free energy landscape of an intrinsically disordered peptide by simulations and experiments"
2206:
Fuxreiter M, Simon I, Bondos S (August 2011). "Dynamic protein-DNA recognition: beyond what can be seen".
1630:
1341:
1293:
869:
313:
Many unstructured proteins undergo transitions to more ordered states upon binding to their targets (e.g.
219:
Intrinsic disorder is particularly elevated among proteins that regulate chromatin and transcription, and
195:
also demonstrated the presence of large flexible linkers and termini in many solved structural ensembles.
175:
473:
Folded proteins have a high density (partial specific volume of 0.72-0.74 mL/g) and commensurately small
1666:
Sandhu KS (2009). "Intrinsic disorder explains diverse nuclear roles of chromatin remodeling proteins".
1422:
Bu Z, Callaway DJ (2011). "Proteins MOVE! Protein dynamics and long-range allostery in cell signaling".
467:
280:
244:
3661:
Granata D, Baftizadeh F, Habchi J, Galvagnion C, De Simone A, Camilloni C, et al. (October 2015).
3388:
Chong SH, Chatterjee P, Ham S (May 2017). "Computer
Simulations of Intrinsically Disordered Proteins".
616:
Databases have been established to annotate protein sequences with intrinsic disorder information. The
477:. Hence, unfolded proteins can be detected by methods that are sensitive to molecular size, density or
2116:"Recognition by host nuclear transport proteins drives disorder-to-order transition in Hendra virus V"
3961:
3857:
3674:
3479:
3397:
3215:
2916:
2821:
2810:"Diverse metastable structures formed by small oligomers of Ξ±-synuclein probed by force spectroscopy"
2727:
2590:
2455:
2254:
2127:
1726:
1249:
4009:
1346:
1635:
1468:"At the dawn of the 21st century: Is dynamics the missing link for understanding enzyme catalysis?"
1298:
1142:
van der Lee R, Buljan M, Lang B, Weatheritt RJ, Daughdrill GW, Dunker AK, et al. (July 2014).
874:
498:
398:
394:
180:
118:
95:
4079:
3881:
3744:
3607:
3286:
3239:
3139:
2661:
2479:
2047:
1691:
1603:
933:
688:
Intrinsically unstructured proteins have been implicated in a number of diseases. Aggregation of
558:
502:
494:
474:
321:
260:
166:
672:
are often trained on different datasets. The disorder prediction category is a part of biannual
17:
3989:
3930:
3873:
3830:
3779:
3736:
3700:
3643:
3599:
3554:
3505:
3448:
3413:
3370:
3335:
3278:
3231:
3188:
3131:
3096:
3061:
3026:
2977:
2942:
2885:
2849:
2790:
2755:
2696:
2653:
2618:
2559:
2471:
2413:
2371:
2329:
2280:
2223:
2188:
2153:
2096:
2039:
2004:
1969:
1934:
1899:
1850:
1801:
1752:
1683:
1648:
1595:
1551:
1497:
1445:
1435:
1399:
1359:
1311:
1265:
1222:
1173:
1124:
1075:
1020:
971:
925:
887:
832:
703:
587:
478:
333:
158:
59:
39:
1395:
599:. Blue and red arrows point to missing residues on receptor and growth hormone, respectively.
3979:
3969:
3920:
3912:
3865:
3820:
3810:
3771:
3728:
3690:
3682:
3635:
3589:
3581:
3544:
3536:
3495:
3487:
3440:
3405:
3362:
3325:
3317:
3270:
3223:
3178:
3170:
3123:
3088:
3053:
3016:
3008:
2969:
2932:
2924:
2877:
2839:
2829:
2782:
2745:
2735:
2688:
2645:
2608:
2598:
2549:
2539:
2506:
2463:
2405:
2363:
2319:
2311:
2270:
2262:
2215:
2180:
2143:
2135:
2086:
2078:
2031:
1996:
1961:
1926:
1889:
1881:
1840:
1832:
1791:
1783:
1742:
1734:
1675:
1640:
1585:
1541:
1533:
1487:
1479:
1427:
1391:
1351:
1303:
1257:
1212:
1204:
1163:
1155:
1114:
1106:
1065:
1055:
1010:
1002:
963:
917:
879:
824:
733:
565:
405:
276:
248:
188:
111:
103:
3409:
2022:
Sandhu KS, Dash D (July 2007). "Dynamic alpha-helices: conformations that do not conform".
4083:
4046:
3468:"Multiscale ensemble modeling of intrinsically disordered proteins: p53 N-terminal domain"
2579:"Determining biophysical protein stability in lysates by a fast proteolysis assay, FASTpp"
2409:
698:
337:
200:
126:
107:
585:
REMARK465 - missing electron densities in X-ray structure representing protein disorder (
3965:
3861:
3678:
3483:
3401:
3219:
2920:
2825:
2731:
2594:
2459:
2258:
2131:
1845:
1820:
1730:
1546:
1521:
1426:. Advances in Protein Chemistry and Structural Biology. Vol. 83. pp. 163β221.
1253:
3984:
3949:
3925:
3901:"Digested disorder: Quarterly intrinsic disorder digest (January/February/March, 2013)"
3900:
3825:
3798:
3695:
3662:
3549:
3524:
3500:
3467:
3330:
3305:
3183:
3158:
3021:
2996:
2937:
2904:
2844:
2809:
2750:
2715:
2613:
2578:
2554:
2527:
2324:
2299:
2275:
2242:
2148:
2115:
2091:
2066:
1894:
1869:
1796:
1771:
1747:
1710:
1492:
1467:
1431:
1217:
1192:
1168:
1143:
1119:
1094:
1070:
1039:
1015:
990:
778:
554:
522:
345:
251:. Many disordered proteins have the binding affinity with their receptors regulated by
130:
99:
91:
79:
3950:"Genealogy of an ancient protein family: the Sirtuins, a family of disordered members"
2443:
2000:
1644:
1307:
883:
4092:
4019:
3885:
3797:
Ciemny MP, Badaczewska-Dawid AE, Pikuzinska M, Kolinski A, Kmiecik S (January 2019).
3611:
3444:
3290:
1821:"Differential Retention of Pfam Domains Contributes to Long-term Evolutionary Trends"
1570:
1040:"Dynamic multifactor hubs interact transiently with sites of active transcription in
908:, Wright PE (March 2005). "Intrinsically unstructured proteins and their functions".
793:
689:
661:
or matrix calculations, based on different structural and/or biophysical properties.
357:
220:
3748:
3143:
2665:
2430:
2051:
1695:
1607:
937:
3948:
Costantini S, Sharma A, Raucci R, Costantini M, Autiero I, Colonna G (March 2013).
3304:
Best RB, Zhu X, Shim J, Lopes PE, Mittal J, Feig M, Mackerell AD (September 2012).
3243:
2997:"TOP-IDP-scale: a new amino acid scale measuring propensity for intrinsic disorder"
2483:
1711:"Young Genes are Highly Disordered as Predicted by the Preadaptation Hypothesis of
739:
546:
365:
different affinity values for the same system in a different concentration regime.
102:
proteins. They are sometimes considered as a separate class of proteins along with
35:
30:
3585:
2834:
2740:
2692:
2603:
2367:
2171:
Fuxreiter M (January 2012). "Fuzziness: linking regulation to protein dynamics".
1261:
1240:
Anfinsen CB (July 1973). "Principles that govern the folding of protein chains".
125:
interactions that are highly cooperative and dynamic, lending them importance in
4061:
2315:
1787:
788:
526:
463:
381:
329:
272:
204:
122:
87:
47:
4066:
3012:
2714:
Minde DP, Radli M, Forneris F, Maurice MM, RΓΌdiger SG (2013). Buckle AM (ed.).
2219:
2139:
1930:
1590:
1537:
3540:
3491:
3366:
3092:
3057:
2544:
1965:
1355:
967:
905:
828:
51:
3732:
3639:
3274:
1836:
3974:
1772:"Gene Birth Contributes to Structural Disorder Encoded by Overlapping Genes"
1738:
693:
657:
sites. There are different approaches for predicting IDP structure, such as
325:
284:
256:
3993:
3934:
3877:
3834:
3783:
3740:
3704:
3647:
3603:
3558:
3509:
3452:
3417:
3374:
3339:
3282:
3235:
3192:
3135:
3100:
3065:
3030:
2981:
2973:
2946:
2889:
2853:
2794:
2759:
2700:
2657:
2622:
2563:
2475:
2417:
2375:
2333:
2284:
2227:
2192:
2157:
2100:
2043:
2008:
1973:
1938:
1903:
1854:
1805:
1756:
1687:
1652:
1599:
1555:
1501:
1449:
1403:
1363:
1315:
1226:
1177:
1128:
1079:
1024:
975:
929:
891:
4015:
MobiDB: a comprehensive database of intrinsic protein disorder annotations
3157:
Wise-Scira O, Dunn A, Aloglu AK, Sakallioglu IT, Coskuner O (March 2013).
2444:"Structural disorder of monomeric Ξ±-synuclein persists in mammalian cells"
1269:
1006:
377:
includes proteins that contain IDRs as well as fully disordered proteins.
145:
3815:
3594:
2082:
2067:"Drawing on disorder: How viruses use histone mimicry to their advantage"
1885:
1095:"Intrinsically disordered proteins in cellular signalling and regulation"
763:
514:
506:
228:
86:. IDPs range from fully unstructured to partially structured and include
3227:
2467:
2266:
1060:
3431:
Fox SJ, Kannan S (September 2017). "Probing the dynamics of disorder".
3127:
2995:
Campen A, Williams RM, Brown CJ, Meng J, Uversky VN, Dunker AK (2008).
2928:
2184:
2035:
1483:
989:
Andreeva A, Howorth D, Chothia C, Kulesha E, Murzin AG (January 2014).
768:
617:
510:
451:
validation of IDR predictions is now possible using biotin 'painting'.
71:
3916:
3869:
3775:
3686:
3321:
3174:
2881:
2786:
1208:
1159:
591:
2649:
812:
Majorek K, Kozlowski L, Jakalski M, Bujnicki JM (December 18, 2008).
773:
621:
224:
1679:
1110:
921:
2511:
2498:
2351:
1569:
Collins MO, Yu L, Campuzano I, Grant SG, Choudhary JS (July 2008).
1522:"Interaction modules that impart specificity to disordered protein"
1191:
Song J, Lee MS, Carlberg I, Vener AV, Markley JL (December 2006).
783:
715:
714:
314:
1819:
James, Jennifer E; Nelson, Paul G; Masel, Joanna (4 April 2023).
1144:"Classification of intrinsically disordered regions and proteins"
2499:"Biotinylation by proximity labelling favours unfolded proteins"
702:Ξ±-synuclein protein and associated disease mechanisms. Many key
673:
538:
279:. They also allow their binding partners to induce larger scale
121:. For example, IDPs have been identified to participate in weak
680:
as REMARK465, missing electron densities in X-ray structures).
573:
to visualise the spatio-temporal flexibility of IDPs directly.
513:
groups exposed to solvent, so that they are readily cleaved by
3525:"Constructing ensembles for intrinsically disordered proteins"
551:
542:
83:
4014:
3206:
Dobson CM (December 2003). "Protein folding and misfolding".
2808:
Neupane K, Solanki A, Sosova I, Belov M, Woodside MT (2014).
2681:
Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics
991:"SCOP2 prototype: a new approach to protein structure mining"
821:
Prediction of Protein Structures, Functions, and Interactions
521:
and exhibit a small dispersion (<1 ppm) in their 1H amide
2356:
The International Journal of Biochemistry & Cell Biology
497:. Unfolded proteins are also characterized by their lack of
3079:
Tompa P (June 2011). "Unstructural biology coming of age".
2577:
Minde DP, Maurice MM, RΓΌdiger SG (2012). Uversky VN (ed.).
2243:"Extreme disorder in an ultrahigh-affinity protein complex"
509:
spectroscopy. Unfolded proteins also have exposed backbone
174:
choose one when binding to other substrates. In the 1960s,
4071:
537:
Bulk methods to study IDP structure and dynamics include
259:
remodeling functions. Genes that have recently been born
2903:
Min D, Kim K, Hyeon C, Cho YH, Shin YK, Yoon TY (2013).
4076:
4057:
Gallery of images of intrinsically disordered proteins
4062:
First IDP journal covering all topics of IDP research
707:
inhibiting them, and thus counteracting the disease.
4051:
393:, i.e. sequences with over-representation of a few
193:
Nuclear magnetic resonance spectroscopy of proteins
1868:Prakash A, Shin J, Rajan S, Yoon HS (April 2016).
1515:
1513:
1511:
3574:Journal of Biomolecular Structure & Dynamics
1709:Wilson BA, Foy SG, Neme R, Masel J (June 2017).
165:. These early structures suggested that a fixed
82:interaction partners, such as other proteins or
4010:Intrinsically disordered protein at Proteopedia
2352:"Intrinsically disordered proteins from A to Z"
1461:
1459:
1417:
1415:
1413:
1377:
1375:
1373:
505:(esp. a pronounced minimum at ~200 nm) or
854:
852:
850:
848:
823:. John Wiley & Sons, Ltd. pp. 39β62.
4052:DP Database of Disordered Protein Predictions
2391:
2389:
2387:
2385:
1286:Journal of Molecular Graphics & Modelling
862:Journal of Molecular Graphics & Modelling
814:"First Steps of Protein Structure Prediction"
665:create a more competent and exact predictor.
352:Disorder in the bound state (fuzzy complexes)
8:
3433:Progress in Biophysics and Molecular Biology
2345:
2343:
1327:
1325:
223:predictions indicate that is more common in
46:were morphed. Secondary structure elements:
3803:International Journal of Molecular Sciences
2526:Minde DP, Ramakrishna M, Lilley KS (2020).
2497:Minde DP, Ramakrishna M, Lilley KS (2018).
3764:Journal of Chemical Theory and Computation
3721:Journal of Chemical Theory and Computation
3628:Journal of Chemical Theory and Computation
3310:Journal of Chemical Theory and Computation
949:
947:
501:, as assessed by far-UV (170-250 nm)
137:, interactions, evolution and regulation.
4072:Database of experimentally validated IDPs
3983:
3973:
3924:
3824:
3814:
3694:
3593:
3548:
3499:
3329:
3182:
3020:
2936:
2843:
2833:
2749:
2739:
2612:
2602:
2553:
2543:
2510:
2323:
2274:
2147:
2090:
1893:
1844:
1795:
1746:
1634:
1589:
1545:
1491:
1345:
1297:
1216:
1167:
1118:
1069:
1059:
1014:
873:
719:MD simulation of the Glutaredoxin 1 from
2298:Feng H, Zhou BR, Bai Y (November 2018).
1396:10.1146/annurev.biophys.37.032807.125924
580:
561:to monitor secondary structure of IDPs.
470:studies may also be a sign of disorder.
144:
29:
3466:Terakawa T, Takada S (September 2011).
2065:Tarakhovsky A, Prinjha RK (July 2018).
804:
3410:10.1146/annurev-physchem-052516-050843
1099:Nature Reviews. Molecular Cell Biology
315:Molecular Recognition Features (MoRFs)
3529:Current Opinion in Structural Biology
3355:Current Opinion in Structural Biology
3081:Current Opinion in Structural Biology
3046:Current Opinion in Structural Biology
2410:10.1146/annurev-biochem-072711-164947
1919:Current Protein & Peptide Science
956:Current Opinion in Structural Biology
910:Nature Reviews Molecular Cell Biology
386:
98:, or flexible linkers in large multi-
7:
2071:The Journal of Experimental Medicine
1770:Willis S, Masel J (September 2018).
1093:Wright PE, Dyson HJ (January 2015).
648:List of disorder prediction software
27:Protein without a fixed 3D structure
3390:Annual Review of Physical Chemistry
3263:The Journal of Physical Chemistry B
1578:Molecular & Cellular Proteomics
1520:Cermakova K, Hodges HC (May 2023).
1466:Kamerlin SC, Warshel A (May 2010).
545:for atomistic ensemble refinement,
491:small angle X-ray scattering (SAXS)
3523:Fisher CK, Stultz CM (June 2011).
1432:10.1016/B978-0-12-381262-9.00005-7
654:
531:Fast parallel proteolysis (FASTpp)
466:. The lack of electron density in
171:central dogma of molecular biology
78:, typically in the absence of its
25:
3905:Intrinsically Disordered Proteins
746:MD simulations, or methods using
3445:10.1016/j.pbiomolbio.2017.05.008
1668:Journal of Molecular Recognition
541:for ensemble shape information,
231:than in known structures in the
179:observed in vitro. As stated in
64:intrinsically disordered protein
18:Intrinsically disordered protein
3850:The Journal of Chemical Physics
1825:Molecular Biology and Evolution
253:post-translational modification
2208:Trends in Biochemical Sciences
1989:Trends in Biochemical Sciences
1719:Nature Ecology & Evolution
1526:Trends in Biochemical Sciences
1424:Protein Structure and Diseases
605:Disorder prediction algorithms
487:analytical ultracentrifugation
440:The first direct evidence for
157:In the 1930s-1950s, the first
74:that lacks a fixed or ordered
34:Conformational flexibility in
1:
3586:10.1080/07391102.2016.1196151
2398:Annual Review of Biochemistry
2001:10.1016/S0968-0004(03)00003-3
1645:10.1016/S0022-2836(02)00969-5
1308:10.1016/s1093-3263(00)00138-8
884:10.1016/s1093-3263(00)00138-8
483:size exclusion chromatography
2835:10.1371/journal.pone.0086495
2741:10.1371/journal.pone.0077257
2693:10.1016/j.bbapap.2015.01.004
2604:10.1371/journal.pone.0046147
2368:10.1016/j.biocel.2011.04.001
1954:Journal of Molecular Biology
1623:Journal of Molecular Biology
1334:Journal of Molecular Biology
1262:10.1126/science.181.4096.223
3001:Protein and Peptide Letters
2316:10.1021/acs.biochem.8b01075
1788:10.1534/genetics.118.301249
1384:Annual Review of Biophysics
629:Predicting IDPs by sequence
519:hydrogen-deuterium exchange
309:Coupled folding and binding
167:three-dimensional structure
76:three-dimensional structure
4120:
3013:10.2174/092986608785849164
2350:Uversky VN (August 2011).
2220:10.1016/j.tibs.2011.04.006
2140:10.1038/s41598-017-18742-8
1931:10.2174/138920312799277974
1591:10.1074/mcp.M700564-MCP200
1538:10.1016/j.tibs.2023.01.004
1001:(Database issue): D310β4.
645:
493:, and measurements of the
3541:10.1016/j.sbi.2011.04.001
3492:10.1016/j.bpj.2011.08.003
3367:10.1016/j.sbi.2017.01.006
3163:ACS Chemical Neuroscience
3093:10.1016/j.sbi.2011.03.012
3058:10.1016/j.sbi.2011.03.014
2545:10.1038/s42003-020-0758-y
1966:10.1016/j.jmb.2006.07.087
1356:10.1016/j.jmb.2004.02.002
968:10.1016/j.sbi.2008.10.002
829:10.1002/9780470741894.ch2
4028:isordered proteins with
3954:BMC Evolutionary Biology
3733:10.1021/acs.jctc.8b01042
3640:10.1021/acs.jctc.5b00047
3275:10.1021/acs.jpcb.1c07035
391:low complexity sequences
3975:10.1186/1471-2148-13-60
1739:10.1038/s41559-017-0146
819:. In Bujnicki J (ed.).
413:Experimental validation
362:conformational ensemble
277:protein domain dynamics
163:protein crystallography
2974:10.1002/cphc.200800210
2532:Communications Biology
1874:Nucleic Acids Research
1837:10.1093/molbev/msad073
995:Nucleic Acids Research
724:
600:
468:X-ray crystallographic
342:human papillomaviruses
281:conformational changes
154:
55:
4099:Proteins by structure
4077:IDP ensemble database
2909:Nature Communications
718:
692:is the cause of many
584:
300:Pre-structured motifs
245:allosteric regulation
148:
33:
3816:10.3390/ijms20030606
2870:Analytical Chemistry
2173:Molecular BioSystems
2083:10.1084/jem.20180099
711:Computer simulations
684:Disorder and disease
119:biological functions
3966:2013BMCEE..13...60C
3899:Uversky VN (2013).
3862:2021JChPh.155l5103G
3679:2015NatSR...515449G
3484:2011BpJ...101.1450T
3472:Biophysical Journal
3402:2017ARPC...68..117C
3269:(49): 13366β13375.
3228:10.1038/nature02261
3220:2003Natur.426..884D
2921:2013NatCo...4.1705M
2826:2014PLoSO...986495N
2732:2013PLoSO...877257M
2595:2012PLoSO...746147M
2468:10.1038/nature16531
2460:2016Natur.530...45T
2267:10.1038/nature25762
2259:2018Natur.555...61B
2132:2018NatSR...8..358A
1731:2017NatEE...1..146W
1254:1973Sci...181..223A
1061:10.7554/eLife.40497
1007:10.1093/nar/gkt1242
577:Disorder annotation
499:secondary structure
399:secondary structure
322:Short Linear Motifs
176:Levinthal's paradox
4082:2018-03-10 at the
4045:2020-05-02 at the
3667:Scientific Reports
3259:Trypanosoma Brucei
3128:10.1002/prot.21075
2929:10.1038/ncomms2692
2185:10.1039/c1mb05234a
2120:Scientific Reports
2036:10.1002/prot.21328
1886:10.1093/nar/gkw001
1484:10.1002/prot.22654
725:
721:Trypanosoma brucei
704:tumour suppressors
690:misfolded proteins
642:Prediction methods
612:Disorder databases
601:
559:Circular Dichroism
503:circular dichroism
495:diffusion constant
475:radius of gyration
369:Structural aspects
159:protein structures
155:
56:
4104:Protein structure
3917:10.4161/idp.25496
3870:10.1063/5.0062687
3776:10.1021/ct500287c
3687:10.1038/srep15449
3322:10.1021/ct300400x
3175:10.1021/cn3002027
2882:10.1021/ac3035025
2787:10.1021/cr400297g
2310:(48): 6645β6648.
1248:(4096): 223β230.
1209:10.1021/bi062148m
1160:10.1021/cr400525m
1154:(13): 6589β6631.
694:synucleinopathies
479:hydrodynamic drag
112:membrane proteins
60:molecular biology
16:(Redirected from
4111:
3998:
3997:
3987:
3977:
3945:
3939:
3938:
3928:
3896:
3890:
3889:
3845:
3839:
3838:
3828:
3818:
3794:
3788:
3787:
3770:(6): 2224β2231.
3759:
3753:
3752:
3727:(4): 2597β2607.
3715:
3709:
3708:
3698:
3658:
3652:
3651:
3634:(6): 2776β2782.
3622:
3616:
3615:
3597:
3580:(8): 1813β1823.
3569:
3563:
3562:
3552:
3520:
3514:
3513:
3503:
3478:(6): 1450β1458.
3463:
3457:
3456:
3428:
3422:
3421:
3385:
3379:
3378:
3350:
3344:
3343:
3333:
3316:(9): 3257β3273.
3301:
3295:
3294:
3254:
3248:
3247:
3214:(6968): 884β90.
3203:
3197:
3196:
3186:
3154:
3148:
3147:
3111:
3105:
3104:
3076:
3070:
3069:
3041:
3035:
3034:
3024:
2992:
2986:
2985:
2957:
2951:
2950:
2940:
2900:
2894:
2893:
2864:
2858:
2857:
2847:
2837:
2805:
2799:
2798:
2775:Chemical Reviews
2770:
2764:
2763:
2753:
2743:
2711:
2705:
2704:
2676:
2670:
2669:
2650:10.1038/nmeth740
2633:
2627:
2626:
2616:
2606:
2574:
2568:
2567:
2557:
2547:
2523:
2517:
2516:
2514:
2494:
2488:
2487:
2439:
2433:
2428:
2422:
2421:
2393:
2380:
2379:
2362:(8): 1090β1103.
2347:
2338:
2337:
2327:
2295:
2289:
2288:
2278:
2238:
2232:
2231:
2203:
2197:
2196:
2168:
2162:
2161:
2151:
2111:
2105:
2104:
2094:
2077:(7): 1777β1787.
2062:
2056:
2055:
2019:
2013:
2012:
1984:
1978:
1977:
1949:
1943:
1942:
1914:
1908:
1907:
1897:
1880:(6): 2909β2925.
1865:
1859:
1858:
1848:
1816:
1810:
1809:
1799:
1767:
1761:
1760:
1750:
1706:
1700:
1699:
1663:
1657:
1656:
1638:
1618:
1612:
1611:
1593:
1575:
1566:
1560:
1559:
1549:
1517:
1506:
1505:
1495:
1463:
1454:
1453:
1419:
1408:
1407:
1379:
1368:
1367:
1349:
1329:
1320:
1319:
1301:
1280:
1274:
1273:
1237:
1231:
1230:
1220:
1203:(51): 15633β43.
1188:
1182:
1181:
1171:
1148:Chemical Reviews
1139:
1133:
1132:
1122:
1090:
1084:
1083:
1073:
1063:
1035:
1029:
1028:
1018:
986:
980:
979:
951:
942:
941:
902:
896:
895:
877:
856:
843:
842:
818:
809:
769:DisProt database
734:replica exchange
594:
566:optical tweezers
517:, undergo rapid
464:NMR spectroscopy
406:circuit topology
387:biological roles
267:Flexible linkers
249:enzyme catalysis
239:Biological roles
233:protein database
189:electron density
181:Anfinsen's Dogma
21:
4119:
4118:
4114:
4113:
4112:
4110:
4109:
4108:
4089:
4088:
4084:Wayback Machine
4047:Wayback Machine
4036:nnotations and
4006:
4001:
3947:
3946:
3942:
3898:
3897:
3893:
3847:
3846:
3842:
3796:
3795:
3791:
3761:
3760:
3756:
3717:
3716:
3712:
3660:
3659:
3655:
3624:
3623:
3619:
3571:
3570:
3566:
3522:
3521:
3517:
3465:
3464:
3460:
3430:
3429:
3425:
3387:
3386:
3382:
3352:
3351:
3347:
3303:
3302:
3298:
3256:
3255:
3251:
3205:
3204:
3200:
3156:
3155:
3151:
3113:
3112:
3108:
3078:
3077:
3073:
3043:
3042:
3038:
2994:
2993:
2989:
2968:(13): 1859β66.
2959:
2958:
2954:
2902:
2901:
2897:
2866:
2865:
2861:
2807:
2806:
2802:
2781:(6): 3281β317.
2772:
2771:
2767:
2713:
2712:
2708:
2678:
2677:
2673:
2635:
2634:
2630:
2576:
2575:
2571:
2525:
2524:
2520:
2496:
2495:
2491:
2454:(7588): 45β50.
2441:
2440:
2436:
2429:
2425:
2395:
2394:
2383:
2349:
2348:
2341:
2297:
2296:
2292:
2253:(7694): 61β66.
2240:
2239:
2235:
2205:
2204:
2200:
2170:
2169:
2165:
2113:
2112:
2108:
2064:
2063:
2059:
2021:
2020:
2016:
1986:
1985:
1981:
1951:
1950:
1946:
1916:
1915:
1911:
1867:
1866:
1862:
1818:
1817:
1813:
1769:
1768:
1764:
1725:(6): 0146β146.
1708:
1707:
1703:
1680:10.1002/jmr.915
1665:
1664:
1660:
1620:
1619:
1615:
1573:
1568:
1567:
1563:
1519:
1518:
1509:
1465:
1464:
1457:
1442:
1421:
1420:
1411:
1381:
1380:
1371:
1347:10.1.1.120.5605
1331:
1330:
1323:
1282:
1281:
1277:
1239:
1238:
1234:
1190:
1189:
1185:
1141:
1140:
1136:
1111:10.1038/nrm3920
1092:
1091:
1087:
1037:
1036:
1032:
988:
987:
983:
953:
952:
945:
922:10.1038/nrm1589
904:
903:
899:
858:
857:
846:
839:
816:
811:
810:
806:
802:
774:MobiDB database
760:
713:
686:
670:neural networks
659:neural networks
650:
644:
631:
614:
586:
579:
525:as measured by
523:chemical shifts
460:
438:
415:
371:
358:fuzzy complexes
354:
311:
302:
293:
269:
241:
213:
201:alpha-synuclein
161:were solved by
143:
54:(blue arrows).
28:
23:
22:
15:
12:
11:
5:
4117:
4115:
4107:
4106:
4101:
4091:
4090:
4087:
4086:
4074:
4069:
4064:
4059:
4054:
4049:
4017:
4012:
4005:
4004:External links
4002:
4000:
3999:
3940:
3891:
3856:(12): 125103.
3840:
3789:
3754:
3710:
3653:
3617:
3564:
3535:(3): 426β431.
3515:
3458:
3423:
3380:
3345:
3296:
3249:
3198:
3169:(3): 498β508.
3149:
3106:
3087:(3): 419β425.
3071:
3036:
3007:(9): 956β963.
2987:
2952:
2895:
2876:(4): 2449β56.
2859:
2800:
2765:
2726:(10): e77257.
2706:
2671:
2638:Nature Methods
2628:
2589:(10): e46147.
2569:
2518:
2512:10.1101/274761
2489:
2434:
2423:
2381:
2339:
2290:
2233:
2198:
2163:
2106:
2057:
2014:
1979:
1960:(5): 1043β59.
1944:
1909:
1860:
1811:
1782:(1): 303β313.
1762:
1701:
1658:
1636:10.1.1.132.682
1613:
1584:(7): 1331β48.
1561:
1532:(5): 477β490.
1507:
1478:(6): 1339β75.
1455:
1440:
1409:
1369:
1321:
1299:10.1.1.113.556
1275:
1232:
1183:
1134:
1085:
1030:
981:
943:
916:(3): 197β208.
897:
875:10.1.1.113.556
844:
837:
803:
801:
798:
797:
796:
791:
786:
781:
779:Molten globule
776:
771:
766:
759:
756:
748:coarse-grained
744:multicanonical
712:
709:
685:
682:
646:Main article:
643:
640:
630:
627:
613:
610:
578:
575:
555:chemical shift
459:
453:
437:
431:
414:
411:
370:
367:
353:
350:
310:
307:
301:
298:
292:
289:
283:by long-range
268:
265:
240:
237:
212:
209:
142:
139:
131:cell signaling
127:DNA regulation
92:molten globule
80:macromolecular
26:
24:
14:
13:
10:
9:
6:
4:
3:
2:
4116:
4105:
4102:
4100:
4097:
4096:
4094:
4085:
4081:
4078:
4075:
4073:
4070:
4068:
4065:
4063:
4060:
4058:
4055:
4053:
4050:
4048:
4044:
4041:
4039:
4035:
4031:
4027:
4024:ntrinsically
4023:
4018:
4016:
4013:
4011:
4008:
4007:
4003:
3995:
3991:
3986:
3981:
3976:
3971:
3967:
3963:
3959:
3955:
3951:
3944:
3941:
3936:
3932:
3927:
3922:
3918:
3914:
3911:(1): e25496.
3910:
3906:
3902:
3895:
3892:
3887:
3883:
3879:
3875:
3871:
3867:
3863:
3859:
3855:
3851:
3844:
3841:
3836:
3832:
3827:
3822:
3817:
3812:
3808:
3804:
3800:
3793:
3790:
3785:
3781:
3777:
3773:
3769:
3765:
3758:
3755:
3750:
3746:
3742:
3738:
3734:
3730:
3726:
3722:
3714:
3711:
3706:
3702:
3697:
3692:
3688:
3684:
3680:
3676:
3672:
3668:
3664:
3657:
3654:
3649:
3645:
3641:
3637:
3633:
3629:
3621:
3618:
3613:
3609:
3605:
3601:
3596:
3595:11311/1004711
3591:
3587:
3583:
3579:
3575:
3568:
3565:
3560:
3556:
3551:
3546:
3542:
3538:
3534:
3530:
3526:
3519:
3516:
3511:
3507:
3502:
3497:
3493:
3489:
3485:
3481:
3477:
3473:
3469:
3462:
3459:
3454:
3450:
3446:
3442:
3438:
3434:
3427:
3424:
3419:
3415:
3411:
3407:
3403:
3399:
3395:
3391:
3384:
3381:
3376:
3372:
3368:
3364:
3360:
3356:
3349:
3346:
3341:
3337:
3332:
3327:
3323:
3319:
3315:
3311:
3307:
3300:
3297:
3292:
3288:
3284:
3280:
3276:
3272:
3268:
3264:
3260:
3253:
3250:
3245:
3241:
3237:
3233:
3229:
3225:
3221:
3217:
3213:
3209:
3202:
3199:
3194:
3190:
3185:
3180:
3176:
3172:
3168:
3164:
3160:
3153:
3150:
3145:
3141:
3137:
3133:
3129:
3125:
3121:
3117:
3110:
3107:
3102:
3098:
3094:
3090:
3086:
3082:
3075:
3072:
3067:
3063:
3059:
3055:
3051:
3047:
3040:
3037:
3032:
3028:
3023:
3018:
3014:
3010:
3006:
3002:
2998:
2991:
2988:
2983:
2979:
2975:
2971:
2967:
2963:
2956:
2953:
2948:
2944:
2939:
2934:
2930:
2926:
2922:
2918:
2914:
2910:
2906:
2899:
2896:
2891:
2887:
2883:
2879:
2875:
2871:
2863:
2860:
2855:
2851:
2846:
2841:
2836:
2831:
2827:
2823:
2820:(1): e86495.
2819:
2815:
2811:
2804:
2801:
2796:
2792:
2788:
2784:
2780:
2776:
2769:
2766:
2761:
2757:
2752:
2747:
2742:
2737:
2733:
2729:
2725:
2721:
2717:
2710:
2707:
2702:
2698:
2694:
2690:
2687:(5): 381β90.
2686:
2682:
2675:
2672:
2667:
2663:
2659:
2655:
2651:
2647:
2644:(3): 207β12.
2643:
2639:
2632:
2629:
2624:
2620:
2615:
2610:
2605:
2600:
2596:
2592:
2588:
2584:
2580:
2573:
2570:
2565:
2561:
2556:
2551:
2546:
2541:
2537:
2533:
2529:
2522:
2519:
2513:
2508:
2504:
2500:
2493:
2490:
2485:
2481:
2477:
2473:
2469:
2465:
2461:
2457:
2453:
2449:
2445:
2438:
2435:
2432:
2427:
2424:
2419:
2415:
2411:
2407:
2403:
2399:
2392:
2390:
2388:
2386:
2382:
2377:
2373:
2369:
2365:
2361:
2357:
2353:
2346:
2344:
2340:
2335:
2331:
2326:
2321:
2317:
2313:
2309:
2305:
2301:
2294:
2291:
2286:
2282:
2277:
2272:
2268:
2264:
2260:
2256:
2252:
2248:
2244:
2237:
2234:
2229:
2225:
2221:
2217:
2214:(8): 415β23.
2213:
2209:
2202:
2199:
2194:
2190:
2186:
2182:
2179:(1): 168β77.
2178:
2174:
2167:
2164:
2159:
2155:
2150:
2145:
2141:
2137:
2133:
2129:
2125:
2121:
2117:
2110:
2107:
2102:
2098:
2093:
2088:
2084:
2080:
2076:
2072:
2068:
2061:
2058:
2053:
2049:
2045:
2041:
2037:
2033:
2030:(1): 109β22.
2029:
2025:
2018:
2015:
2010:
2006:
2002:
1998:
1994:
1990:
1983:
1980:
1975:
1971:
1967:
1963:
1959:
1955:
1948:
1945:
1940:
1936:
1932:
1928:
1924:
1920:
1913:
1910:
1905:
1901:
1896:
1891:
1887:
1883:
1879:
1875:
1871:
1864:
1861:
1856:
1852:
1847:
1842:
1838:
1834:
1830:
1826:
1822:
1815:
1812:
1807:
1803:
1798:
1793:
1789:
1785:
1781:
1777:
1773:
1766:
1763:
1758:
1754:
1749:
1744:
1740:
1736:
1732:
1728:
1724:
1720:
1716:
1714:
1705:
1702:
1697:
1693:
1689:
1685:
1681:
1677:
1673:
1669:
1662:
1659:
1654:
1650:
1646:
1642:
1637:
1632:
1629:(3): 573β84.
1628:
1624:
1617:
1614:
1609:
1605:
1601:
1597:
1592:
1587:
1583:
1579:
1572:
1565:
1562:
1557:
1553:
1548:
1543:
1539:
1535:
1531:
1527:
1523:
1516:
1514:
1512:
1508:
1503:
1499:
1494:
1489:
1485:
1481:
1477:
1473:
1469:
1462:
1460:
1456:
1451:
1447:
1443:
1441:9780123812629
1437:
1433:
1429:
1425:
1418:
1416:
1414:
1410:
1405:
1401:
1397:
1393:
1389:
1385:
1378:
1376:
1374:
1370:
1365:
1361:
1357:
1353:
1348:
1343:
1340:(3): 635β45.
1339:
1335:
1328:
1326:
1322:
1317:
1313:
1309:
1305:
1300:
1295:
1291:
1287:
1279:
1276:
1271:
1267:
1263:
1259:
1255:
1251:
1247:
1243:
1236:
1233:
1228:
1224:
1219:
1214:
1210:
1206:
1202:
1198:
1194:
1187:
1184:
1179:
1175:
1170:
1165:
1161:
1157:
1153:
1149:
1145:
1138:
1135:
1130:
1126:
1121:
1116:
1112:
1108:
1104:
1100:
1096:
1089:
1086:
1081:
1077:
1072:
1067:
1062:
1057:
1053:
1049:
1045:
1043:
1034:
1031:
1026:
1022:
1017:
1012:
1008:
1004:
1000:
996:
992:
985:
982:
977:
973:
969:
965:
962:(6): 756β64.
961:
957:
950:
948:
944:
939:
935:
931:
927:
923:
919:
915:
911:
907:
901:
898:
893:
889:
885:
881:
876:
871:
867:
863:
855:
853:
851:
849:
845:
840:
838:9780470517673
834:
830:
826:
822:
815:
808:
805:
799:
795:
794:Dark proteome
792:
790:
787:
785:
782:
780:
777:
775:
772:
770:
767:
765:
762:
761:
757:
755:
751:
749:
745:
741:
737:
736:simulations,
735:
729:
722:
717:
710:
708:
705:
700:
695:
691:
683:
681:
679:
675:
671:
666:
662:
660:
656:
649:
641:
639:
635:
628:
626:
623:
619:
611:
609:
606:
598:
593:
589:
583:
576:
574:
572:
567:
562:
560:
556:
553:
548:
544:
540:
535:
532:
528:
524:
520:
516:
512:
508:
504:
500:
496:
492:
488:
484:
480:
476:
471:
469:
465:
457:
454:
452:
450:
447:Larger-scale
445:
443:
435:
432:
430:
428:
424:
420:
412:
410:
407:
402:
400:
396:
392:
388:
383:
378:
374:
368:
366:
363:
359:
351:
349:
347:
343:
339:
335:
331:
327:
323:
318:
316:
308:
306:
299:
297:
291:Linear motifs
290:
288:
286:
282:
278:
274:
266:
264:
262:
258:
254:
250:
246:
238:
236:
234:
230:
226:
222:
221:bioinformatic
217:
210:
208:
206:
202:
196:
194:
190:
185:
182:
177:
172:
168:
164:
160:
152:
147:
140:
138:
136:
132:
128:
124:
120:
115:
113:
109:
105:
101:
97:
93:
89:
85:
81:
77:
73:
69:
65:
61:
53:
49:
45:
41:
38:protein (PDB:
37:
32:
19:
4037:
4033:
4029:
4025:
4021:
3957:
3953:
3943:
3908:
3904:
3894:
3853:
3849:
3843:
3806:
3802:
3792:
3767:
3763:
3757:
3724:
3720:
3713:
3670:
3666:
3656:
3631:
3627:
3620:
3577:
3573:
3567:
3532:
3528:
3518:
3475:
3471:
3461:
3436:
3432:
3426:
3393:
3389:
3383:
3358:
3354:
3348:
3313:
3309:
3299:
3266:
3262:
3258:
3252:
3211:
3207:
3201:
3166:
3162:
3152:
3119:
3115:
3109:
3084:
3080:
3074:
3052:(3): 412β8.
3049:
3045:
3039:
3004:
3000:
2990:
2965:
2962:ChemPhysChem
2961:
2955:
2912:
2908:
2898:
2873:
2869:
2862:
2817:
2813:
2803:
2778:
2774:
2768:
2723:
2719:
2709:
2684:
2680:
2674:
2641:
2637:
2631:
2586:
2582:
2572:
2535:
2531:
2521:
2502:
2492:
2451:
2447:
2437:
2426:
2401:
2397:
2359:
2355:
2307:
2304:Biochemistry
2303:
2293:
2250:
2246:
2236:
2211:
2207:
2201:
2176:
2172:
2166:
2123:
2119:
2109:
2074:
2070:
2060:
2027:
2023:
2017:
1992:
1988:
1982:
1957:
1953:
1947:
1925:(1): 34β54.
1922:
1918:
1912:
1877:
1873:
1863:
1828:
1824:
1814:
1779:
1775:
1765:
1722:
1718:
1712:
1704:
1671:
1667:
1661:
1626:
1622:
1616:
1581:
1577:
1564:
1529:
1525:
1475:
1471:
1423:
1387:
1383:
1337:
1333:
1292:(1): 26β59.
1289:
1285:
1278:
1245:
1241:
1235:
1200:
1197:Biochemistry
1196:
1186:
1151:
1147:
1137:
1105:(1): 18β29.
1102:
1098:
1088:
1051:
1047:
1041:
1033:
998:
994:
984:
959:
955:
913:
909:
900:
868:(1): 26β59.
865:
861:
820:
807:
752:
740:metadynamics
738:
730:
726:
720:
687:
667:
663:
655:linear motif
651:
636:
632:
615:
602:
563:
547:Fluorescence
536:
472:
461:
455:
448:
446:
441:
439:
433:
426:
422:
418:
416:
403:
379:
375:
372:
355:
330:Hendra virus
319:
312:
303:
294:
270:
242:
218:
214:
197:
186:
156:
116:
67:
63:
57:
4067:IDP Journal
3396:: 117β134.
3361:: 147β154.
3122:(1): 1β14.
2915:(4): 1705.
2404:: 553β584.
1995:(2): 81β5.
1715:Gene Birth"
789:Random coil
699:Ξ±-synuclein
382:hydrophobic
326:RNA viruses
273:amino acids
123:multivalent
88:random coil
4093:Categories
3809:(3): 606.
2126:(1): 358.
1674:(1): 1β8.
1390:: 215β46.
1054:: e40497.
1042:Drosophila
800:References
481:, such as
458:approaches
436:approaches
348:proteins.
96:aggregates
44:NMR models
4040:iterature
4032:xtensive
3960:(1): 60.
3886:238249229
3673:: 15449.
3612:205576649
3439:: 57β62.
3291:244942842
2538:(1): 38.
1631:CiteSeerX
1342:CiteSeerX
1294:CiteSeerX
870:CiteSeerX
678:PDB files
515:proteases
346:host cell
285:allostery
257:chromatin
229:proteomes
211:Abundance
52:Ξ²-strands
48:Ξ±-helices
4080:Archived
4043:Archived
4020:IDEAL -
3994:23497088
3935:28516015
3878:34598583
3835:30708941
3784:26580746
3749:75138292
3741:30855964
3705:26498066
3648:26575570
3604:27366858
3559:21530234
3510:21943426
3453:28554553
3418:28226222
3375:28259050
3340:23341755
3283:34870419
3236:14685248
3193:23374074
3144:30231497
3136:16856179
3116:Proteins
3101:21514142
3066:21514145
3031:18991772
2982:18698566
2947:23591872
2890:23327569
2854:24475132
2814:PLOS ONE
2795:24432838
2760:24130866
2720:PLOS ONE
2701:25603119
2666:21364478
2658:15782190
2623:23056252
2583:PLOS ONE
2564:31969649
2476:26808899
2418:24606139
2376:21501695
2334:30430826
2285:29466338
2228:21620710
2193:21927770
2158:29321677
2101:29934321
2052:96719019
2044:17407165
2024:Proteins
2009:12575995
1974:16935303
1939:22044148
1904:26762975
1855:36947137
1846:10089649
1806:30026186
1776:Genetics
1757:28642936
1696:33010897
1688:18802931
1653:12381310
1608:22193414
1600:18388127
1556:36754681
1547:10106370
1502:20099310
1472:Proteins
1450:21570668
1404:18573080
1364:15019783
1316:11381529
1227:17176085
1178:24773235
1129:25531225
1080:30589412
1044:embryos"
1025:24293656
976:18952168
938:18068406
930:15738986
906:Dyson HJ
892:11381529
764:IDPbyNMR
758:See also
697:protein
507:infrared
456:In vitro
427:in vitro
395:residues
328:such as
151:ensemble
135:sequence
104:globular
3985:3599600
3962:Bibcode
3926:5424799
3858:Bibcode
3826:6386871
3696:4620491
3675:Bibcode
3550:3112268
3501:3177054
3480:Bibcode
3398:Bibcode
3331:3549273
3244:1036192
3216:Bibcode
3184:3605821
3022:2676888
2938:3644077
2917:Bibcode
2845:3901707
2822:Bibcode
2751:3793970
2728:Bibcode
2614:3463568
2591:Bibcode
2555:6976632
2503:bioRxiv
2484:4461465
2456:Bibcode
2325:7984725
2276:6264893
2255:Bibcode
2149:5762688
2128:Bibcode
2092:6028506
1895:4824100
1797:6116962
1748:5476217
1727:Bibcode
1713:De Novo
1493:2841229
1270:4124164
1250:Bibcode
1242:Science
1218:2533273
1169:4095912
1120:4405151
1071:6307861
1016:3964979
618:DisProt
511:peptide
449:in vivo
442:in vivo
434:In vivo
423:in vivo
419:in vivo
261:de novo
225:genomes
141:History
129:and in
108:fibrous
72:protein
70:) is a
50:(red),
3992:
3982:
3933:
3923:
3884:
3876:
3833:
3823:
3782:
3747:
3739:
3703:
3693:
3646:
3610:
3602:
3557:
3547:
3508:
3498:
3451:
3416:
3373:
3338:
3328:
3289:
3281:
3242:
3234:
3208:Nature
3191:
3181:
3142:
3134:
3099:
3064:
3029:
3019:
2980:
2945:
2935:
2888:
2852:
2842:
2793:
2758:
2748:
2699:
2664:
2656:
2621:
2611:
2562:
2552:
2482:
2474:
2448:Nature
2416:
2374:
2332:
2322:
2283:
2273:
2247:Nature
2226:
2191:
2156:
2146:
2099:
2089:
2050:
2042:
2007:
1972:
1937:
1902:
1892:
1853:
1843:
1804:
1794:
1755:
1745:
1694:
1686:
1651:
1633:
1606:
1598:
1554:
1544:
1500:
1490:
1448:
1438:
1402:
1362:
1344:
1314:
1296:
1268:
1225:
1215:
1176:
1166:
1127:
1117:
1078:
1068:
1023:
1013:
974:
936:
928:
890:
872:
835:
622:MobiDB
100:domain
94:-like
36:SUMO-1
3882:S2CID
3745:S2CID
3608:S2CID
3287:S2CID
3240:S2CID
3140:S2CID
2662:S2CID
2480:S2CID
2048:S2CID
1831:(4).
1692:S2CID
1604:S2CID
1574:(PDF)
1048:eLife
934:S2CID
817:(PDF)
784:Prion
338:HIV-1
62:, an
3990:PMID
3931:PMID
3874:PMID
3831:PMID
3780:PMID
3737:PMID
3701:PMID
3644:PMID
3600:PMID
3555:PMID
3506:PMID
3449:PMID
3414:PMID
3371:PMID
3336:PMID
3279:PMID
3232:PMID
3189:PMID
3132:PMID
3097:PMID
3062:PMID
3027:PMID
2978:PMID
2943:PMID
2886:PMID
2850:PMID
2791:PMID
2756:PMID
2697:PMID
2685:1854
2654:PMID
2619:PMID
2560:PMID
2472:PMID
2414:PMID
2372:PMID
2330:PMID
2281:PMID
2224:PMID
2189:PMID
2154:PMID
2097:PMID
2040:PMID
2005:PMID
1970:PMID
1935:PMID
1900:PMID
1851:PMID
1802:PMID
1753:PMID
1684:PMID
1649:PMID
1596:PMID
1552:PMID
1498:PMID
1446:PMID
1436:ISBN
1400:PMID
1360:PMID
1312:PMID
1266:PMID
1223:PMID
1174:PMID
1125:PMID
1076:PMID
1021:PMID
972:PMID
926:PMID
888:PMID
833:ISBN
674:CASP
592:1a22
557:and
539:SAXS
425:and
340:and
247:and
227:and
203:and
110:and
40:1a5r
3980:PMC
3970:doi
3921:PMC
3913:doi
3866:doi
3854:155
3821:PMC
3811:doi
3772:doi
3729:doi
3691:PMC
3683:doi
3636:doi
3590:hdl
3582:doi
3545:PMC
3537:doi
3496:PMC
3488:doi
3476:101
3441:doi
3437:128
3406:doi
3363:doi
3326:PMC
3318:doi
3271:doi
3267:125
3261:".
3224:doi
3212:426
3179:PMC
3171:doi
3124:doi
3089:doi
3054:doi
3017:PMC
3009:doi
2970:doi
2933:PMC
2925:doi
2878:doi
2840:PMC
2830:doi
2783:doi
2779:114
2746:PMC
2736:doi
2689:doi
2646:doi
2609:PMC
2599:doi
2550:PMC
2540:doi
2507:doi
2464:doi
2452:530
2406:doi
2364:doi
2320:PMC
2312:doi
2271:PMC
2263:doi
2251:555
2216:doi
2181:doi
2144:PMC
2136:doi
2087:PMC
2079:doi
2075:215
2032:doi
1997:doi
1962:doi
1958:362
1927:doi
1890:PMC
1882:doi
1841:PMC
1833:doi
1792:PMC
1784:doi
1780:210
1743:PMC
1735:doi
1676:doi
1641:doi
1627:323
1586:doi
1542:PMC
1534:doi
1488:PMC
1480:doi
1428:doi
1392:doi
1352:doi
1338:337
1304:doi
1258:doi
1246:181
1213:PMC
1205:doi
1164:PMC
1156:doi
1152:114
1115:PMC
1107:doi
1066:PMC
1056:doi
1011:PMC
1003:doi
964:doi
918:doi
880:doi
825:doi
597:VMD
588:PDB
571:AFM
552:NMR
543:NMR
527:NMR
334:HCV
205:tau
149:An
84:RNA
68:IDP
58:In
4095::
3988:.
3978:.
3968:.
3958:13
3956:.
3952:.
3929:.
3919:.
3907:.
3903:.
3880:.
3872:.
3864:.
3852:.
3829:.
3819:.
3807:20
3805:.
3801:.
3778:.
3768:10
3766:.
3743:.
3735:.
3725:15
3723:.
3699:.
3689:.
3681:.
3669:.
3665:.
3642:.
3632:11
3630:.
3606:.
3598:.
3588:.
3578:35
3576:.
3553:.
3543:.
3533:21
3531:.
3527:.
3504:.
3494:.
3486:.
3474:.
3470:.
3447:.
3435:.
3412:.
3404:.
3394:68
3392:.
3369:.
3359:42
3357:.
3334:.
3324:.
3312:.
3308:.
3285:.
3277:.
3265:.
3238:.
3230:.
3222:.
3210:.
3187:.
3177:.
3165:.
3161:.
3138:.
3130:.
3120:65
3118:.
3095:.
3085:21
3083:.
3060:.
3050:21
3048:.
3025:.
3015:.
3005:15
3003:.
2999:.
2976:.
2964:.
2941:.
2931:.
2923:.
2911:.
2907:.
2884:.
2874:85
2872:.
2848:.
2838:.
2828:.
2816:.
2812:.
2789:.
2777:.
2754:.
2744:.
2734:.
2722:.
2718:.
2695:.
2683:.
2660:.
2652:.
2640:.
2617:.
2607:.
2597:.
2585:.
2581:.
2558:.
2548:.
2534:.
2530:.
2505:.
2501:.
2478:.
2470:.
2462:.
2450:.
2446:.
2412:.
2402:83
2400:.
2384:^
2370:.
2360:43
2358:.
2354:.
2342:^
2328:.
2318:.
2308:57
2306:.
2302:.
2279:.
2269:.
2261:.
2249:.
2245:.
2222:.
2212:36
2210:.
2187:.
2175:.
2152:.
2142:.
2134:.
2122:.
2118:.
2095:.
2085:.
2073:.
2069:.
2046:.
2038:.
2028:68
2026:.
2003:.
1993:28
1991:.
1968:.
1956:.
1933:.
1923:13
1921:.
1898:.
1888:.
1878:44
1876:.
1872:.
1849:.
1839:.
1829:40
1827:.
1823:.
1800:.
1790:.
1778:.
1774:.
1751:.
1741:.
1733:.
1721:.
1717:.
1690:.
1682:.
1672:22
1670:.
1647:.
1639:.
1625:.
1602:.
1594:.
1580:.
1576:.
1550:.
1540:.
1530:48
1528:.
1524:.
1510:^
1496:.
1486:.
1476:78
1474:.
1470:.
1458:^
1444:.
1434:.
1412:^
1398:.
1388:37
1386:.
1372:^
1358:.
1350:.
1336:.
1324:^
1310:.
1302:.
1290:19
1288:.
1264:.
1256:.
1244:.
1221:.
1211:.
1201:45
1199:.
1195:.
1172:.
1162:.
1150:.
1146:.
1123:.
1113:.
1103:16
1101:.
1097:.
1074:.
1064:.
1050:.
1046:.
1019:.
1009:.
999:42
997:.
993:.
970:.
960:18
958:.
946:^
932:.
924:.
912:.
886:.
878:.
866:19
864:.
847:^
831:.
742:,
590::
489:,
485:,
429:.
401:.
336:,
332:,
207:.
114:.
106:,
90:,
4038:L
4034:A
4030:E
4026:D
4022:I
3996:.
3972::
3964::
3937:.
3915::
3909:1
3888:.
3868::
3860::
3837:.
3813::
3786:.
3774::
3751:.
3731::
3707:.
3685::
3677::
3671:5
3650:.
3638::
3614:.
3592::
3584::
3561:.
3539::
3512:.
3490::
3482::
3455:.
3443::
3420:.
3408::
3400::
3377:.
3365::
3342:.
3320::
3314:8
3293:.
3273::
3246:.
3226::
3218::
3195:.
3173::
3167:4
3146:.
3126::
3103:.
3091::
3068:.
3056::
3033:.
3011::
2984:.
2972::
2966:9
2949:.
2927::
2919::
2913:4
2892:.
2880::
2856:.
2832::
2824::
2818:9
2797:.
2785::
2762:.
2738::
2730::
2724:8
2703:.
2691::
2668:.
2648::
2642:2
2625:.
2601::
2593::
2587:7
2566:.
2542::
2536:3
2515:.
2509::
2486:.
2466::
2458::
2420:.
2408::
2378:.
2366::
2336:.
2314::
2287:.
2265::
2257::
2230:.
2218::
2195:.
2183::
2177:8
2160:.
2138::
2130::
2124:8
2103:.
2081::
2054:.
2034::
2011:.
1999::
1976:.
1964::
1941:.
1929::
1906:.
1884::
1857:.
1835::
1808:.
1786::
1759:.
1737::
1729::
1723:1
1698:.
1678::
1655:.
1643::
1610:.
1588::
1582:7
1558:.
1536::
1504:.
1482::
1452:.
1430::
1406:.
1394::
1366:.
1354::
1318:.
1306::
1272:.
1260::
1252::
1229:.
1207::
1180:.
1158::
1131:.
1109::
1082:.
1058::
1052:7
1027:.
1005::
978:.
966::
940:.
920::
914:6
894:.
882::
841:.
827::
66:(
20:)
Text is available under the Creative Commons Attribution-ShareAlike License. Additional terms may apply.
