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BMC Structural Biology - Latest Articles   [more] [xml]
 2014-10-18T00:00:00Z A PDB-wide, evolution-based assessment of protein¿protein interfaces
Background: Thanks to the growth in sequence and structure databases, more than 50 million sequences are now available in UniProt and 100,000 structures in the PDB. Rich information about protein?protein interfaces can be obtained by a comprehensive study of protein contacts in the PDB, their sequence conservation and geometric features. Results: An automated computational pipeline was developed to run our Evolutionary Protein?Protein Interface Classifier (EPPIC) software on the entire PDB and store the results in a relational database, currently containing > 800,000 interfaces. This allows the analysis of interface data on a PDB-wide scale. Two large benchmark datasets of biological interfaces and crystal contacts, each containing about 3000 entries, were automatically generated based on criteria thought to be strong indicators of interface type. The BioMany set of biological interfaces includes NMR dimers solved as crystal structures and interfaces that are preserved across diverse crystal forms, as catalogued by the Protein Common Interface Database (ProtCID) from Xu and Dunbrack. The second dataset, XtalMany, is derived from interfaces that would lead to infinite assemblies and are therefore crystal contacts. BioMany and XtalMany were used to benchmark the EPPIC approach. The performance of EPPIC was also compared to classifications from the Protein Interfaces, Surfaces, and Assemblies (PISA) program on a PDB-wide scale, finding that the two approaches give the same call in about 85% of PDB interfaces. By comparing our safest predictions to the PDB author annotations, we provide a lower-bound estimate of the error rate of biological unit annotations in the PDB. Additionally, we developed a PyMOL plugin for direct download and easy visualization of EPPIC interfaces for any PDB entry. Both the datasets and the PyMOL plugin are available at http://www.eppic-web.org/ewui/\#downloads. Conclusions: Our computational pipeline allows us to analyze protein?protein contacts and their sequence conservation across the entire PDB. Two new benchmark datasets are provided, which are over an order of magnitude larger than existing manually curated ones. These tools enable the comprehensive study of several aspects of protein?protein contacts in the PDB and represent a basis for future, even larger scale studies of protein?protein interactions.
 2014-10-15T00:00:00Z Molecular dynamics simulations of the Nip7 proteins from the marine deep- and shallow-water Pyrococcus species
Background: The identification of the mechanisms of adaptation of protein structures to extreme environmental conditions is a challenging task of structural biology. We performed molecular dynamics (MD) simulations of the Nip7 protein involved in RNA processing from the shallow-water (P. furiosus) and the deep-water (P. abyssi) marine hyperthermophylic archaea at different temperatures (300 and 373?K) and pressures (0.1, 50 and 100?MPa). The aim was to disclose similarities and differences between the deep- and shallow-sea protein models at different temperatures and pressures. Results: The current results demonstrate that the 3D models of the two proteins at all the examined values of pressures and temperatures are compact, stable and similar to the known crystal structure of the P. abyssi Nip7. The structural deviations and fluctuations in the polypeptide chain during the MD simulations were the most pronounced in the loop regions, their magnitude being larger for the C-terminal domain in both proteins. A number of highly mobile segments the protein globule presumably involved in protein-protein interactions were identified. Regions of the polypeptide chain with significant difference in conformational dynamics between the deep- and shallow-water proteins were identified. Conclusions: The results of our analysis demonstrated that in the examined ranges of temperatures and pressures, increase in temperature has a stronger effect on change in the dynamic properties of the protein globule than the increase in pressure. The conformational changes of both the deep- and shallow-sea protein models under increasing temperature and pressure are non-uniform. Our current results indicate that amino acid substitutions between shallow- and deep-water proteins only slightly affect overall stability of two proteins. Rather, they may affect the interactions of the Nip7 protein with its protein or RNA partners.
 2014-09-23T00:00:00Z Buried chloride stereochemistry in the Protein Data Bank
Background: Despite the chloride anion is involved in fundamental biological processes, its interactions with proteins are little known. In particular, we lack a systematic survey of its coordination spheres. Results: The analysis of a non-redundant set (pairwise sequence identity < 30%) of 1739 high resolution (<2 Å) crystal structures that contain at least one chloride anion shows that the first coordination spheres of the chlorides are essentially constituted by hydrogen bond donors. Amongst the side-chains positively charged, arginine interacts with chlorides much more frequently than lysine. Although the most common coordination number is 4, the coordination stereochemistry is closer to the expected geometry when the coordination number is 5, suggesting that this is the coordination number towards which the chlorides tend when they interact with proteins. Conclusions: The results of these analyses are useful in interpreting, describing, and validating new protein crystal structures that contain chloride anions.
 2014-09-17T12:00:00Z Structural insight into the recognition of amino-acylated initiator tRNA by eIF5B in the 80S initiation complex
Background: From bacteria to eukarya, the specific recognition of the amino-acylated initiator tRNA by the universally conserved translational GTPase eIF5B/IF2 is one of the most central interactions in the process of translation initiation. However, the molecular details, particularly also in the context of ribosomal initiation complexes, are only partially understood. Results: A reinterpretation of the 6.6 Å resolution cryo-electron microscopy (cryo-EM) structure of the eukaryal 80S initiation complex using the recently published crystal structure of eIF5B reveals that domain IV of eIF5B forms extensive interaction interfaces with the Met-tRNAi, which, in contrast to the previous model, directly involve the methionylated 3′ CCA-end of the acceptor stem. These contacts are mediated by a conserved surface area, which is homologous to the surface areas mediating the interactions between IF2 and fMet-tRNAfMet as well as between domain II of EF-Tu and amino-acylated elongator tRNAs. Conclusions: The reported observations provide novel direct structural insight into the specific recognition of the methionylated acceptor stem by eIF5B domain IV and demonstrate its universality among eIF5B/IF2 orthologs in the three domains of life.
 2014-07-19T00:00:00Z A simple method for finding a protein¿s ligand-binding pockets
Background: This paper provides a simple and rapid method for a protein-clustering strategy. The basic idea implemented here is to use computational geometry methods to predict and characterize ligand-binding pockets of a given protein structure. In addition to geometrical characteristics of the protein structure, we consider some simple biochemical properties that help recognize the best candidates for pockets in a protein’s active site. Results: Our results are shown to produce good agreement with known empirical results. Conclusions: The method presented in this paper is a low-cost rapid computational method that could be used to classify proteins and other biomolecules, and furthermore could be useful in reducing the cost and time of drug discovery.
 2014-07-07T00:00:00Z Characterization of the SAM domain of the PKD-related protein ANKS6 and its interaction with ANKS3
Background: Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic disorder leading to end-stage renal failure in humans. In the PKD/Mhm(cy/+) rat model of ADPKD, the point mutation R823W in the sterile alpha motif (SAM) domain of the protein ANKS6 is responsible for disease. SAM domains are known protein-protein interaction domains, capable of binding each other to form polymers and heterodimers. Despite its physiological importance, little is known about the function of ANKS6 and how the R823W point mutation leads to PKD. Recent work has revealed that ANKS6 interacts with a related protein called ANKS3. Both ANKS6 and ANKS3 have a similar domain structure, with ankyrin repeats at the N-terminus and a SAM domain at the C-terminus. Results: The SAM domain of ANKS3 is identified as a direct binding partner of the ANKS6 SAM domain. We find that ANKS3-SAM polymerizes and ANKS6-SAM can bind to one end of the polymer. We present crystal structures of both the ANKS3-SAM polymer and the ANKS3-SAM/ANKS6-SAM complex, revealing the molecular details of their association. We also learn how the R823W mutation disrupts ANKS6 function by dramatically destabilizing the SAM domain such that the interaction with ANKS3-SAM is lost. Conclusions: ANKS3 is a direct interacting partner of ANKS6. By structurally and biochemically characterizing the interaction between the ANKS3 and ANKS6 SAM domains, our work provides a basis for future investigation of how the interaction between these proteins mediates kidney function.
 2014-05-29T00:00:00Z High-resolution crystal structure of spin labelled (T21R1) azurin from Pseudomonas aeruginosa: a challenging structural benchmark for in silico spin labelling algorithms
Background: EPR-based distance measurements between spin labels in proteins have become a valuable tool in structural biology. The direct translation of the experimental distances into structural information is however often impaired by the intrinsic flexibility of the spin labelled side chains. Different algorithms exist that predict the approximate conformation of the spin label either by using pre-computed rotamer libraries of the labelled side chain (rotamer approach) or by simply determining its accessible volume (accessible volume approach). Surprisingly, comparisons with many experimental distances have shown that both approaches deliver the same distance prediction accuracy of about 3 Å. Results: Here, instead of comparing predicted and experimental distances, we test the ability of both approaches to predict the actual conformations of spin labels found in a new high-resolution crystal structure of spin labelled azurin (T21R1). Inside the crystal, the label is found in two very different environments which serve as a challenging test for the in silico approaches. Conclusions: Our results illustrate why simple and more sophisticated programs lead to the same prediciton error. Thus, a more precise treatment of the complete environment of the label and also its interactions with the environment will be needed to increase the accuracy of in silico spin labelling algorithms.
 2014-05-23T00:00:00Z Sequence analysis on the information of folding initiation segments in ferredoxin-like fold proteins
Background: While some studies have shown that the 3D protein structures are more conservative than their amino acid sequences, other experimental studies have shown that even if two proteins share the same topology, they may have different folding pathways. There are many studies investigating this issue with molecular dynamics or Go-like model simulations, however, one should be able to obtain the same information by analyzing the proteins’ amino acid sequences, if the sequences contain all the information about the 3D structures. In this study, we use information about protein sequences to predict the location of their folding segments. We focus on proteins with a ferredoxin-like fold, which has a characteristic topology. Some of these proteins have different folding segments. Results: Despite the simplicity of our methods, we are able to correctly determine the experimentally identified folding segments by predicting the location of the compact regions considered to play an important role in structural formation. We also apply our sequence analyses to some homologues of each protein and confirm that there are highly conserved folding segments despite the homologues’ sequence diversity. These homologues have similar folding segments even though the homology of two proteins’ sequences is not so high. Conclusion: Our analyses have proven useful for investigating the common or different folding features of the proteins studied.
 2014-04-24T00:00:00Z High resolution structure of cleaved Serpin 42 Da from Drosophila melanogaster
Background: The Drosophila melanogaster Serpin 42 Da gene (previously Serpin 4) encodes a serine protease inhibitor that is capable of remarkable functional diversity through the alternative splicing of four different reactive centre loop exons. Eight protein isoforms of Serpin 42 Da have been identified to date, targeting the protease inhibitor to both different proteases and cellular locations. Biochemical and genetic studies suggest that Serpin 42 Da inhibits target proteases through the classical serpin ‘suicide’ inhibition mechanism, however the crystal structure of a representative Serpin 42 Da isoform remains to be determined. Results: We report two high-resolution crystal structures of Serpin 42 Da representing the A/B isoforms in the cleaved conformation, belonging to two different space-groups and diffracting to 1.7 Å and 1.8 Å. Structural analysis reveals the archetypal serpin fold, with the major elements of secondary structure displaying significant homology to the vertebrate serpin, neuroserpin. Key residues known to have central roles in the serpin inhibitory mechanism are conserved in both the hinge and shutter regions of Serpin 42 Da. Furthermore, these structures identify important conserved interactions that appear to be of crucial importance in allowing the Serpin 42 Da fold to act as a versatile template for multiple reactive centre loops that have different sequences and protease specificities. Conclusions: In combination with previous biochemical and genetic studies, these structures confirm for the first time that the Serpin 42 Da isoforms are typical inhibitory serpin family members with the conserved serpin fold and inhibitory mechanism. Additionally, these data reveal the remarkable structural plasticity of serpins, whereby the basic fold is harnessed as a template for inhibition of a large spectrum of proteases by reactive centre loop exon ‘switching’. This is the first structure of a Drosophila serpin reported to date, and will provide a platform for future mutational studies in Drosophila to ascertain the functional role of each of the Serpin 42 Da isoforms.
 2014-04-15T00:00:00Z Designing and evaluating the MULTICOM protein local and global model quality prediction methods in the CASP10 experiment
Background: Protein model quality assessment is an essential component of generating and using protein structural models. During the Tenth Critical Assessment of Techniques for Protein Structure Prediction (CASP10), we developed and tested four automated methods (MULTICOM-REFINE, MULTICOM-CLUSTER, MULTICOM-NOVEL, and MULTICOM-CONSTRUCT) that predicted both local and global quality of protein structural models. Results: MULTICOM-REFINE was a clustering approach that used the average pairwise structural similarity between models to measure the global quality and the average Euclidean distance between a model and several top ranked models to measure the local quality. MULTICOM-CLUSTER and MULTICOM-NOVEL were two new support vector machine-based methods of predicting both the local and global quality of a single protein model. MULTICOM-CONSTRUCT was a new weighted pairwise model comparison (clustering) method that used the weighted average similarity between models in a pool to measure the global model quality. Our experiments showed that the pairwise model assessment methods worked better when a large portion of models in the pool were of good quality, whereas single-model quality assessment methods performed better on some hard targets when only a small portion of models in the pool were of reasonable quality. Conclusions: Since digging out a few good models from a large pool of low-quality models is a major challenge in protein structure prediction, single model quality assessment methods appear to be poised to make important contributions to protein structure modeling. The other interesting finding was that single-model quality assessment scores could be used to weight the models by the consensus pairwise model comparison method to improve its accuracy.


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BMC Bioinformatics - Latest Articles   [more] [xml]
 2014-10-22T00:00:00Z SummonChimera infers integrated viral genomes with nucleotide precision from NGS data
Background: Viral integration into a host genome is defined by two chimeric junctions that join viral and host DNA. Recently, computational tools have been developed that utilize NGS data to detect chimeric junctions. These methods identify individual viral-host junctions but do not associate chimeric pairs as an integration event. Without knowing the chimeric boundaries of an integration, its genetic content cannot be determined. Results: Summonchimera is a Perl program that associates chimera pairs to infer the complete viral genomic integration event to the nucleotide level within single or paired-end NGS data. SummonChimera integration prediction was verified on a set of single-end IonTorrent reads from a purified Salmonella bacterium with an integrated bacteriophage. Furthermore, SummonChimera predicted integrations from experimentally verified Hepatitis B Virus chimeras within a paired-end Whole Genome Sequencing hepatocellular carcinoma tumor database. Conclusions: SummonChimera identified all experimentally verified chimeras detected by current computational methods. Further, SummonChimera integration inference precisely predicted bacteriophage integration. The application of SummonChimera to cancer NGS accurately identifies deletion of host and viral sequence during integration. The precise nucleotide determination of an integration allows prediction of viral and cellular gene transcription patterns.


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BMC Genomics - Latest Articles   [more] [xml]
 2014-10-21T00:00:00Z Census-based rapid and accurate metagenome taxonomic profiling
Background: Understanding the taxonomic composition of a sample, whether from patient, food or environment, is important to several types of studies including pathogen diagnostics, epidemiological studies, biodiversity analysis and food quality regulation. With the decreasing costs of sequencing, metagenomic data is quickly becoming the preferred typed of data for such analysis. Results: Rapidly defining the taxonomic composition (both taxonomic profile and relative frequency) in a metagenomic sequence dataset is challenging because the task of mapping millions of sequence reads from a metagenomic study to a non-redundant nucleotide database such as the NCBI non-redundant nucleotide database (nt) is a computationally intensive task. We have developed a robust subsampling-based algorithm implemented in a tool called CensuScope meant to take a 'sneak peak' into the population distribution and estimate taxonomic composition as if a census was taken of the metagenomic landscape. CensuScope is a rapid and accurate metagenome taxonomic profiling tool that randomly extracts a small number of reads (based on user input) and maps them to NCBI's nt database. This process is repeated multiple times to ascertain the taxonomic composition that is found in majority of the iterations, thereby providing a robust estimate of the population and measures of the accuracy for the results. Conclusion: CensuScope can be run on a laptop or on a high-performance computer. Based on our analysis we are able to provide some recommendations in terms of the number of sequence reads to analyze and the number of iterations to use. For example, to quantify taxonomic groups present in the sample at a level of 1% or higher a subsampling size of 250 random reads with 50 iterations yields a statistical power of >99%. Windows and UNIX versions of CensuScope are available for download at https://hive.biochemistry.gwu.edu/dna.cgi?cmd=censuscope. CensuScope is also available through the High-performance Integrated Virtual Environment (HIVE) and can be used in conjunction with other HIVE analysis and visualization tools.


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BMC Biochemistry - Latest Articles   [more] [xml]
 2014-10-09T00:00:00Z Alleviation effect of arbutin on oxidative stress generated through tyrosinase reaction with l-tyrosine and l-DOPA
Background: Hydroxyl radical that has the highest reactivity among reactive oxygen species (ROS) is generated through l-tyrosine-tyrosinase reaction. Thus, the melanogenesis might induce oxidative stress in the skin. Arbutin (p-hydroxyphenyl-β-d-glucopyranoside), a well-known tyrosinase inhibitor has been widely used for the purpose of skin whitening. The aim of the present study was to examine if arbutin could suppress the hydroxyl radical generation via tyrosinase reaction with its substrates, l-tyrosine and l-DOPA. Results: The hydroxyl radical, which was determined by an electron spin resonance-spin trapping technique, was generated by the addition of not only l-tyrosine but l-DOPA to tyrosinase in a concentration dependent manner. Arbutin could inhibit the hydroxyl radical generation in the both reactions. Conclusion: It is presumed that arbutin could alleviate oxidative stress derived from the melanogenic pathway in the skin in addition to its function as a whitening agent in cosmetics.


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Nature   [more] [xml]
 2005-01-19 Einstein is dead
Until its next revolution, much of the glory of physics will be in engineering. It is a shame that the physicists who do so much of it keep so quiet about it.

Einstein is dead

Nature 433, 179 (2005). doi:10.1038/433179a

Until its next revolution, much of the glory of physics will be in engineering. It is a shame that the physicists who do so much of it keep so quiet about it.



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Science: Current Issue   [more] [xml]
 2014-10-17 [Special Issue Report] On the prevalence of small-scale twist in the solar chromosphere and transition region
The solar chromosphere and transition region (TR) form an interface between the Sun’s surface and its hot outer atmosphere. There, most of the nonthermal energy that powers the solar atmosphere is transformed into heat, although the detailed mechanism remains elusive. High-resolution (0.33–arc second) observations with NASA’s Interface Region Imaging Spectrograph (IRIS) reveal a chromosphere and TR that are replete with twist or torsional motions on sub–arc second scales, occurring in active regions, quiet Sun regions, and coronal holes alike. We coordinated observations with the Swedish 1-meter Solar Telescope (SST) to quantify these twisting motions and their association with rapid heating to at least TR temperatures. This view of the interface region provides insight into what heats the low solar atmosphere. Authors: B. De Pontieu, L. Rouppe van der Voort, S. W. McIntosh, T. M. D. Pereira, M. Carlsson, V. Hansteen, H. Skogsrud, J. Lemen, A. Title, P. Boerner, N. Hurlburt, T. D. Tarbell, J. P. Wuelser, E. E. De Luca, L. Golub, S. McKillop, K. Reeves, S. Saar, P. Testa, H. Tian, C. Kankelborg, S. Jaeggli, L. Kleint, J. Martinez-Sykora

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