Automated structure determination

The core of the current version of Candid is implemented in standard Fortran-77 and has been built upon the data structures and into the framework of the user interface of the program Dyana. The standard schedule and parameters for a complete automated structure determination with Candid and Dyana are specified in a script written in the interpreted command language Inclan that gives the user high flexibility in the way automated structure determination is performed without the need to modify the compiled core part of Candid [26]. 

An Automated Structure Determination System for MS/MS Data", 190th ACS National Meeting, Chicago, IL (1985). 

Structure-based drug discovery involves determination of many cocrystal structures with different ligands bound to the same target protein. In such cases, where the structure of the protein is well known, automated structure determination procedures rely on molecular replacement to supply the... 

Gronwald, W. and Kalbitzer, H. R. (2004). Automated structure determination of proteins by NMR spectroscopy. Prog. Nucl. Magn. Reson. Spectrosc. 44, 33-96. 

In addition to the in vitro studies of well-defined systems that have been discussed here, NMR spectroscopy can also be applied to living systems or complex substance mixtures (146). This broad applicability is an advantage of NMR spectroscopy over X-ray crystallography. Early in vivo NMR studies that mostly identify small metabolite molecules by P or H ID experiments have led to different applications. In-cell NMR uses isotopic labeling combined with two or higher dimensional NMR experiments for structural studies of the phosphorylation state of a given protein in the cellular environment or of intrinsically unstructured proteins. In-cell NMR applications in prokaryotic systems cover structural and functional studies (i.e., protein-protein interactions, protein dynamics, automated structure determination, and de novo resonance assignments (147-149)). 

Guntert P (2009) Automated structure determination from NMR spectra. Fur Biophys 138 129-143... 

Takeda M, Ikeya T, Giintert P, Kainosho M (2007) Automated structure determination of proteins with the SAIL-FLYA NMR method. Nat Protoc 2 2896-2902... 

R 119 J.P. Frahm, P. Dechent, J. Baudewig and K.D. Merboldt, Advances in Functional MRI of the Human Brain , p. 1 R 120 W. Gronwald and H.R. Kalbitzer, Automated Structure Determination of Proteins by NMR Spectroscopy , p. 33 R 121 P. Permi and A. Annila, Coherence Transfer in Proteins , p. 97 R 122 R.A. Atkinson and B. Kieffer, The Role of Protein Motions in Molecular Recognition Insights from Heteronuclear NMR Relaxation Measurements , p. 141... 

Now that automated diffractometers and sophisticated computer data-reduction systems have become routinely used, the task involved in conducting an X-ray crystal-structure examination has been enormously simplified. As a result, the number of structures determined each year by crystallography has escalated dramatically. The logistics of maintaining this series in the original form would now entail such stupendous demands on our space that a volume of Advances could be completely occupied by this one article alone. As the original purpose of this series... 

Giintert P, Braun W, Billeter W, Wiithrich K. Automated stereospecific 1H NMR assignments and their impact on the precision of protein structure determinations in solution. J Am Chem Soc 1989 111 3997-4004. 

Due to the statistical nature of split synthesis, an average 20 beads per member must be used to ensure that all library members are prepared successfully This requirement results in increased reagent consumption and extra effort in screening and structural determination. One of the most powerful aspects of the rf memory chips is the ability to perform automated sorting of library members. Thus a complete library may be prepared with each member synthesized only once... 

It has been recognized that many of the time-consuming interactive tasks carried out by an expert during the process of spectral analysis could be done more efficiently by automated computational systems [6]. Over the past few years, this potential has been realized to some degree. Today automated methods for NMR structure determination are playing a more and more prominent role and can be expected to largely supersede the conventional manual approaches to solving three-dimensional protein structures in solution. 

Fig. 2.3 Flowchart of NMR structure determination using the Candid method for automated NOE cross peak assignment.

A large number of methods have been established to address the gathering structural information. Some are based on the biophysical properties of the studied molecules, others on their chemical composition. A most important final step is to properly relate the structural knowledge to the inferred functionality. Currently, X-ray crystallography is the predominant technique for 3D structure determination, owing to its now practical simplicity, ease, and high level of automation as compared to the formerly tedious and time... 

Brunzelle, J. S., Shafaee, P, Yang, X., Weigand, S., Ren, Z. and Anderson, W. F. (2003). Automated crystallographic system for high-throughput protein structure determination. Acta Crystallogr. D 59,1138-1144. 

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