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==Historical summary==
Macromolecular crystallography was preceded by the older field of small-molecule [[x-ray crystallography]] (for structures with less than a few hundred atoms). Small-molecule [[diffraction]] data extends to much higher [[Resolution (electron density)|resolution]] than feasible for macromolecules, and has a very clean mathematical relationship between the data and the atomic model. The residual, or R-factor, measures the agreement between the experimental data and the values back-calculated from the atomic model. For a well-determined small-molecule structure the R-factor is nearly as small as the uncertainty in the experimental data (well under 5%). Therefore, that one test by itself provides most of the validation needed, but a number of additional consistency and methodology checks are done by automated software<ref>{{Cite journal | vauthors = Spek AL |year=2003 |title=Single-crystal structure validation with the program PLATON |journal=Journal of Applied Crystallography |volume= 36 |pages=7–13 |doi=10.1107/S0021889802022112}}</ref> as a requirement for small-molecule crystal structure papers submitted to the [[International Union of Crystallography]] (IUCr) journals such as [[Acta Crystallographica]] section B or C. Atomic coordinates of these small-molecule structures are archived and accessed through the [[Cambridge Structural Database]] (CSD)<ref>{{cite journal | vauthors = Allen FH | title = The Cambridge Structural Database: a quarter of a million crystal structures and rising | journal = Acta Crystallographica
The first macromolecular validation software was developed around 1990, for proteins. It included Rfree [[cross-validation (statistics)|cross-validation]] for model-to-data match,<ref name="Rfree">{{cite journal | vauthors = Brünger AT | title = Free R value: a novel statistical quantity for assessing the accuracy of crystal structures | journal = Nature | volume = 355 | issue = 6359 | pages = 472–5 | date = January 1992 | pmid = 18481394 | doi = 10.1038/355472a0 | author-link = Axel T. Brunger | bibcode = 1992Natur.355..472B }}</ref> bond length and angle parameters for covalent geometry,<ref name="Engh">{{cite journal |vauthors=Engh RA, Huber R |year=1991 |title=Accurate bond and angle parameters for X-ray protein structure refinement |journal=Acta Crystallographica A |volume=47 |issue=4 |pages=392–400|doi=10.1107/s0108767391001071 }}</ref> and sidechain and backbone conformational criteria.<ref name="Ponder&Richards">{{cite journal |vauthors=Ponder JW, Richards FM |year=1987 |title=Tertiary templates for proteins. Use of packing criteria in the enumeration of allowed sequences for different structural classes |journal=Journal of Molecular Biology |volume=193 |issue=4 |pages=775–791 |doi=10.1016/0022-2836(87)90358-5|pmid=2441069 }}</ref><ref name="procheck">{{cite journal |vauthors=Laskowski RA, MacArthur MW, Moss DS, Thornton JM |author4-link=Janet Thornton |year=1993 |title=PROCHECK: a program to check the stereochemical quality of protein structures |journal=Journal of Applied Crystallography |volume=26 |issue=2 |pages=283–291 |doi=10.1107/s0021889892009944}}</ref><ref name="whatif">{{cite journal | vauthors = Hooft RW, Vriend G, Sander C, Abola EE | title = Errors in protein structures | journal = Nature | volume = 381 | issue = 6580 | pages = 272 | date = May 1996 | pmid = 8692262 | doi = 10.1038/381272a0 | bibcode = 1996Natur.381..272H }}</ref> For macromolecular structures, the atomic models are deposited in the [[Protein Data Bank]] (PDB), still the single archive of this data. The PDB was established in the 1970s at [[Brookhaven National Laboratory]],<ref>{{cite journal | vauthors = Bernstein FC, Koetzle TF, Williams GJ, Meyer EF, Brice MD, Rodgers JR, Kennard O, Shimanouchi T, Tasumi M | display-authors = 6 | title = The Protein Data Bank: a computer-based archival file for macromolecular structures | journal = Journal of Molecular Biology | volume = 112 | issue = 3 | pages = 535–42 | date = May 1977 | pmid = 875032 | doi = 10.1016/s0022-2836(77)80200-3 | author7-link = Olga Kennard }}</ref> moved in 2000 to the [http://www.rcsb.org/pdb RCSB] (Research Collaboration for Structural Biology) centered at [[Rutgers]],<ref>{{cite journal | vauthors = Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE | display-authors = 6 | title = The Protein Data Bank | journal = Nucleic Acids Research | volume = 28 | issue = 1 | pages = 235–42 | date = January 2000 | pmid = 10592235 | pmc = 102472 | doi = 10.1093/nar/28.1.235 | author8-link = Philip Bourne | author-link = Helen M. Berman }}</ref> and expanded in 2003 to become the [http://www.wwpdb.org/ wwPDB] (worldwide Protein Data Bank),<ref name="wwPDB">{{cite journal | vauthors = Berman H, Henrick K, Nakamura H | title = Announcing the worldwide Protein Data Bank | journal = Nature Structural Biology | volume = 10 | issue = 12 | pages = 980 | date = December 2003 | pmid = 14634627 | doi = 10.1038/nsb1203-980 | author-link = Helen M. Berman }}</ref> with access sites added in Europe ([http://pdbe.org|PDBe]) and Asia ([http://www.pdbj.org|PDBj]), and with NMR data handled at the [http://www.bmrb.wisc.edu BioMagResBank (BMRB)] in Wisconsin.
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The backbone and side-chain [[dihedral angles]] of protein and RNA have been shown to have specific combinations of angles which are allowed (or forbidden). For protein backbone dihedrals (φ, ψ), this has been addressed by the legendary [[Ramachandran plot|Ramachandran Plot]] while for side-chain dihedrals (χ's), one should refer to the [http://dunbrack.fccc.edu/bbdep2010/Dataset.php Dunbrack's Rotamer library].
Though, mRNA structures are generally short-lived and single-stranded, there are an abundance of non-coding RNAs with different secondary and tertiary folding (tRNA, rRNA etc.) which contain a preponderance of the canonical [[Base pair|Watson-Crick]] (WC) base-pairs, together with significant number of non-Watson Crick (NWC) base-pairs - for which such RNA also qualify for regular structural validation that apply for nucleic acid helices. The standard practice is to analyse the intra- (Transnational: Shift, Slide, Rise; Rotational: Tilt, Roll, Twist) and inter-base-pair geometrical parameters (Transnational: Shear, Stagger, Stretch, Rotational: Buckle, Propeller, Opening) - whether in-range or out-of-range with respect to their suggested values
▲Though, mRNA structures are generally short-lived and single-stranded, there are an abundance of non-coding RNAs with different secondary and tertiary folding (tRNA, rRNA etc.) which contain a preponderance of the canonical [[Base pair|Watson-Crick]] (WC) base-pairs, together with significant number of non-Watson Crick (NWC) base-pairs - for which such RNA also qualify for regular structural validation that apply for nucleic acid helices. The standard practice is to analyse the intra- (Transnational: Shift, Slide, Rise; Rotational: Tilt, Roll, Twist) and inter-base-pair geometrical parameters (Transnational: Shear, Stagger, Stretch, Rotational: Buckle, Propeller, Opening) - whether in-range or out-of-range with respect to their suggested values <ref>{{Cite journal|last=Dickerson|first=Richard E.|date=1989-02-01|title=Definitions and Nomenclature of Nucleic Acid Structure Parameters|url=https://doi.org/10.1080/07391102.1989.10507726|journal=Journal of Biomolecular Structure and Dynamics|volume=6|issue=4|pages=627–634|doi=10.1080/07391102.1989.10507726|issn=0739-1102|pmid=2619931}}</ref><ref>{{Cite journal|last=Olson|first=Wilma K|last2=Bansal|first2=Manju|last3=Burley|first3=Stephen K|last4=Dickerson|first4=Richard E|last5=Gerstein|first5=Mark|last6=Harvey|first6=Stephen C|last7=Heinemann|first7=Udo|last8=Lu|first8=Xiang-Jun|last9=Neidle|first9=Stephen|last10=Shakked|first10=Zippora|last11=Sklenar|first11=Heinz|date=2001-10-12|title=A standard reference frame for the description of nucleic acid base-pair geometry11Edited by P. E. Wright22This is a document of the Nomenclature Committee of IUBMB (NC-IUBMB)/IUPAC-IUBMB Joint Commission on Biochemical Nomenclature (JCBN), whose members are R. Cammack (chairman), A. Bairoch, H.M. Berman, S. Boyce, C.R. Cantor, K. Elliott, D. Horton, M. Kanehisa, A. Kotyk, G.P. Moss, N. Sharon and K.F. Tipton.|url=http://www.sciencedirect.com/science/article/pii/S0022283601949873|journal=Journal of Molecular Biology|language=en|volume=313|issue=1|pages=229–237|doi=10.1006/jmbi.2001.4987|issn=0022-2836|pmid=11601858}}</ref>. These parameters describe the relative orientations of the two paired bases with respect to each other in two strands (intra) along with those of the two stacked base pairs (inter) with respect to each other, and, hence, together, they serve to validate nucleic acid structures in general. Since, RNA-helices are small in length (average: 10-20 bps), the use of electrostatic surface potential as a validation parameter <ref>{{Cite journal|last=Bhattacharyya|first=Dhananjay|last2=Halder|first2=Sukanya|last3=Basu|first3=Sankar|last4=Mukherjee|first4=Debasish|last5=Kumar|first5=Prasun|last6=Bansal|first6=Manju|date=2017-01-19|title=RNAHelix: computational modeling of nucleic acid structures with Watson–Crick and non-canonical base pairs|url=http://dx.doi.org/10.1007/s10822-016-0007-0|journal=Journal of Computer-Aided Molecular Design|volume=31|issue=2|pages=219–235|doi=10.1007/s10822-016-0007-0|issn=0920-654X}}</ref> has been found to be beneficial, particularly for modelling purposes.
==== Packing and Electrostatics: globular proteins ====
For globular proteins, interior atomic packing (arising from short-range, local interactions) of side-chains<ref>{{Cite journal| vauthors = Shen MY, Davis FP, Sali A |date= March 2005|title=The optimal size of a globular protein ___domain: A simple sphere-packing model|journal=Chemical Physics Letters|volume=405|issue=1–3|pages=224–228|doi=10.1016/j.cplett.2005.02.029|issn=0009-2614|bibcode= 2005CPL...405..224S}}</ref><ref>{{cite journal | vauthors = Misura KM, Morozov AV, Baker D | title = Analysis of anisotropic side-chain packing in proteins and application to high-resolution structure prediction | journal = Journal of Molecular Biology | volume = 342 | issue = 2 | pages = 651–64 | date = September 2004 | pmid = 15327962 | doi = 10.1016/j.jmb.2004.07.038 }}</ref><ref>{{cite journal | vauthors = Basu S, Bhattacharyya D, Banerjee R | title = Mapping the distribution of packing topologies within protein interiors shows predominant preference for specific packing motifs | journal = BMC Bioinformatics | volume = 12 | issue = 1 | pages = 195 | date = May 2011 | pmid = 21605466 | pmc = 3123238 | doi = 10.1186/1471-2105-12-195 }}</ref><ref name="The jigsaw puzzle model: search for">{{cite journal | vauthors = Banerjee R, Sen M, Bhattacharya D, Saha P | title = The jigsaw puzzle model: search for conformational specificity in protein interiors | journal = Journal of Molecular Biology | volume = 333 | issue = 1 | pages = 211–26 | date = October 2003 | pmid = 14516754 | doi = 10.1016/j.jmb.2003.08.013 }}</ref> has been shown to be pivotal in the structural stabilization of the protein-fold. On the other hand, the electrostatic harmony (non-local, long-range) of the overall fold<ref name=":2">{{cite journal | vauthors = Basu S, Bhattacharyya D, Banerjee R | title = Self-complementarity within proteins: bridging the gap between binding and folding | journal = Biophysical Journal | volume = 102 | issue = 11 | pages = 2605–14 | date = June 2012 | pmid = 22713576 | pmc = 3368132 | doi = 10.1016/j.bpj.2012.04.029 | bibcode = 2012BpJ...102.2605B }}</ref> has also been shown to be essential for its stabilization. Packing anomalies include steric clashes,<ref>{{cite journal | vauthors = Chen VB, Arendall WB, Headd JJ, Keedy DA, Immormino RM, Kapral GJ, Murray LW, Richardson JS, Richardson DC | display-authors = 6 | title = MolProbity: all-atom structure validation for macromolecular crystallography | journal = Acta Crystallographica
====Carbohydrates====
[[File:(A)-ASN297.svg|thumb|A 2D diagram of an N-glycan linked to an antibody fragment in the structure with PDB accession code '4BYH'. This diagram, which has been generated with Privateer,<ref name=":0"/> follows the standard symbol nomenclature<ref name=":1"/> and includes, in its original svg format, annotations containing validation information, including ring conformation and detected monosaccharide types.]]
The branched and cyclic nature of carbohydrates poses particular problems to structure validation tools.<ref>{{cite journal | vauthors = Agirre J, Davies GJ, Wilson KS, Cowtan KD | title = Carbohydrate structure: the rocky road to automation | journal = Current Opinion in Structural Biology | volume = 44 | pages = 39–47 | date = June 2017 | pmid = 27940408 | doi = 10.1016/j.sbi.2016.11.011 | url = http://eprints.whiterose.ac.uk/109296/1/COStBi_postprint.pdf | series = Carbohydrates • Sequences and topology }}</ref> At higher resolutions, it is possible to determine the sequence/structure of oligo- and poly-saccharides, both as covalent modifications and as ligands. However, at lower resolutions (typically lower than 2.0Å), sequences/structures should either match known structures, or be supported by complementary techniques such as Mass Spectrometry.<ref>{{cite journal | vauthors = Crispin M, Stuart DI, Jones EY | title = Building meaningful models of glycoproteins | journal = Nature Structural & Molecular Biology | volume = 14 | issue = 5 | pages = 354; discussion 354–5 | date = May 2007 | pmid = 17473875 | doi = 10.1038/nsmb0507-354a }}</ref> Also, monosaccharides have clear conformational preferences (saturated rings are typically found in chair conformations),<ref>{{cite journal | vauthors = Davies GJ, Planas A, Rovira C | title = Conformational analyses of the reaction coordinate of glycosidases | journal = Accounts of Chemical Research | volume = 45 | issue = 2 | pages = 308–16 | date = February 2012 | pmid = 21923088 | doi = 10.1021/ar2001765 }}</ref> but errors introduced during model building and/or refinement (wrong linkage chirality or distance, or wrong choice of model - see<ref>{{cite journal | vauthors = Agirre J | title = Strategies for carbohydrate model building, refinement and validation | journal = Acta Crystallographica
A number of carbohydrate validation web services are available at [http://ww.glycosciences.de glycosciences.de] (including nomenclature checks and linkage checks by [http://www.glycosciences.de/tools/pdb-care/ pdb-care],<ref>{{cite journal | vauthors = Lütteke T, von der Lieth CW | title = pdb-care (PDB carbohydrate residue check): a program to support annotation of complex carbohydrate structures in PDB files | journal = BMC Bioinformatics | volume = 5 | pages = 69 | date = June 2004 | pmid = 15180909 | pmc = 441419 | doi = 10.1186/1471-2105-5-69 }}</ref> and cross-validation with Mass Spectrometry data through the use of GlycanBuilder), whereas the [http://www.ccp4.ac.uk CCP4] suite currently distributes [http://www.ccp4.ac.uk/html/privateer.html Privateer],<ref name=":0">{{cite journal | vauthors = Agirre J, Iglesias-Fernández J, Rovira C, Davies GJ, Wilson KS, Cowtan KD | title = Privateer: software for the conformational validation of carbohydrate structures | journal = Nature Structural & Molecular Biology | volume = 22 | issue = 11 | pages = 833–4 | date = November 2015 | pmid = 26581513 | doi = 10.1038/nsmb.3115 }}</ref> which is a tool that is integrated into the model building and refinement process itself. Privateer is able to check stereo- and regio-chemistry, ring conformation and puckering, linkage torsions, and real-space correlation against positive omit density, generating aperiodic torsion restraints on ring bonds, which can be used by any refinement software in order to maintain the monosaccharide's minimal energy conformation.<ref name=":0" />
Privateer also generates scalable two-dimensional SVG diagrams according to the Essentials of Glycobiology<ref name=":1">{{cite journal | vauthors = Varki A, Cummings RD, Aebi M, Packer NH, Seeberger PH, Esko JD, Stanley P, Hart G, Darvill A, Kinoshita T, Prestegard JJ, Schnaar RL, Freeze HH, Marth JD, Bertozzi CR, Etzler ME, Frank M, Vliegenthart JF, Lütteke T, Perez S, Bolton E, Rudd P, Paulson J, Kanehisa M, Toukach P, Aoki-Kinoshita KF, Dell A, Narimatsu H, York W, Taniguchi N, Kornfeld S | display-authors = 6 | title = Symbol Nomenclature for Graphical Representations of Glycans | journal = Glycobiology | volume = 25 | issue = 12 | pages = 1323–4 | date = December 2015 | pmid = 26543186 | pmc = 4643639 | doi = 10.1093/glycob/cwv091 }}</ref> standard symbol nomenclature containing all the validation information as tooltip annotations (see figure). This functionality is currently integrated into other CCP4 programs, such as the molecular graphics program CCP4mg (through the ''Glycoblocks'' 3D representation,<ref>{{cite journal | vauthors = McNicholas S, Agirre J | title = Glycoblocks: a schematic three-dimensional representation for glycans and their interactions | journal = Acta Crystallographica
==Validation for crystallography==
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==In Cyro-EM==
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== In SAXS ==
SAXS (small-angle x-ray scattering) is a rapidly growing area of structure determination, both as a source of approximate 3D structure for initial or difficult cases and as a component of hybrid-method structure determination when combined with NMR, EM, crystallographic, cross-linking, or computational information. There is great interest in the development of reliable validation standards for SAXS data interpretation and for quality of the resulting models, but there are as yet no established methods in general use. Three recent steps in this direction are the creation of a Small-Angle Scattering Validation Task Force committee by the worldwide Protein DataBank and its initial report,<ref name="sasVTF">{{cite journal | vauthors = Trewhella J, Hendrickson WA, Kleywegt GJ, Sali A, Sato M, Schwede T, Svergun DI, Tainer JA, Westbrook J, Berman HM | display-authors = 6 | title = Report of the wwPDB Small-Angle Scattering Task Force: data requirements for biomolecular modeling and the PDB | journal = Structure | volume = 21 | issue = 6 | pages = 875–81 | date = June 2013 | pmid = 23747111 | doi = 10.1016/j.str.2013.04.020 }}</ref> a set of suggested standards for data inclusion in publications,<ref name="Jacques2012">{{cite journal | vauthors = Jacques DA, Guss JM, Svergun DI, Trewhella J | title = Publication guidelines for structural modelling of small-angle scattering data from biomolecules in solution | journal = Acta Crystallographica
==For computational biology==
It is difficult to do meaningful validation of an individual, purely computational, macromolecular model in the absence of experimental data for that molecule, because the model with the best geometry and conformational score may not be the one closest to the right answer. Therefore, much of the emphasis in validation of computational modeling is in assessment of the methods. To avoid bias and wishful thinking, double-blind prediction competitions have been organized, the original example of which (held every 2 years since 1994) is [[CASP]] (Critical Assessment of Structure Prediction) to evaluate predictions of 3D protein structure for newly solved [[x-ray crystallography|crystallographic]] or [[Nuclear magnetic resonance|NMR]] structures held in confidence until the end of the relevant competition.<ref>{{cite journal | vauthors = Moult J, Pedersen JT, Judson R, Fidelis K | title = A large-scale experiment to assess protein structure prediction methods | journal = Proteins | volume = 23 | issue = 3 | pages = ii-v | date = November 1995 | pmid = 8710822 | doi = 10.1002/prot.340230303 | url = https://zenodo.org/record/1229334 }}</ref> The major criterion for CASP evaluation is a weighted score called GDT-TS for the match of Calpha positions between the predicted and the experimental models.<ref>{{cite journal | vauthors = Zemla A | title = LGA: A method for finding 3D similarities in protein structures | journal = Nucleic Acids Research | volume = 31 | issue = 13 | pages = 3370–4 | date = July 2003 | pmid = 12824330 | pmc = 168977 | doi = 10.1093/nar/gkg571 }}</ref>
== See also ==
* [[List of biophysically important macromolecular crystal structures]]
== External links ==▼
===Software and websites===
* Computational prediction
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**[http://nucleix.mbu.iisc.ernet.in/nuparmplus/ NUPARM] (Nucleic Acid validation)
**[http://www.saha.ac.in/biop/bioinformatics.html RNAhelix] (RNA validation)
* X-ray
** [http://eds.bmc.uu.se/eds/ EDS (Electron Density Server)]<ref>{{cite journal | vauthors = Kleywegt GJ, Harris MR, Zou JY, Taylor TC, Wählby A, Jones TA | title = The Uppsala Electron-Density Server | journal = Acta Crystallographica
** [[Coot (software)|Coot]] - modeling software (built-in validation) [http://www.biop.ox.ac.uk/coot/]<ref>{{cite journal | vauthors = Emsley P, Lohkamp B, Scott WG, Cowtan K | title = Features and development of Coot | journal = Acta Crystallographica
** [http://www.cmbi.ru.nl/pdb_redo/ PDB_REDO] - X-ray model optimization: rebuilding and refining all models using contemporary techniques<ref>{{cite journal | vauthors = Joosten RP, Joosten K, Murshudov GN, Perrakis A | title = PDB_REDO: constructive validation, more than just looking for errors | journal = Acta Crystallographica
** [[PROSESS]] - Protein Structure Evaluation Suite & Server
** [[Resolution by Proxy]], ResProx - protein model resolution-by-proxy
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== References ==
{{Reflist|30em}}
▲== External links ==
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== Further reading ==
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