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Acta Crystallographica. Section D, Structural Biology

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https://www.readbyqxmd.com/read/28291763/wonka-and-oommppaa-analysis-of-protein-ligand-interaction-data-to-direct-structure-based-drug-design
#1
Charlotte M Deane, Ian D Wall, Darren V S Green, Brian D Marsden, Anthony R Bradley
In this work, two freely available web-based interactive computational tools that facilitate the analysis and interpretation of protein-ligand interaction data are described. Firstly, WONKA, which assists in uncovering interesting and unusual features (for example residue motions) within ensembles of protein-ligand structures and enables the facile sharing of observations between scientists. Secondly, OOMMPPAA, which incorporates protein-ligand activity data with protein-ligand structural data using three-dimensional matched molecular pairs...
March 1, 2017: Acta Crystallographica. Section D, Structural Biology
https://www.readbyqxmd.com/read/28291762/the-xchemexplorer-graphical-workflow-tool-for-routine-or-large-scale-protein-ligand-structure-determination
#2
Tobias Krojer, Romain Talon, Nicholas Pearce, Patrick Collins, Alice Douangamath, Jose Brandao-Neto, Alexandre Dias, Brian Marsden, Frank von Delft
XChemExplorer (XCE) is a data-management and workflow tool to support large-scale simultaneous analysis of protein-ligand complexes during structure-based ligand discovery (SBLD). The user interfaces of established crystallographic software packages such as CCP4 [Winn et al. (2011), Acta Cryst. D67, 235-242] or PHENIX [Adams et al. (2010), Acta Cryst. D66, 213-221] have entrenched the paradigm that a `project' is concerned with solving one structure. This does not hold for SBLD, where many almost identical structures need to be solved and analysed quickly in one batch of work...
March 1, 2017: Acta Crystallographica. Section D, Structural Biology
https://www.readbyqxmd.com/read/28291761/proper-modelling-of-ligand-binding-requires-an-ensemble-of-bound-and-unbound-states
#3
Nicholas M Pearce, Tobias Krojer, Frank von Delft
Although noncovalent binding by small molecules cannot be assumed a priori to be stoichiometric in the crystal lattice, occupancy refinement of ligands is often avoided by convention. Occupancies tend to be set to unity, requiring the occupancy error to be modelled by the B factors, and residual weak density around the ligand is necessarily attributed to `disorder'. Where occupancy refinement is performed, the complementary, superposed unbound state is rarely modelled. Here, it is shown that superior accuracy is achieved by modelling the ligand as partially occupied and superposed on a ligand-free `ground-state' model...
March 1, 2017: Acta Crystallographica. Section D, Structural Biology
https://www.readbyqxmd.com/read/28291760/gentle-fast-and-effective-crystal-soaking-by-acoustic-dispensing
#4
Patrick M Collins, Jia Tsing Ng, Romain Talon, Karolina Nekrosiute, Tobias Krojer, Alice Douangamath, Jose Brandao-Neto, Nathan Wright, Nicholas M Pearce, Frank von Delft
The steady expansion in the capacity of modern beamlines for high-throughput data collection, enabled by increasing X-ray brightness, capacity of robotics and detector speeds, has pushed the bottleneck upstream towards sample preparation. Even in ligand-binding studies using crystal soaking, the experiment best able to exploit beamline capacity, a primary limitation is the need for gentle and nontrivial soaking regimens such as stepwise concentration increases, even for robust and well characterized crystals...
March 1, 2017: Acta Crystallographica. Section D, Structural Biology
https://www.readbyqxmd.com/read/28291759/the-use-of-small-molecule-structures-to-complement-protein-ligand-crystal-structures-in-drug-discovery
#5
Colin R Groom, Jason C Cole
Many ligand-discovery stories tell of the use of structures of protein-ligand complexes, but the contribution of structural chemistry is such a core part of finding and improving ligands that it is often overlooked. More than 800 000 crystal structures are available to the community through the Cambridge Structural Database (CSD). Individually, these structures can be of tremendous value and the collection of crystal structures is even more helpful. This article provides examples of how small-molecule crystal structures have been used to complement those of protein-ligand complexes to address challenges ranging from affinity, selectivity and bioavailability though to solubility...
March 1, 2017: Acta Crystallographica. Section D, Structural Biology
https://www.readbyqxmd.com/read/28291758/using-more-than-801%C3%A2-296-small-molecule-crystal-structures-to-aid-in-protein-structure-refinement-and-analysis
#6
Jason C Cole, Ilenia Giangreco, Colin R Groom
The Cambridge Structural Database (CSD) is the worldwide resource for the dissemination of all published three-dimensional structures of small-molecule organic and metal-organic compounds. This paper briefly describes how this collection of crystal structures can be used en masse in the context of macromolecular crystallography. Examples highlight how the CSD and associated software aid protein-ligand complex validation, and show how the CSD could be further used in the generation of geometrical restraints for protein structure refinement...
March 1, 2017: Acta Crystallographica. Section D, Structural Biology
https://www.readbyqxmd.com/read/28291757/checkmymetal-a-macromolecular-metal-binding-validation-tool
#7
Heping Zheng, David R Cooper, Przemyslaw J Porebski, Ivan G Shabalin, Katarzyna B Handing, Wladek Minor
Metals are essential in many biological processes, and metal ions are modeled in roughly 40% of the macromolecular structures in the Protein Data Bank (PDB). However, a significant fraction of these structures contain poorly modeled metal-binding sites. CheckMyMetal (CMM) is an easy-to-use metal-binding site validation server for macromolecules that is freely available at http://csgid.org/csgid/metal_sites. The CMM server can detect incorrect metal assignments as well as geometrical and other irregularities in the metal-binding sites...
March 1, 2017: Acta Crystallographica. Section D, Structural Biology
https://www.readbyqxmd.com/read/28291756/twilight-reloaded-the-peptide-experience
#8
Christian X Weichenberger, Edwin Pozharski, Bernhard Rupp
The de facto commoditization of biomolecular crystallography as a result of almost disruptive instrumentation automation and continuing improvement of software allows any sensibly trained structural biologist to conduct crystallographic studies of biomolecules with reasonably valid outcomes: that is, models based on properly interpreted electron density. Robust validation has led to major mistakes in the protein part of structure models becoming rare, but some depositions of protein-peptide complex structure models, which generally carry significant interest to the scientific community, still contain erroneous models of the bound peptide ligand...
March 1, 2017: Acta Crystallographica. Section D, Structural Biology
https://www.readbyqxmd.com/read/28291755/tools-for-ligand-validation-in-coot
#9
Paul Emsley
Coot is a molecular-graphics program primarily aimed at model building using X-ray data. Recently, tools for the manipulation and representation of ligands have been introduced. Here, these new tools for ligand validation and comparison are described. Ligands in the wwPDB have been scored by density-fit, distortion and atom-clash metrics. The distributions of these scores can be used to assess the relative merits of the particular ligand in the protein-ligand complex of interest by means of `sliders' akin to those now available for each accession code on the wwPDB websites...
March 1, 2017: Acta Crystallographica. Section D, Structural Biology
https://www.readbyqxmd.com/read/28291754/estimation-of-the-protein-ligand-interaction-energy-for-model-building-and-validation
#10
Daria A Beshnova, Joana Pereira, Victor S Lamzin
Macromolecular X-ray crystallography is one of the main experimental techniques to visualize protein-ligand interactions. The high complexity of the ligand universe, however, has delayed the development of efficient methods for the automated identification, fitting and validation of ligands in their electron-density clusters. The identification and fitting are primarily based on the density itself and do not take into account the protein environment, which is a step that is only taken during the validation of the proposed binding mode...
March 1, 2017: Acta Crystallographica. Section D, Structural Biology
https://www.readbyqxmd.com/read/28177314/glycoblocks-a-schematic-three-dimensional-representation-for-glycans-and-their-interactions
#11
Stuart McNicholas, Jon Agirre
The close-range interactions provided by covalently linked glycans are essential for the correct folding of glycoproteins and also play a pivotal role in recognition processes. Being able to visualise protein-glycan and glycan-glycan contacts in a clear way is thus of great importance for the understanding of these biological processes. In structural terms, glycosylation sugars glue the protein together via hydrogen bonds, whereas non-covalently bound glycans frequently harness additional stacking interactions...
February 1, 2017: Acta Crystallographica. Section D, Structural Biology
https://www.readbyqxmd.com/read/28177313/strategies-for-carbohydrate-model-building-refinement-and-validation
#12
Jon Agirre
Sugars are the most stereochemically intricate family of biomolecules and present substantial challenges to anyone trying to understand their nomenclature, reactions or branched structures. Current crystallographic programs provide an abstraction layer allowing inexpert structural biologists to build complete protein or nucleic acid model components automatically either from scratch or with little manual intervention. This is, however, still not generally true for sugars. The need for carbohydrate-specific building and validation tools has been highlighted a number of times in the past, concomitantly with the introduction of a new generation of experimental methods that have been ramping up the production of protein-sugar complexes and glycoproteins for the past decade...
February 1, 2017: Acta Crystallographica. Section D, Structural Biology
https://www.readbyqxmd.com/read/28177312/ligand-fitting-with-ccp4
#13
Robert A Nicholls
Crystal structures of protein-ligand complexes are often used to infer biology and inform structure-based drug discovery. Hence, it is important to build accurate, reliable models of ligands that give confidence in the interpretation of the respective protein-ligand complex. This paper discusses key stages in the ligand-fitting process, including ligand binding-site identification, ligand description and conformer generation, ligand fitting, refinement and subsequent validation. The CCP4 suite contains a number of software tools that facilitate this task: AceDRG for the creation of ligand descriptions and conformers, Lidia and JLigand for two-dimensional and three-dimensional ligand editing and visual analysis, Coot for density interpretation, ligand fitting, analysis and validation, and REFMAC5 for macromolecular refinement...
February 1, 2017: Acta Crystallographica. Section D, Structural Biology
https://www.readbyqxmd.com/read/28177311/polder-maps-improving-omit-maps-by-excluding-bulk-solvent
#14
Dorothee Liebschner, Pavel V Afonine, Nigel W Moriarty, Billy K Poon, Oleg V Sobolev, Thomas C Terwilliger, Paul D Adams
The crystallographic maps that are routinely used during the structure-solution workflow are almost always model-biased because model information is used for their calculation. As these maps are also used to validate the atomic models that result from model building and refinement, this constitutes an immediate problem: anything added to the model will manifest itself in the map and thus hinder the validation. OMIT maps are a common tool to verify the presence of atoms in the model. The simplest way to compute an OMIT map is to exclude the atoms in question from the structure, update the corresponding structure factors and compute a residual map...
February 1, 2017: Acta Crystallographica. Section D, Structural Biology
https://www.readbyqxmd.com/read/28177310/combining-x-ray-and-neutron-crystallography-with-spectroscopy
#15
Hanna Kwon, Oliver Smith, Emma Lloyd Raven, Peter C E Moody
X-ray protein crystallography has, through the determination of the three-dimensional structures of enzymes and their complexes, been essential to the understanding of biological chemistry. However, as X-rays are scattered by electrons, the technique has difficulty locating the presence and position of H atoms (and cannot locate H(+) ions), knowledge of which is often crucially important for the understanding of enzyme mechanism. Furthermore, X-ray irradiation, through photoelectronic effects, will perturb the redox state in the crystal...
February 1, 2017: Acta Crystallographica. Section D, Structural Biology
https://www.readbyqxmd.com/read/28177309/getting-the-chemistry-right-protonation-tautomers-and-the-importance-of-h-atoms-in-biological-chemistry
#16
Ben Bax, Chun Wa Chung, Colin Edge
There are more H atoms than any other type of atom in an X-ray crystal structure of a protein-ligand complex, but as H atoms only have one electron they diffract X-rays weakly and are `hard to see'. The positions of many H atoms can be inferred by our chemical knowledge, and such H atoms can be added with confidence in `riding positions'. For some chemical groups, however, there is more ambiguity over the possible hydrogen placements, for example hydroxyls and groups that can exist in multiple protonation states or tautomeric forms...
February 1, 2017: Acta Crystallographica. Section D, Structural Biology
https://www.readbyqxmd.com/read/28177308/an-editor-for-the-generation-and-customization-of-geometry-restraints
#17
Nigel W Moriarty, Eli J Draizen, Paul D Adams
Chemical restraints for use in macromolecular structure refinement are produced by a variety of methods, including a number of programs that use chemical information to generate the required bond, angle, dihedral, chiral and planar restraints. These programs help to automate the process and therefore minimize the errors that could otherwise occur if it were performed manually. Furthermore, restraint-dictionary generation programs can incorporate chemical and other prior knowledge to provide reasonable choices of types and values...
February 1, 2017: Acta Crystallographica. Section D, Structural Biology
https://www.readbyqxmd.com/read/28177307/acedrg-a-stereochemical-description-generator-for-ligands
#18
Fei Long, Robert A Nicholls, Paul Emsley, Saulius Graǽulis, Andrius Merkys, Antanas Vaitkus, Garib N Murshudov
The program AceDRG is designed for the derivation of stereochemical information about small molecules. It uses local chemical and topological environment-based atom typing to derive and organize bond lengths and angles from a small-molecule database: the Crystallography Open Database (COD). Information about the hybridization states of atoms, whether they belong to small rings (up to seven-membered rings), ring aromaticity and nearest-neighbour information is encoded in the atom types. All atoms from the COD have been classified according to the generated atom types...
February 1, 2017: Acta Crystallographica. Section D, Structural Biology
https://www.readbyqxmd.com/read/28177306/validation-and-extraction-of-molecular-geometry-information-from-small-molecule-databases
#19
Fei Long, Robert A Nicholls, Paul Emsley, Saulius Graǽulis, Andrius Merkys, Antanas Vaitkus, Garib N Murshudov
A freely available small-molecule structure database, the Crystallography Open Database (COD), is used for the extraction of molecular-geometry information on small-molecule compounds. The results are used for the generation of new ligand descriptions, which are subsequently used by macromolecular model-building and structure-refinement software. To increase the reliability of the derived data, and therefore the new ligand descriptions, the entries from this database were subjected to very strict validation...
February 1, 2017: Acta Crystallographica. Section D, Structural Biology
https://www.readbyqxmd.com/read/28177305/keep-it-together-restraints-in-crystallographic-refinement-of-macromolecule-ligand-complexes
#20
Roberto A Steiner, Julie A Tucker
A short introduction is provided to the concept of restraints in macromolecular crystallographic refinement. A typical ligand restraint-generation process is then described, covering types of input, the methodology and the mechanics behind the software in general terms, how this has evolved over recent years and what to look for in the output. Finally, the currently available restraint-generation software is compared, concluding with some thoughts for the future.
February 1, 2017: Acta Crystallographica. Section D, Structural Biology
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