Structure validation: Difference between revisions

Revision as of 01:52, 14 August 2024

Latest revision as of 04:39, 1 August 2025

(7 intermediate revisions by 5 users not shown)

Line 1:

{{short description|Process of evaluating 3-dimensional atomic models of biomacromolecules}}

{{Multiple issues|

{{cleanup reorganize|date=May 2019}}

{{Cleanup|reason=this page seems to have been abandoned part way during writing. Contains empty sections.|date=July 2025}}

}}

[[Image:Structure validation concept.jpg|thumb|right|Structure validation concept: model of a protein (each ball is an atom), and magnified region with electron density data and 3 bright flags for problems]]

'''Macromolecular structure validation''' is the process of evaluating reliability for 3-dimensional atomic models of large biological molecules such as [[proteins]] and [[nucleic acids]]. These models, which provide 3D coordinates for each atom in the molecule (see example in the image), come from [[structural biology]] experiments such as [[x-ray crystallography]]<ref name="Rupp">{{harvnb|Rupp|2009}}</ref> or [[nuclear magnetic resonance]] (NMR).<ref name="Cavanagh">{{harvnb|Cavanagh

Line 26 ⟶ 29:

====Geometry====

<ref name="Engh" /><ref name="Gelbin">{{cite journal |vauthors=Gelbin A, Schneider B, Clowney L, ((Hsieh S-H)), Olson WK, Berman HM |author6-link=Helen M. Berman |year=1996 |title=Geometric parameters in Nucleic Acids:Sugar and Phosphate Constituents |journal=Journal of the American Chemical Society |volume=118 |issue=3 |pages=519–529 |doi=10.1021/ja9528846 |bibcode=1996JAChS.118..519G }}</ref><ref>{{cite journal | vauthors = Schultze P, Feigon J | title = Chirality errors in nucleic acid structures | journal = Nature | volume = 387 | issue = 6634 | pages = 668 | date = June 1997 | pmid = 9192890 | doi = 10.1038/42632 | bibcode = 1997Natur.387..668S | s2cid = 4318780 | doi-access = free }}</ref>

====Conformation (dihedrals): protein & RNA====

Line 34 ⟶ 37:

==== 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 | pagesarticle-number = 195 | date = May 2011 | pmid = 21605466 | pmc = 3123238 | doi = 10.1186/1471-2105-12-195 | doi-access = free }}</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 Section D | volume = 66 | issue = Pt 1 | pages = 12–21 | date = January 2010 | pmid = 20057044 | pmc = 2803126 | doi = 10.1107/S0907444909042073 | bibcode = 2010AcCrD..66...12C }}</ref> short contacts,<ref name="The jigsaw puzzle model: search for"/> holes<ref>{{cite journal | vauthors = Sheffler W, Baker D | title = RosettaHoles: rapid assessment of protein core packing for structure prediction, refinement, design, and validation | journal = Protein Science | volume = 18 | issue = 1 | pages = 229–39 | date = January 2009 | pmid = 19177366 | pmc = 2708028 | doi = 10.1002/pro.8 }}</ref> and cavities<ref>{{cite journal | vauthors = Chakravarty S, Varadarajan R | title = Residue depth: a novel parameter for the analysis of protein structure and stability | journal = Structure | volume = 7 | issue = 7 | pages = 723–32 | date = July 1999 | pmid = 10425675 | doi = 10.1016/s0969-2126(99)80097-5 | doi-access = free }}</ref> while electrostatic disharmony<ref name=":2" /><ref>{{cite journal | vauthors = Basu S, Bhattacharyya D, Banerjee R | title = Applications of complementarity plot in error detection and structure validation of proteins | journal = Indian Journal of Biochemistry & Biophysics | volume = 51 | issue = 3 | pages = 188–200 | date = June 2014 | pmid = 25204080 }}</ref> refer to unbalanced partial charges in the protein core (particularly relevant for designed protein interiors). While the clash-score of [http://molprobity.biochem.duke.edu/ Molprobity] identifies steric clashes at a very high resolution, the [[Complementarity plot|Complementarity Plot]] combines packing anomalies with electrostatic imbalance of side-chains and signals for either or both.

====Carbohydrates====

Line 41 ⟶ 44:

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 | s2cid = 2020697 | doi-access = free }}</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 Section D | volume = 73 | issue = Pt 2 | pages = 171–186 | date = February 2017 | pmid = 28177313 | pmc = 5297920 | doi = 10.1107/S2059798316016910 | bibcode = 2017AcCrD..73..171A | url = http://journals.iucr.org/d/issues/2017/02/00/ba5257/ }}</ref> for recommendations on carbohydrate model building and refinement and<ref>{{cite journal | vauthors = Lütteke T | title = Analysis and validation of carbohydrate three-dimensional structures | journal = Acta Crystallographica Section D | volume = 65 | issue = Pt 2 | pages = 156–68 | date = February 2009 | pmid = 19171971 | pmc = 2631634 | doi = 10.1107/S0907444909001905 | bibcode = 2009AcCrD..65..156L }}</ref><ref>{{cite book | vauthors = Lütteke T, von der Lieth CW | title = Glycomics | chapter = Data mining the PDB for glyco-related data | series = Methods in Molecular Biology | volume = 534 | pages = 293–310 | date = 2009-01-01 | pmid = 19277543 | doi = 10.1007/978-1-59745-022-5_21 | isbn = 978-1-58829-774-7 }}</ref><ref>{{cite journal | vauthors = Joosten RP, Lütteke T | title = Carbohydrate 3D structure validation | journal = Current Opinion in Structural Biology | volume = 44 | pages = 9–17 | date = June 2017 | pmid = 27816840 | doi = 10.1016/j.sbi.2016.10.010 | url = http://eprints.whiterose.ac.uk/109296/1/COStBi_postprint.pdf }}</ref> for reviews on general errors in carbohydrate structures) can bring their atomic models out of the more likely low-energy state. Around 20% of the deposited carbohydrate structures are in a higher-energy conformation not justified by the structural data (measured using real-space correlation coefficient).<ref>{{cite journal | vauthors = Agirre J, Davies G, Wilson K, Cowtan K | title = Carbohydrate anomalies in the PDB | journal = Nature Chemical Biology | volume = 11 | issue = 5 | pages = 303 | date = May 2015 | pmid = 25885951 | doi = 10.1038/nchembio.1798 | url = http://eprints.whiterose.ac.uk/95242/1/AgirreDaviesWIlsonCowtan_self_archived.pdf | doi-access = free }}</ref>

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 | pagesarticle-number = 69 | date = June 2004 | pmid = 15180909 | pmc = 441419 | doi = 10.1186/1471-2105-5-69 | doi-access = free }}</ref> and cross-validation with Mass Spectrometry data through the use of GlycanBuilder), whereas the [[Collaborative Computational Project Number 4|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 | s2cid = 33800088 | url = http://eprints.whiterose.ac.uk/95794/1/Privateer_selfarchived.pdf }}</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 Section D | volume = 73 | issue = Pt 2 | pages = 187–194 | date = February 2017 | pmid = 28177314 | pmc = 5297921 | doi = 10.1107/S2059798316013553 | bibcode = 2017AcCrD..73..187M }}</ref> which conforms to the standard symbol nomenclature<ref name=":1" />) and the suite's graphical interface, CCP4i2.

Line 75 ⟶ 78:

===Data Validation: Chemical Shifts, NOEs, RDCs===

;AVS: Assignment validation suite ([https://www.ncbi.nlm.nih.gov/pubmed/14872126 AVS]) checks the chemical shifts list in BioMagResBank (BMRB) format for problems.<ref name="pmid14872126">{{cite journal | vauthors = Moseley HN, Sahota G, Montelione GT | title = Assignment validation software suite for the evaluation and presentation of protein resonance assignment data | journal = Journal of Biomolecular NMR | volume = 28 | issue = 4 | pages = 341–55 | date = April 2004 | pmid = 14872126 | doi = 10.1023/B:JNMR.0000015420.44364.06 | s2cid = 14483199 }}</ref>

;PSVS: Protein Structure Validation Server at the NESG based on information retrieval statistics<ref name="HuangPowers2005">{{cite journal | vauthors = Huang YJ, Powers R, Montelione GT | title = Protein NMR recall, precision, and F-measure scores (RPF scores): structure quality assessment measures based on information retrieval statistics | journal = Journal of the American Chemical Society | volume = 127 | issue = 6 | pages = 1665–74 | date = February 2005 | pmid = 15701001 | doi = 10.1021/ja047109h | bibcode = 2005JAChS.127.1665H }}</ref>

;[[PROSESS]]: PROSESS (Protein Structure Evaluation Suite & Server) is a new web server that offers an assessment of protein structural models by NMR chemical shifts as well as NOEs, geometrical, and knowledge-based parameters.

;LACS:Linear analysis of chemical shifts is used for absolute referencing of chemical shift data.

Line 136 ⟶ 139:

** [http://vadar.wishartlab.com/ VADAR - Volume, Area, Dihedral Angle Reporter]

* NMR

** [http://psvs-1_4-dev.nesg.org/ PSVS (Protein Structure Validation Server at the NESG)]<ref name="HuangPowers2005"/>

** [http://code.google.com/p/cing/ CING (Common Interface for NMR structure Generation) software]

** [http://www.ebi.ac.uk/thornton-srv/software/PROCHECK/ ProCheck] - stereochemical quality check for X-ray and NMR<ref>{{cite journal | vauthors = Laskowski RA, Rullmannn JA, MacArthur MW, Kaptein R, Thornton JM | title = AQUA and PROCHECK-NMR: programs for checking the quality of protein structures solved by NMR | journal = Journal of Biomolecular NMR | volume = 8 | issue = 4 | pages = 477–86 | date = December 1996 | pmid = 9008363 | doi = 10.1007/bf00228148 | s2cid = 45664105 }}</ref>

** [httphttps://spin.niddk.nih.gov/bax/nmrserver/talos/ TALOS+ Software & Server] (server for predicting protein backbone torsion angles from chemical shift)

** [http://vadar.wishartlab.com/ VADAR - Volume, Area, Dihedral Angle Reporter]

** [[PROSESS]] - Protein Structure Evaluation Suite & Server

Line 147 ⟶ 149:

** [http://www.wwpdb.org/em/ EMDB at the PDB, info on ftp download of maps]

** [https://cci.lbl.gov/ceres CERES], rebuilds (and hopefully improves) Cyro-EM models using the latest version of PHENIX<ref>{{cite journal |last1=Liebschner |first1=D |last2=Afonine |first2=PV |last3=Moriarty |first3=NW |last4=Poon |first4=BK |last5=Chen |first5=VB |last6=Adams |first6=PD |title=CERES: a cryo-EM re-refinement system for continuous improvement of deposited models. |journal=Acta Crystallographica Section D |date=1 January 2021 |volume=77 |issue=Pt 1 |pages=48–61 |doi=10.1107/S2059798320015879 |pmid=33404525|pmc=7787109 |bibcode=2021AcCrD..77...48L |doi-access=free }}</ref>

=== Link references ===

{{reflist}}

== Further reading ==

{{Refbegin}}

*{{Cite book | last1 = Cavanagh | first1 = John | last2 = Fairbrother | first2 = Wayne J. | last3 = Palmer | first3 = Arthur G. III | last4 = Skelton | first4 = Nicholas J. | name-list-style = vanc |title=Protein NMR Spectroscopy: Principles and Practice |edition=2nd |year=2006 |publisher=Academic Press |isbn=978-0-12-164491-8 |ref={{harvid|Cavanagh|2006}} }}

*{{Cite book |last= Rupp |first=Bernhard | name-list-style = vanc |title=Biomolecular Crystallography: Principles, Practice, and Application to Structural Biology |year=2009 |publisher=Garland Science |isbn=978-0815340812 }}

=== Link references ===

{{Refbegin}}

{{Refend}}