Structure-related Information Research Articles

MutLBSgeneDB: mutated ligand binding site gene DataBase.

Mutations at the ligand binding sites (LBSs) can influence protein structure stability, binding affinity with small molecules, and drug resistance in cancer patients. Our recent analysis revealed that ligand binding residues had a significantly higher mutation rate than other parts of the protein. Here, we built mutLBSgeneDB (mutated Ligand Binding Site gene DataBase) available at http://zhaobioinfo.org/mutLBSgeneDB. We collected and curated over 2300 genes (mutLBSgenes) having ∼12 000 somatic mutations at ∼10 000 LBSs across 16 cancer types and selected 744 drug targetable genes (targetable_mutLBSgenes) by incorporating kinases, transcription factors, pharmacological genes, and cancer driver genes. We analyzed LBS mutation information, differential gene expression network, drug response correlation with gene expression, and protein stability changes for all mutLBSgenes using integrated genetic, genomic, transcriptomic, proteomic, network and functional information. We calculated and compared the binding affinities of 20 carefully selected genes with their drugs in wild type and mutant forms. mutLBSgeneDB provides a user-friendly web interface for searching and browsing through seven categories of annotations: Gene summary, Mutated information, Protein structure related information, Differential gene expression and gene-gene network, Phenotype information, Pharmacological information, and Conservation information. mutLBSgeneDB provides a useful resource for functional genomics, protein structure, drug and disease research communities.

Ontology-based image navigation: exploring 3.0-T MR neurography of the brachial plexus using AIM and RadLex.

Disorders of the peripheral nervous system have traditionally been evaluated using clinical history, physical examination, and electrodiagnostic testing. In selected cases, imaging modalities such as magnetic resonance (MR) neurography may help further localize or characterize abnormalities associated with peripheral neuropathies, and the clinical importance of such techniques is increasing. However, MR image interpretation with respect to peripheral nerve anatomy and disease often presents a diagnostic challenge because the relevant knowledge base remains relatively specialized. Using the radiology knowledge resource RadLex®, a series of RadLex queries, the Annotation and Image Markup standard for image annotation, and a Web services-based software architecture, the authors developed an application that allows ontology-assisted image navigation. The application provides an image browsing interface, allowing users to visually inspect the imaging appearance of anatomic structures. By interacting directly with the images, users can access additional structure-related information that is derived from RadLex (eg, muscle innervation, muscle attachment sites). These data also serve as conceptual links to navigate from one portion of the imaging atlas to another. With 3.0-T MR neurography of the brachial plexus as the initial area of interest, the resulting application provides support to radiologists in the image interpretation process by allowing efficient exploration of the MR imaging appearance of relevant nerve segments, muscles, bone structures, vascular landmarks, anatomic spaces, and entrapment sites, and the investigation of neuromuscular relationships.

Robust speech recognition using harmonic features

In this study, the authors propose a speech recognition system using harmonic structure related information to detect harmonic features in noisy environment. The proposed algorithm first extracts the harmonic components contained inside the speech signals using sine function convolution. By setting the frequency of the sine function as equal to the fundamental frequency of speech signals, harmonic components can be extracted out. The reconstructed signal obtained by summing up the extracted harmonic components is found to have a high degree of correlation with the original signal. The extracted frame energy measure of the harmonic components has been further processed to become dynamic harmonic features and then used together with the European Telecommunications Standards Institute (ETSI) front-end processed mel-frequency cepstral coefficients (MFCC) feature or the perceptual linear prediction (PLP) feature in the speech recognition system. The proposed enhanced speech recognition system shows a better recognition rate over the ETSI front-end processed MFCC (or PLP)-based speech recognition system.

Baseline-free real-time assessment of structural changes

This article addresses the subject of data-driven structural health monitoring and proposes a real-time strategy to conduct structural assessment without the need to define a baseline period, in which the monitored structure is assumed healthy and unchanged. Independence from baseline references is achieved using unsupervised discrimination machine-learning methods, widely known as clustering algorithms, which are able to find groups in data relying only on their intrinsic features and without requiring prior knowledge as input. Real-time capability is based on the definition of symbolic data, which allows describing large amounts of information without loss of generality or structural-related information. The efficiency of the proposed methodology is illustrated using an experimental case study in which structural changes were imposed to a suspended bridge during an extensive rehabilitation programme. A single-value novelty index capable of describing multi-sensor data is proposed, and its effectiveness in identifying structural changes in real time, using outlier analysis, is discussed.

PolySac3DB: an annotated data base of 3 dimensional structures of polysaccharides

Polysaccharides are ubiquitously present in the living world. Their structural versatility makes them important and interesting components in numerous biological and technological processes ranging from structural stabilization to a variety of immunologically important molecular recognition events. The knowledge of polysaccharide three-dimensional (3D) structure is important in studying carbohydrate-mediated host-pathogen interactions, interactions with other bio-macromolecules, drug design and vaccine development as well as material science applications or production of bio-ethanol. PolySac3DB is an annotated database that contains the 3D structural information of 157 polysaccharide entries that have been collected from an extensive screening of scientific literature. They have been systematically organized using standard names in the field of carbohydrate research into 18 categories representing polysaccharide families. Structure-related information includes the saccharides making up the repeat unit(s) and their glycosidic linkages, the expanded 3D representation of the repeat unit, unit cell dimensions and space group, helix type, diffraction diagram(s) (when applicable), experimental and/or simulation methods used for structure description, link to the abstract of the publication, reference and the atomic coordinate files for visualization and download. The database is accompanied by a user-friendly graphical user interface (GUI). It features interactive displays of polysaccharide structures and customized search options for beginners and experts, respectively. The site also serves as an information portal for polysaccharide structure determination techniques. The web-interface also references external links where other carbohydrate-related resources are available. PolySac3DB is established to maintain information on the detailed 3D structures of polysaccharides. All the data and features are available via the web-interface utilizing the search engine and can be accessed at http://polysac3db.cermav.cnrs.fr .

RMol: a toolset for transforming SD/Molfile structure information into R objects

BackgroundThe graph-theoretical analysis of molecular networks has a long tradition in chemoinformatics. As demonstrated frequently, a well designed format to encode chemical structures and structure-related information of organic compounds is the Molfile format. But when it comes to use modern programming languages for statistical data analysis in Bio- and Chemoinformatics, R as one of the most powerful free languages lacks tools to process Molfile data collections and import molecular network data into R.ResultsWe design an R object which allows a lossless information mapping of structural information from Molfiles into R objects. This provides the basis to use the RMol object as an anchor for connecting Molfile data collections with R libraries for analyzing graphs. Associated with the RMol objects, a set of R functions completes the toolset to organize, describe and manipulate the converted data sets. Further, we bypass R-typical limits for manipulating large data sets by storing R objects in bz-compressed serialized files instead of employing RData files.ConclusionsBy design, RMol is a R toolset without dependencies to other libraries or programming languages. It is useful to integrate into pipelines for serialized batch analysis by using network data and, therefore, helps to process sdf-data sets in R efficiently. It is freely available under the BSD licence. The script source can be downloaded from http://sourceforge.net/p/rmol-toolset.

PolySac3DB: an annotated data base of 3 dimensional structures of polysaccharides

BackgroundPolysaccharides are ubiquitously present in the living world. Their structural versatility makes them important and interesting components in numerous biological and technological processes ranging from structural stabilization to a variety of immunologically important molecular recognition events. The knowledge of polysaccharide three-dimensional (3D) structure is important in studying carbohydrate-mediated host-pathogen interactions, interactions with other bio-macromolecules, drug design and vaccine development as well as material science applications or production of bio-ethanol.DescriptionPolySac3DB is an annotated database that contains the 3D structural information of 157 polysaccharide entries that have been collected from an extensive screening of scientific literature. They have been systematically organized using standard names in the field of carbohydrate research into 18 categories representing polysaccharide families. Structure-related information includes the saccharides making up the repeat unit(s) and their glycosidic linkages, the expanded 3D representation of the repeat unit, unit cell dimensions and space group, helix type, diffraction diagram(s) (when applicable), experimental and/or simulation methods used for structure description, link to the abstract of the publication, reference and the atomic coordinate files for visualization and download. The database is accompanied by a user-friendly graphical user interface (GUI). It features interactive displays of polysaccharide structures and customized search options for beginners and experts, respectively. The site also serves as an information portal for polysaccharide structure determination techniques. The web-interface also references external links where other carbohydrate-related resources are available.ConclusionPolySac3DB is established to maintain information on the detailed 3D structures of polysaccharides. All the data and features are available via the web-interface utilizing the search engine and can be accessed at http://polysac3db.cermav.cnrs.fr.

Analysis of free oligosaccharides by negative-ion electrospray ion trap tandem mass spectrometry in the presence of H 2PO 4− anions

Positive-ion mode-tandem mass spectrometry has become a frequently used tool for the structural analysis of neutral saccharides. However, their behavior in the positive-ion mode is not always adequate for oligosaccharides structure identification. Thus, fragmentation of [M−H] − or anion adducts produced in the negative-ion mode MS, offers an alternative as their fragmentation patterns provide more structure-related information. The main drawback of the negative-ion mode MS of neutral saccharides is the low sensitivity. In this study, we tested several salts as additives of saccharide samples for sensitivity improvement in the negative-ion mode. The addition of NH 4H 2PO 4 forming [M+H 2PO 4] − seemed to be the best choice due to a relatively high sensitivity increase in both MS and MS n spectra. Moreover, the salt content could be monitored by the presence of phosphate clusters at high salt-saccharide ratios and salting effects could thereby be avoided. Compared to other tested salts, fragmentation spectra of phosphate adducts also contained additional fragments which improved both the certainty and accuracy of the structural identification. The NH 4H 2PO 4 addition was applied to collected fractions from brewing samples separation where oligosaccharides derived from starch, fructans and oligosaccharides of the raffinose family were detected and identified. Our suggested approach is a promising alternative to a more common mass spectrometric analysis of neutral oligosaccharides in the positive-ion mode or chloride or nitrate additions in the negative-ion mode.

A multi-step NMR screen for the identification and evaluation of chemical leads for drug discovery.

A multi-step NMR based screening assay is described for identifying and evaluating chemical leads for their ability to bind a target protein. The multi-step NMR assay provides structure-related information while being an integral part of a structure based drug discovery and design program. The fundamental principle of the multi-step NMR assay is to combine distinct 1D and 2D NMR techniques, in such a manner, that the inherent strengths and weakness associated with each technique is complementary to each other in the screen. By taking advantage of the combined strengths of 1D and 2D NMR experiments, it is possible to minimize protein requirements and experiment time and differentiate between non-specific and stoichiometric binders while being able to verify ligand binding, determine a semi-quantitative dissociation constant, identify the ligand binding site and rapidly determine a protein-ligand co-structure. Furthermore, the quality and physical behavior of the ligand is readily evaluated to determine its appropriateness as a chemical lead. The utility of the multi-step NMR assay is demonstrated with the use of PrgI from Salmonella typhimurium and human serum albumin (HSA) as target proteins.

Modeling activated states of GPCRs: the rhodopsin template.

Activation of G Protein-Coupled Receptors (GPCRs) is an allosteric mechanism triggered by ligand binding and resulting in conformational changes transduced by the transmembrane domain. Models of the activated forms of GPCRs have become increasingly necessary for the development of a clear understanding of signal propagation into the cell. Experimental evidence points to a multiplicity of conformations related to the activation of the receptor, rendered important physiologically by the suggestion that different conformations may be responsible for coupling to different signaling pathways. In contrast to the inactive state of rhodopsin (RHO) for which several high quality X-ray structures are available, the structure-related information for the active states of rhodopsin and all other GPCRs is indirect. We have collected and stored such information in a repository we maintain for activation-specific structural data available for rhodopsin-like GPCRs, http://www.physiology.med.cornell.edu/GPCRactivation/gpcrindex.html . Using these data as structural constraints, we have applied Simulated Annealing Molecular Dynamics to construct a number of different active state models of RHO starting from the known inactive structure. The common features of the models indicate that TM3 and TM5 play an important role in activation, in addition to the well-established rearrangement of TM6. Some of the structural changes observed in these models occur in regions that were not involved in the constraints, and have not been previously tested experimentally; they emerge as interesting candidates for further experimental exploration of the conformational space of activated GPCRs. We show that none of the normal modes calculated from the inactive structure has a dominant contribution along the path of conformational rearrangement from inactive to the active forms of RHO in the models. This result may differentiate rhodopsin from other GPCRs, and the reasons for this difference are discussed in the context of the structural properties and the physiological function of the protein.

도로교의 GIS 기반 지진피해평가체계 구축을 위한 데이터베이스 설계

본 연구에서는 도로교의 지진피해평가체계를 구축하기 위해 필요한 정보항목들을 정의하고 우리나라 실정에 맞는 데이터 베이스 구축방법을 제시하였다. 도로교 지진피해평가를 위한 정보요소는 크게 구조물 관련 정보와 위치관련 정보로 구분하였다. 구조물 관련정보는 도로망에 위치한 교량의 지진피해를 예측하는데 필요한 도로교의 취약도 곡선 정보항목으로 구성하였다. 위치관련 정보항목인 도로망의 데이터구조는 상세한 교차로 모델링이 가능하도록 기존의 GIS 데이터구조를 보다 세분화하여 정의하였다. 고속도로망에 위치한 110개의 교량을 대상으로 시범 시스템을 개발하였으며, 제시된 데이터베이스 구축 방법은 도로망의 신속한 피해복구를 위한 의사결정 지원체계 구축에 효과적으로 활용이 가능함을 보였다. The essential information elements for the Earthquake Damage Evaluation System (EDES) of highway bridges are defined in this study, and a database construction method, which fits the circumstances of Korea, is proposed. The information elements for the EDES of highway bridges are categorized in two groups: structure related information, location related information. The structure related information is composed of the fragility curve information which is necessary for earthquake damage evaluation of highway bridges. The data structure of road network, which represents the location related information, is defined in more detail than the existing GIS-based data structure of road network for modeling of junctions. A pilot GIS-based EDES subjected to 110 bridges on expressway in Korea is developed, and it is verified that the proposed database construction method for the EDES can be used to develop a decision making system for quick retrofitting of the seismic damages of highway bridges and road network.

Detectability enhancement of spectrophotometric detectors by the use of multidimensional gas chromatography

AbstractMultidimensional gas chromatography (2D GC) is demonstrated as a way to improve limits of detectability of spectrophotometric detectors. UV and IR detectors are generally less sensitive than mass spectrometers or other GC detectors. This has placed some limitations on the useful capabilities provided by spectrophotometric detectors, such as the ability to provide structure‐related information for a particular analyte. In this paper, we report results from interfacing a 2D GC instrument to a UV detector. Symmetry factor and the ratio of retention time divided by peak width did not show deterioration of the quality of chromatography when a megabore column was used with this detector. Furthermore, an increase in the limits of detectability over that attainable in a single‐column system was realized by using the 2D GC system. However, the low flow (1 mL/min) imposed by the use of a microbore column (250 μm ID) caused significant tailing when the UV detector was used.

Transfer of Structure-Related and Arbitrary Information in Analogical Reasoning

Analogies can aid learners in understanding a new domain, yet misunderstandings may occur if they are applied too broadly. The present studies examined transfer of two types of information. Participants read analogical source and target stories. The source stories in Experiments 1–3 included two additional sentences that could be transferred to the target. One of the sentences was related to the analogical structure, while the other was more arbitrary. Participants transferred the structure-related information significantly more often than the arbitrary information both when retrieving source stories from memory (Experiment 1) and when having access to them (Experiment 2). Participants in Experiment 3 were explicitly encouraged to consider both types of information for transfer. Results showed the structure-related information was selected as the appropriate transfer sentence. Experiment 4 examined the possibility that reading both types of information in the source stories influenced transfer rates. Some participants received stories with both the structure-related and arbitrary information while others received stories with only one type of information. Again, participants transferred the structure-related information to a greater extent than the arbitrary information. Furthermore, no differences in transfer were found between participants who received both types of information in the source domain versus those who received only one type of information. Overall, the results of the studies provide evidence that learners will preferentially transfer information related to the shared analogical structure.

MS/NMR: a structure-based approach for discovering protein ligands and for drug design by coupling size exclusion chromatography, mass spectrometry, and nuclear magnetic resonance spectroscopy.

A protocol is described for rapidly screening small organic molecules for their ability to bind a target protein while obtaining structure-related information as part of a structure-based drug discovery and design program. The methodology takes advantage of and combines the inherent strengths of size exclusion gel chromatography, mass spectrometry, and NMR to identify bound complexes in a relatively universal high-throughput screening approach. Size exclusion gel chromatography in the spin column format provides the high-speed separation of a protein-ligand complex from free ligands. The spin column eluent is then analyzed under denaturing conditions by electrospray ionization mass spectrometry (MS) for the presence of small molecular weight compounds formerly bound to the protein. Hits identified by MS are then individually assayed by chemical shift perturbations in a 2D 1H-15N HSQC NMR spectrum to verify specific interactions of the compound with the protein and identification of the binding site on the protein. The utility of the MS/NMR assay is demonstrated with the use of the catalytic fragment of human fibroblast collagenase (MMP-1) as a target protein and the screening of a library consisting of approximately 32 000 compounds for the identification of molecules that exhibit specific binding to the RGS4 protein.

Non-homology knowledge-based prediction of the papain prosegment folding pattern: a description of plausible folding and activation mechanisms

A detailed knowledge of three-dimensional conformations is necessary in order to understand the close relationship between protein structure and function. Among current methodologies, homology modeling is an important tool for obtaining reliable geometries and it provides a direct alternative to X-ray or NMR techniques. In contrast, predictive methods with no three-dimensional template (non-homology) still require further validation and systematization. Here, we present a non-homology knowledge-based strategy for the structural prediction of the proregion of a cysteine proteinase zymogen. This method analyzes individual sequences and multiple alignments of homologous sequences, making use of different published algorithms and incorporating all available structure-related information to obtain improved predictions. Our strategy yielded acceptable secondary structure and general three-dimensional assignments when compared with crystallographic data from homologous proteins. We discuss our successes and failures as a contribution to non-homology prediction development. In addition, based on the information analyzed and generated in this work, we propose plausible folding and activation mechanisms for thiol-proteinase precursors that attempt to shed light on the molecular basis of prosegment functions.

Modeling formalisms for dynamic structure systems

We present a new concept for a system network to represent systems that are able to undergo structural change. Change in structure is defined in general terms, and includes the addition and deletion of systems and the modification of the relations among components. The structure of a system network is stored in the network executive. Any change in structure-related information is mapped into modifications in the network structure. Based on these concepts, we derive three new system specifications that provide a shorthand notation to specify classes of dynamic structure systems. These new formalisms are: dynamic structure discrete time system, dynamic structure differential equation specified systems, and dynamic structure discrete event system specification. We demonstrate that these formalisms are closed under coupling, making hierarchical model construction possible. formalisms are described using set theoretic notation and general systems theory concepts.

Analysis of pyridinoline and its derivatives by scanning-array four-sector tandem mass spectrometry

Structures of the trifunctional crosslink molecules, pyridinoline, deoxypyridinoline and glucosylgalactosyl-pyridinoline, have been characterized by positive-ion liquid secondary-ion mass spectrometry (LSIMS) and collision-induced dissociation with scanning-array four-sector tandem mass spectrometry. It has been found that: (i) the naturally occurring cations (Cat+) are readily desorbed by positive-ion LSIMS utilizing glycerol + thioglycerol (1:1) as liquid matrix and dominate the spectra, facilitating accurate mass measurement; (ii) changing the matrix to 3-nitrobenzyl alcohol leaves little evidence of the cation, and (iii) collision-induced dissociation of the cations (Cat+) of pyridinoline, deoxypyridinoline and glucosylgalatosyl-pyridinoline gives a wealth of fragmentation for structure elucidation. These fundamental studies of tandem mass spectra of the known trifunctional crosslink molecules provided valuable structure-related information, which help in the identification of the tissue-specific peptides containing these crosslinks. Artefact ions in these tandem mass spectra are remarkably abundant.