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Structural Interpretation (structural + interpretation)
Selected AbstractsStructural interpretation of mutations and SNPs using STRAP-NTPROTEIN SCIENCE, Issue 1 2006Christoph Gille Abstract Visualization of residue positions in protein alignments and mapping onto suitable structural models is an important first step in the interpretation of mutations or polymorphisms in terms of protein function, interaction, and thermodynamic stability. Selecting and highlighting large numbers of residue positions in a protein structure can be time-consuming and tedious with currently available software. Previously, a series of tasks and analyses had to be performed one-by-one to map mutations onto 3D protein structures; STRAP-NT is an extension of STRAP that automates these tasks so that users can quickly and conveniently map mutations onto 3D protein structures. When the structure of the protein of interest is not yet available, a related protein can frequently be found in the structure databases. In this case the alignment of both proteins becomes the crucial part of the analysis. Therefore we embedded these program modules into the Java-based multiple sequence alignment program STRAP-NT. STRAP-NT can simultaneously map an arbitrary number of mutations denoted using either the nucleotide or amino acid sequence. When the designations of the mutations refer to genomic sites, STRAP-NT translates them into the corresponding amino acid positions, taking intron,exon boundaries into account. STRAP-NT tightly integrates a number of current protein structure viewers (currently PYMOL, RASMOL, JMOL, and VMD) with which mutations and polymorphisms can be directly displayed on the 3D protein structure model. STRAP-NT is available at the PDB site and at http://www.charite.de/bioinf/strap/ or http://strapjava.de. [source] Evolution of allosteric models for hemoglobinIUBMB LIFE, Issue 8-9 2007William A. Eaton Abstract We compare various allosteric models that have been proposed to explain cooperative oxygen binding to hemoglobin, including the two-state allosteric model of Monod, Wyman, and Changeux (MWC), the Cooperon model of Brunori, the model of Szabo and Karplus (SK) based on the stereochemical mechanism of Perutz, the generalization of the SK model by Lee and Karplus (SKL), and the Tertiary Two-State (TTS) model of Henry, Bettati, Hofrichter and Eaton. The preponderance of experimental evidence favors the TTS model which postulates an equilibrium between high (r)- and low (t)-affinity tertiary conformations that are present in both the T and R quaternary structures. Cooperative oxygenation in this model arises from the shift of T to R, as in MWC, but with a significant population of both r and t conformations in the liganded T and in the unliganded R quaternary structures. The TTS model may be considered a combination of the SK and SKL models, and these models provide a framework for a structural interpretation of the TTS parameters. The most compelling evidence in favor of the TTS model is the nanosecond - millisecond carbon monoxide (CO) rebinding kinetics in photodissociation experiments on hemoglobin encapsulated in silica gels. The polymeric network of the gel prevents any tertiary or quaternary conformational changes on the sub-second time scale, thereby permitting the subunit conformations prior to CO photodissociation to be determined from their ligand rebinding kinetics. These experiments show that a large fraction of liganded subunits in the T quaternary structure have the same functional conformation as liganded subunits in the R quaternary structure, an experimental finding inconsistent with the MWC, Cooperon, SK, and SKL models, but readily explained by the TTS model as rebinding to r subunits in T. We propose an additional experiment to test another key prediction of the TTS model, namely that a fraction of subunits in the unliganded R quaternary structure has the same functional conformation (t) as unliganded subunits in the T quaternary structure. [source] Applying pattern recognition methods plus quantum and physico-chemical molecular descriptors to analyze the anabolic activity of structurally diverse steroidsJOURNAL OF COMPUTATIONAL CHEMISTRY, Issue 3 2008Yoanna María Alvarez-Ginarte Abstract The great cost associated with the development of new anabolic,androgenic steroid (AASs) makes necessary the development of computational methods that shorten the drug discovery pipeline. Toward this end, quantum, and physicochemical molecular descriptors, plus linear discriminant analysis (LDA) were used to analyze the anabolic/androgenic activity of structurally diverse steroids and to discover novel AASs, as well as also to give a structural interpretation of their anabolic,androgenic ratio (AAR). The obtained models are able to correctly classify 91.67% (86.27%) of the AASs in the training (test) sets, respectively. The results of predictions on the 10% full-out cross-validation test also evidence the robustness of the obtained model. Moreover, these classification functions are applied to an "in house" library of chemicals, to find novel AASs. Two new AASs are synthesized and tested for in vivo activity. Although both AASs are less active than some commercially AASs, this result leaves a door open to a virtual variational study of the structure of the two compounds, to improve their biological activity. The LDA-assisted QSAR models presented here, could significantly reduce the number of synthesized and tested AASs, as well as could increase the chance of finding new chemical entities with higher AAR. © 2007 Wiley Periodicals, Inc. J Comput Chem, 2008 [source] Discrete-element modelling of detachment foldingBASIN RESEARCH, Issue 4 2005Stuart Hardy ABSTRACT A two-dimensional, discrete-element modelling technique is used to investigate the initiation and growth of detachment folds in sedimentary rocks above a weak décollement level. The model depicts the sedimentary rocks as an assemblage of spheres that obey Newton's equations of motion and that interact with elastic forces under the influence of gravity. Faulting or fracturing between neighbouring elements is represented by a transition from repulsive,attractive forces to solely repulsive forces. The sedimentary sequence is mechanically heterogeneous, consisting of intercalated layers of markedly different strengths and thicknesses. The interlayering of weak and strong layers within the sedimentary rocks promotes the localization of flexural flow deformation within the weak layers. Even with simple displacement boundary conditions, and straightforward interlayering of weak and strong layers, the structural geometries that develop are complex, with a combination of box, lift-off and disharmonic detachment fold styles forming above the décollement. In detail, it is found that the modelled folds grow by both limb rotation and limb lengthening. The combination of these two mechanisms results in uplift patterns above the folds that are difficult, or misleading, to interpret in terms of simple kinematic models. Comparison of modelling results with natural examples and with kinematic models highlights the complexities of structural interpretation in such settings. [source] Analysis of Campylobacter jejuni capsular loci reveals multiple mechanisms for the generation of structural diversity and the ability to form complex heptosesMOLECULAR MICROBIOLOGY, Issue 1 2005Andrey V. Karlyshev Summary We recently demonstrated that Campylobacter jejuni produces a capsular polysaccharide (CPS) that is the major antigenic component of the classical Penner serotyping system distinguishing Campylobacter into >60 groups. Although the wide variety of C. jejuni serotypes are suggestive of structural differences in CPS, the genetic mechanisms of such differences are unknown. In this study we sequenced biosynthetic cps regions, ranging in size from 15 to 34 kb, from selected C. jejuni strains of HS:1, HS:19, HS:23, HS:36, HS:23/36 and HS:41 serotypes. Comparison of the determined cps sequences of the HS:1, HS:19 and HS:41 strains with the sequenced strain, NCTC11168 (HS:2), provides evidence for multiple mechanisms of structural variation including exchange of capsular genes and entire clusters by horizontal transfer, gene duplication, deletion, fusion and contingency gene variation. In contrast, the HS:23, HS:36 and HS:23/36 cps sequences were highly conserved. We report the first detailed structural analysis of 81-176 (HS:23/36) and G1 (HS:1) and refine the previous structural interpretations of the HS:19, HS:23, HS:36 and HS:41 serostrains. For the first time, we demonstrate the commonality and function of a second heptose biosynthetic pathway for Campylobacter CPS independent of the pathway for lipooligosaccharide (LOS) biosynthesis and identify a novel heptosyltransferase utilized by this alternate pathway. Furthermore, we show the retention of two functional heptose isomerases in Campylobacter and the sharing of a phosphatase for both LOS and CPS heptose biosynthesis. [source] | |||||||||||||