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Xplor-NIH is a highly sophisticated and flexible biomolecular structure determination program which includes an interface to the legacy X-PLOR program. The main developers are Charles Schwieters and Marius Clore of the National Institutes of Health. Xplor-NIH is based on a C++ framework with an extensive Python interface enabling very powerful and easy scripting of complex structure determination and refinement protocols. Restraints derived from all current solution and many solid state nuclear magnetic resonance (NMR) and X-ray scattering experiments can be accommodated during structure calculations. Extensive facilities are also available for many types of ensemble calculations where the experimental data cannot be accounted for by a unique structure. Many of the structure calculation protocols involve the use of simulated annealing designed to overcome local minima on the path of the global minimum region of the target function. These calculations can be carried out using any combination of Cartesian, torsion angle and rigid body dynamics and minimization. Currently Xplor-NIH is the most versatile, comprehensive and widely used structure determination/refinement package in NMR structure determination.
The Karplus equation, named after Martin Karplus, describes the correlation between 3J-coupling constants and dihedral torsion angles in nuclear magnetic resonance spectroscopy:
The residual dipolar coupling between two spins in a molecule occurs if the molecules in solution exhibit a partial alignment leading to an incomplete averaging of spatially anisotropic dipolar couplings.
The Journal of Biomolecular NMR publishes research on technical developments and innovative applications of nuclear magnetic resonance spectroscopy for the study of structure and dynamic properties of biopolymers in solution, liquid crystals, solids and mixed environments. Some of the main topics include experimental and computational approaches for the determination of three-dimensional structures of proteins and nucleic acids, advancements in the automated analysis of NMR spectra, and new methods to probe and interpret molecular motions.
In biomolecular structure, CING stands for the Common Interface for NMR structure Generation and is known for structure and NMR data validation.
The Re-referenced Protein Chemical shift Database (RefDB) is an NMR spectroscopy database of carefully corrected or re-referenced chemical shifts, derived from the BioMagResBank (BMRB). The database was assembled by using a structure-based chemical shift calculation program to calculate expected protein (1)H, (13)C and (15)N chemical shifts from X-ray or NMR coordinate data of previously assigned proteins reported in the BMRB. The comparison is automatically performed by a program called SHIFTCOR. The RefDB database currently provides reference-corrected chemical shift data on more than 2000 assigned peptides and proteins. Data from the database indicates that nearly 25% of BMRB entries with (13)C protein assignments and 27% of BMRB entries with (15)N protein assignments require significant chemical shift reference readjustments. Additionally, nearly 40% of protein entries deposited in the BioMagResBank appear to have at least one assignment error. Users may download, search or browse the database through a number of methods available through the RefDB website. RefDB provides a standard chemical shift resource for biomolecular NMR spectroscopists, wishing to derive or compute chemical shift trends in peptides and proteins.
SHIFTCOR is a freely available web server as well as a stand-alone computer program for protein chemical shift re-referencing. Chemical shift referencing is a particularly widespread problem in biomolecular NMR with up to 25% of existing NMR chemical shift assignments being improperly referenced. Some of these referencing problems can lead to systematic errors of between 1.0 to 2.5 ppm. Errors of this magnitude can play havoc with any attempt to compare assignments between proteins or to structurally interpret chemical shifts. Identifying which proteins are mis-assigned or improperly referenced can be challenging, as can correcting the errors once they are found. The SHIFTCOR program was designed to assist with identifying and fixing these chemical shift referencing problems. Specifically it compares, identifies, corrects and re-references 1H, 13C and 15N backbone chemical shifts of peptides and proteins by comparing the observed chemical shifts with the predicted chemical shifts derived from the 3D structure of the protein(s) of interest [1]. The predicted chemical shifts are calculated using the ShiftX program. The SHIFTCOR program was originally used to construct a database of properly re-referenced protein chemical shift assignments called RefDB. RefDB is a web-accessible database of more than 2000 correctly referenced protein chemical shift assignments. While originally available as a stand-alone program only, SHIFTCOR has since been released for general use as a web server.
Random coil index (RCI) predicts protein flexibility by calculating an inverse weighted average of backbone secondary chemical shifts and predicting values of model-free order parameters as well as per-residue RMSD of NMR and molecular dynamics ensembles from this parameter.
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, come from structural biology experiments such as x-ray crystallography or nuclear magnetic resonance (NMR). The validation has three aspects: 1) checking on the validity of the thousands to millions of measurements in the experiment; 2) checking how consistent the atomic model is with those experimental data; and 3) checking consistency of the model with known physical and chemical properties.
GeNMR method is the first fully automated template-based method of protein structure determination that utilizes both NMR chemical shifts and NOE -based distance restraints.
Protein Structure Evaluation Suite & Server (PROSESS) is a freely available web server for protein structure validation. It has been designed at the University of Alberta to assist with the process of evaluating and validating protein structures solved by NMR spectroscopy.
CS23D is a web server to generate 3D structural models from NMR chemical shifts. CS23D combines maximal fragment assembly with chemical shift threading, de novo structure generation, chemical shift-based torsion angle prediction, and chemical shift refinement. CS23D makes use of RefDB and ShiftX.
The chemical shift index or CSI is a widely employed technique in protein nuclear magnetic resonance spectroscopy that can be used to display and identify the location as well as the type of protein secondary structure found in proteins using only backbone chemical shift data The technique was invented by David S. Wishart in 1992 for analyzing 1Hα chemical shifts and then later extended by him in 1994 to incorporate 13C backbone shifts. The original CSI method makes use of the fact that 1Hα chemical shifts of amino acid residues in helices tends to be shifted upfield relative to their random coil values and downfield in beta strands. Similar kinds of upfield and downfield trends are also detectable in backbone 13C chemical shifts.
Protein chemical shift prediction is a branch of biomolecular nuclear magnetic resonance spectroscopy that aims to accurately calculate protein chemical shifts from protein coordinates. Protein chemical shift prediction was first attempted in the late 1960s using semi-empirical methods applied to protein structures solved by X-ray crystallography. Since that time protein chemical shift prediction has evolved to employ much more sophisticated approaches including quantum mechanics, machine learning and empirically derived chemical shift hypersurfaces. The most recently developed methods exhibit remarkable precision and accuracy.
Resolution by Proxy (ResProx) is a method for assessing the equivalent X-ray resolution of NMR-derived protein structures. ResProx calculates resolution from coordinate data rather than from electron density or other experimental inputs. This makes it possible to calculate the resolution of a structure regardless of how it was solved. ResProx was originally designed to serve as a simple, single-number evaluation that allows straightforward comparison between the quality/resolution of X-ray structures and the quality of a given NMR structure. However, it can also be used to assess the reliability of an experimentally reported X-ray structure resolution, to evaluate protein structures solved by unconventional or hybrid means and to identify fraudulent structures deposited in the PDB. ResProx incorporates more than 25 different structural features to determine a single resolution-like value. ResProx values are reported in Angstroms. Tests on thousands of X-ray structures show that ResProx values match very closely to resolution values reported by X-ray crystallographers. Resolution-by-proxy values can be calculated for newly determined protein structures using a freely accessible ResProx web server. This server accepts protein coordinate data and generates a resolution estimate for that input structure.
Probabilistic Approach for protein NMR Assignment Validation (PANAV) is a freely available stand-alone program that is used for protein chemical shift re-referencing. Chemical shift referencing is a problem in protein nuclear magnetic resonance as >20% of reported NMR chemical shift assignments appear to be improperly referenced. For certain nuclei these referencing issues can cause systematic chemical shift errors of between 1.0 and 2.5 ppm. Chemical shift errors of this magnitude often make it very difficult to compare NMR chemical shift assignments between proteins. It also makes it very hard to structurally interpret chemical shifts. Unlike most other chemical shift re-referencing tools PANAV employs a structure-independent protocol. That is, with PANAV there is no need to know the structure of the protein in advance of correcting any chemical shift referencing errors. This makes PANAV particularly useful for NMR studies involving novel or newly assigned proteins, where the structure has yet to be determined. Indeed, this scenario represents the vast majority of assignment cases in biomolecular NMR. PANAV uses residue-specific and secondary structure-specific chemical shift distributions that were calculated over short fragments of correctly referenced proteins to identify mis-assigned resonances. More specifically, PANAV compares the initial chemical shift assignments to the expected chemical shifts based on their local sequence and expected/predicted secondary structure. In this way, PANAV is able to identify and re-reference mis-referenced chemical shift assignments. PANAV can also identify potentially mis-assigned resonances as well. PANAV has been extensively tested and compared against a large number of existing re-referencing or mis-assignment detection programs. These assessments indicate that PANAV is equal to or superior to existing approaches.
Volume, Area, Dihedral Angle Reporter (VADAR) is a freely available protein structure validation web server that was developed as a collaboration between Dr. Brian Sykes and Dr. David Wishart at the University of Alberta. VADAR consists of over 15 different algorithms and programs for assessing and validating peptide and protein structures from their PDB coordinate data. VADAR is capable of determining secondary structure, identifying and classifying six different types of beta turns, determining and calculating the strength of C=O -- N-H hydrogen bonds, calculating residue-specific accessible surface areas (ASA), calculating residue volumes, determining backbone and side chain torsion angles, assessing local structure quality, evaluating global structure quality, and identifying residue "outliers". The results have been validated through extensive comparison to published data and careful visual inspection. VADAR produces both text and graphical output with most of the quantitative data presented in easily viewed tables. In particular, VADAR's output is presented in a vertical, tabular format with most of the sequence data, residue numbering and any other calculated property or feature presented from top to bottom, rather than from left to right.
ShiftX is a freely available web server for rapidly calculating protein chemical shifts from protein X-ray coordinates. Protein chemical shift prediction is particularly useful in verifying protein chemical shift assignments, adjusting mis-referenced chemical shifts, refining NMR protein structures and assisting with the NMR assignment of unassigned proteins that have either had their structures determined by X-ray or NMR methods.
Professor Ramakrishna Vijayacharya Hosur is an Indian biophysical scientist, known for his expertise in the areas of nuclear magnetic resonance and molecular biophysics. The Government of India honoured him, in 2014, by awarding him the Padma Shri, the fourth highest civilian award, for his contributions to the fields of science and technology.
David S. Wishart is a Canadian researcher in metabolomics and a Distinguished University Professor in the Department of Biological Sciences and the Department of Computing Science at the University of Alberta. Wishart also holds cross appointments in the Faculty of Pharmacy and Pharmaceutical Sciences and the Department of Laboratory Medicine and Pathology in the Faculty of Medicine and Dentistry. Additionally, Wishart holds a joint appointment in metabolomics at the Pacific Northwest National Laboratory in Richland, Washington. Wishart is well known for his pioneering contributions to the fields of protein NMR spectroscopy, bioinformatics, cheminformatics and metabolomics. In 2011, Wishart founded the Metabolomics Innovation Centre (TMIC), which is Canada's national metabolomics laboratory.
References
- 1 2 Berjanskii, MV; Neal S; Wishart DS (2006). "PREDITOR: a web server for predicting protein torsion angle restraints". Nucleic Acids Res. 34 (Web Server issue): W63-9. doi:10.1093/nar/gkl341. PMC 1538894 . PMID 16845087.
- 1 2 3 Wishart, DS (2011). "Interpreting protein chemical shift data". Prog. Nucl. Magn. Reson. Spectrosc. 58 (1–2): 62–87. doi:10.1016/j.pnmrs.2010.07.004. PMID 21241884.
- ↑ Karplus, M (1963). "Vicinal Proton Coupling in Nuclear Magnetic Resonance". J. Am. Chem. Soc. 85 (18): 2870–2871. doi:10.1021/ja00901a059.
- ↑ Cornilescu, G; Delaglio G; Bax A. (1999). "Protein backbone angle restraints from searching a database for chemical shift and sequence homology". J. Biomol. NMR. 13 (3): 289–302. doi:10.1023/A:1008392405740. PMID 10212987. S2CID 4991394.
- ↑ Shen, Y; Delaglio F; Cornilescu G; Bax A. (2009). "TALOS+: a hybrid method for predicting protein backbone torsion angles from NMR chemical shifts". J. Biomol. NMR. 44 (4): 213–223. doi:10.1007/s10858-009-9333-z. PMC 2726990 . PMID 19548092.
- ↑ Cheung, MS; Maguire ML; Stevens TJ; Broadhurst RW. (Feb 2010). "DANGLE: A Bayesian inferential method for predicting protein backbone dihedral angles and secondary structure". J Magn Reson. 202 (2): 223–33. Bibcode:2010JMagR.202..223C. doi:10.1016/j.jmr.2009.11.008. PMID 20015671.