Contact prediction in protein modeling: Scoring, folding and refinement of coarse-grained models

<p>Abstract</p> <p>Background</p> <p>Several different methods for contact prediction succeeded within the Sixth Critical Assessment of Techniques for Protein Structure Prediction (CASP6). The most relevant were non-local contact predictions for targets from the most difficult categories: fold recognition-analogy and new fold. Such contacts could provide valuable structural information in case a template structure cannot be found in the PDB.</p> <p>Results</p> <p>We described comprehensive tests of the effectiveness of contact data in various aspects of de novo modeling with CABS, an algorithm which was used successfully in CASP6 by the Kolinski-Bujnicki group. We used the predicted contacts in a simple scoring function for the post-simulation ranking of protein models and as a soft bias in the folding simulations and in the fold-refinement procedure. The latter approach turned out to be the most successful. The CABS force field used in the Replica Exchange Monte Carlo simulations cooperated with the true contacts and discriminated the false ones, which resulted in an improvement of the majority of Kolinski-Bujnicki's protein models. In the modeling we tested different sets of predicted contact data submitted to the CASP6 server. According to our results, the best performing were the contacts with the accuracy balanced with the coverage, obtained either from the best two predictors only or by a consensus from as many predictors as possible.</p> <p>Conclusion</p> <p>Our tests have shown that theoretically predicted contacts can be very beneficial for protein structure prediction. Depending on the protein modeling method, a contact data set applied should be prepared with differently balanced coverage and accuracy of predicted contacts. Namely, high coverage of contact data is important for the model ranking and high accuracy for the folding simulations.</p

Advanced ankylosing spondylitis diagnosed after infection of the digestive tract — case report

Inflammatory spondyloarthrophaties (SpA) are a group of diseases with a close aetiology and clinical course. Infections , especially bacterial, of the digestive tract are possible causes of SpA. Infectious pathogens may penetrate the mucous membrane of the gastrointestinal tract, of the urogenital tracts, respiratory tract and induce the reactive arthritis or exacerbate the previously diagnosed, chronic SpA. Dysbiosis also plays an important role in the pathogenesis of SpA. In the report, authors presented a case of a patient with a long-time backbone pain, in whom Yersinia enterocolitica infection of the digestive tract preceded the peripheral arthritis and inflammatory pain of the spine. The radiological images showed the characteristic changes of the advanced ankylosing spondylitis

"Cladonia uncialis" as a valuable raw material of biosynthetic compounds against clinical strains of bacteria and fungi

Cladonia uncialis is a lichen species with confirmed antibacterial activity and whose genome has been recently sequenced, enabling first attempts in its functional characterization. In this work, we investigated activity of the C. uncialis acetone extract (CUE) and usnic acid (UA) enantiomers against ten clinical microbial strains causing skin infections. The results showed that CUE, containing (–)-UA and squamatic acid, assayed at the same concentrations as UA, was noticeably more active than (–)-UA alone, in its pure form. The studied CUE displayed an activity that was comparable to that of (+)-UA observed for Staphylococcus epidermidis and Enterococcus faecium (18–24 mm zone of growth inhibition), but did not display any activity against fungal strains. The CUE demonstrated low cytotoxicity against HaCaT cells, in comparison to UA enantiomers, which is important for its therapeutic use. Results of the antioxidant assay (DPPH) indicated low antioxidant activity (IC50>200 µg/mL) of CUE, while the total phenolic content was 70.36 mg Gallic Acid Equivalent/g of the dry extrac

Bacterial RNA virus MS2 exposure increases the expression of cancer progression genes in the LNCaP prostate cancer cell line

Bacteriophages effectively counteract diverse bacterial infections, and their ability to treat most types of cancer has been explored using phage engineering or phage-virus hybrid platforms. In the present study, it was demonstrated that the bacteriophage MS2 can affect the expression of genes associated with the proliferation and survival of LNCaP prostate epithelial cells. LNCaP cells were exposed to bacteriophage MS2 at a concentration of 1x10(7) plaque forming units/ml for 24-48 h. After exposure, various cellular parameters, including cell viability, morphology, and changes in gene expression, were examined. MS2 affected cell viability adversely, reducing viability by 25% in the first 4 h of treatment; however, cell viability recovered within 24-48 h. Similarly, the AKT, androgen receptor, integrin alpha 5, integrin beta 1, MAPK1, MAPK3, STAT3, and peroxisome proliferator-activated receptor-gamma coactivator 1 alpha genes, which are involved in various normal cellular processes and tumor progression, were significantly upregulated, whereas the expression levels of HSP90, ITGB5, ITGB3, HSP27, ITGAV, and PI3K genes were unchanged. Therefore, based on viability and gene expression changes, bacteriophage MS2 severely impaired LNCaP cells by reducing anchorage-dependent survival and androgen signaling. A caveolin-mediated endocytosis mechanism for MS2-mediated signaling in prostate cancer cells was proposed based on reports involving bacteriophages T4, M13, and MS2, and their interactions with LNCaP and PC3 cell lines

Bacterial RNA virus MS2 exposure increases the expression of cancer progression genes in the LNCaP prostate cancer cell line

Bacteriophages effectively counteract diverse bacterial infections, and their ability to treat most types of cancer has been explored using phage engineering or phage-virus hybrid platforms. In the present study, it was demonstrated that the bacteriophage MS2 can affect the expression of genes associated with the proliferation and survival of LNCaP prostate epithelial cells. LNCaP cells were exposed to bacteriophage MS2 at a concentration of 1x10(7) plaque forming units/ml for 24-48 h. After exposure, various cellular parameters, including cell viability, morphology, and changes in gene expression, were examined. MS2 affected cell viability adversely, reducing viability by 25% in the first 4 h of treatment; however, cell viability recovered within 24-48 h. Similarly, the AKT, androgen receptor, integrin alpha 5, integrin beta 1, MAPK1, MAPK3, STAT3, and peroxisome proliferator-activated receptor-gamma coactivator 1 alpha genes, which are involved in various normal cellular processes and tumor progression, were significantly upregulated, whereas the expression levels of HSP90, ITGB5, ITGB3, HSP27, ITGAV, and PI3K genes were unchanged. Therefore, based on viability and gene expression changes, bacteriophage MS2 severely impaired LNCaP cells by reducing anchorage-dependent survival and androgen signaling. A caveolin-mediated endocytosis mechanism for MS2-mediated signaling in prostate cancer cells was proposed based on reports involving bacteriophages T4, M13, and MS2, and their interactions with LNCaP and PC3 cell lines

Additional file 1: of Rosetta Broker for membrane protein structure prediction: concentrative nucleoside transporter 3 and corticotropin-releasing factor receptor 1 test cases

Settings for the Rosetta Broker simulations. The Rosetta execution command included minirosetta.mpi.linuxgccrelease and flags presented in Table S1. Additional input files for the Rosetta Broker simulation are listed in Table S2 together with their contents. (DOCX 15 kb

Drug Repositioning For Allosteric Modulation of VIP and PACAP Receptors

Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) are two neuropeptides that contribute to the regulation of intestinal motility and secretion, exocrine and endocrine secretions, and homeostasis of the immune system. Their biological effects are mediated by three receptors named VPAC1, VPAC2 and PAC1 that belong to class B GPCRs. VIP and PACAP receptors have been identified as potential therapeutic targets for the treatment of chronic inflammation, neurodegenerative diseases and cancer. However, pharmacological use of endogenous ligands for these receptors is limited by their lack of specificity (PACAP binds with high affinity to VPAC1, VPAC2 and PAC1 receptors while VIP recognizes both VPAC1 and VPAC2 receptors), their poor oral bioavailability (VIP and PACAP are 27- to 38-amino acid peptides) and their short half-life. Therefore, the development of non-peptidic small molecules or specific stabilized peptidic ligands is of high interest. Structural similarities between VIP and PACAP receptors are major causes of difficulties in the design of efficient and selective compounds that could be used as therapeutics. In this study we performed structure-based virtual screening against the subset of the ZINC15 drug library. This drug repositioning screen provided new applications for a known drug: ticagrelor, a P2Y12 purinergic receptor antagonist. Ticagrelor inhibits both VPAC1 and VPAC2 receptors which was confirmed in VIP-binding and calcium mobilization assays. A following analysis of detailed ticagrelor binding modes to all three VIP and PACAP receptors with molecular dynamics revealed its allosteric mechanism of action. Using a validated homology model of inactive VPAC1 and a recently released cryo-EM structure of active VPAC1 we described how ticagrelor could block conformational changes in the region of ‘tyrosine toggle switch’ required for the receptor activation. We also discuss possible modifications of ticagrelor comparing other P2Y12 antagonist – cangrelor, closely related to ticagrelor but not active for VPAC1/VPAC2. This comparison with inactive cangrelor could lead to further improvement of the ticagrelor activity and selectivity for VIP and PACAP receptor sub-types.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Contact prediction in protein modeling: Scoring, folding and refinement of coarse-grained models-4

E scoring function was based on the contact data set from the best two predictors (Baker and PROFcon). The accuracy of the contact data used for scoring 5 models of each target is plotted against the RMSD of the model ranked as first in CASP6 by the Kolinski-Bujnicki group (green squares) and against the RMSD of the protein model ranked as first by the contact-based scoring function (red lines which join corresponding points). Results for NF and FR/A categories are presented separately. The most significant improvement is observed in the case of FR/A targets with the accuracy of the contact prediction range of 15–30%. In a similar way the results of the refinement simulations are presented in the right-hand panels (b). The refinement simulations performed better than the post-simulation ranking of the models.<p><b>Copyright information:</b></p><p>Taken from "Contact prediction in protein modeling: Scoring, folding and refinement of coarse-grained models"</p><p>http://www.biomedcentral.com/1472-6807/8/36</p><p>BMC Structural Biology 2008;8():36-36.</p><p>Published online 11 Aug 2008</p><p>PMCID:PMC2527566.</p><p></p