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Synthetic protein alignments by CCMgen quantify noise in residue-residue contact prediction [article]

Susann Vorberg, Stefan Seemayer, Johannes Soeding
2018 bioRxiv   pre-print
Compensatory mutations between protein residues that are in physical contact with each other can manifest themselves as statistical couplings between the corresponding columns in a multiple sequence alignment (MSA) of the protein family. Conversely, high coupling coefficients predict residues contacts. Methods for de-novo protein structure prediction based on this approach are becoming increasingly reliable. Their main limitation is the strong systematic and statistical noise in the estimation
more » ... f coupling coefficients, which has so far limited their application to very large protein families. While most research has focused on boosting contact prediction quality by adding external information, little progress has been made to improve the statistical procedure at the core. In that regard, our lack of understanding of the sources of noise poses a major obstacle. We have developed CCMgen, the first method for simulating protein evolution by providing full control over the generation of realistic synthetic MSAs with pairwise statistical couplings between residue positions. This procedure requires an exact statistical model that reliably reproduces observed alignment statistics. We also provide CCMpredPy, an implementation of persistent contrastive divergence (PCD), a precise inference technique that enables us to learn the required high-quality models. We demonstrate how CCMgen can facilitate the development and testing of contact prediction methods by analyzing the systematic noise contributions from phylogeny and entropy. For that purpose, we propose a simple entropy correction (EC) strategy which disentangles the correction for both sources of noise. We find that entropy contributes typically roughly twice as much noise as phylogeny.
doi:10.1101/344333 fatcat:2sfeqkguo5h2pdxqsjwyarrnfe

Synthetic protein alignments by CCMgen quantify noise in residue-residue contact prediction

Susann Vorberg, Stefan Seemayer, Johannes Söding
2018 PLoS Computational Biology  
Compensatory mutations between protein residues in physical contact can manifest themselves as statistical couplings between the corresponding columns in a multiple sequence alignment (MSA) of the protein family. Conversely, large coupling coefficients predict residue contacts. Methods for de-novo protein structure prediction based on this approach are becoming increasingly reliable. Their main limitation is the strong systematic and statistical noise in the estimation of coupling coefficients,
more » ... which has so far limited their application to very large protein families. While most research has focused on improving predictions by adding external information, little progress has been made to improve the statistical procedure at the core, because our lack of understanding of the sources of noise poses a major obstacle. First, we show theoretically that the expectation value of the coupling score assuming no coupling is proportional to the product of the square roots of the column entropies, and we propose a simple entropy bias correction (EntC) that subtracts out this expectation value. Second, we show that the average product correction (APC) includes the correction of the entropy bias, partly explaining its success. Third, we have developed CCMgen, the first method for simulating protein evolution and generating realistic synthetic MSAs with pairwise statistical residue couplings. Fourth, to learn exact statistical models that reliably reproduce observed alignment statistics, we developed CCMpredPy, an implementation of the persistent contrastive divergence (PCD) method for exact inference. Fifth, we demonstrate how CCMgen and CCMpredPy can facilitate the development of contact prediction methods by analysing the systematic noise contributions from phylogeny and entropy. Using the entropy bias correction, we can disentangle both sources of noise and find that entropy contributes roughly twice as much noise as phylogeny.
doi:10.1371/journal.pcbi.1006526 pmid:30395601 pmcid:PMC6237422 fatcat:ytrblnou7zfffgk67vmek5fkja

CCMpred—fast and precise prediction of protein residue–residue contacts from correlated mutations

Stefan Seemayer, Markus Gruber, Johannes Söding
2014 Computer applications in the biosciences : CABIOS  
CCMpred -Supplementary Information Stefan Seemayer, Markus Gruber and Johannes Söding Markov Random Field Model The following section will outline the mathematical model in our contact prediction method  ... 
doi:10.1093/bioinformatics/btu500 pmid:25064567 pmcid:PMC4201158 fatcat:bb274zyv3bcmhfqdkk7pu4dlvq

A structural model of the active ribosome-bound membrane protein insertase YidC

Stephan Wickles, Abhishek Singharoy, Jessica Andreani, Stefan Seemayer, Lukas Bischoff, Otto Berninghausen, Johannes Soeding, Klaus Schulten, Eli O van der Sluis, Roland Beckmann
2014 eLife  
The integration of most membrane proteins into the cytoplasmic membrane of bacteria occurs co-translationally. The universally conserved YidC protein mediates this process either individually as a membrane protein insertase, or in concert with the SecY complex. Here, we present a structural model of YidC based on evolutionary co-variation analysis, lipid-versus-protein-exposure and molecular dynamics simulations. The model suggests a distinctive arrangement of the conserved five transmembrane
more » ... mains and a helical hairpin between transmembrane segment 2 (TM2) and TM3 on the cytoplasmic membrane surface. The model was used for docking into a cryo-electron microscopy reconstruction of a translating YidC-ribosome complex carrying the YidC substrate FOc. This structure reveals how a single copy of YidC interacts with the ribosome at the ribosomal tunnel exit and identifies a site for membrane protein insertion at the YidC protein-lipid interface. Together, these data suggest a mechanism for the co-translational mode of YidC-mediated membrane protein insertion.
doi:10.7554/elife.03035 pmid:25012291 pmcid:PMC4124156 fatcat:2park6rpcngangzt6pcx7s2mpa

Cartilage Destruction Mediated by Synovial Fibroblasts Does Not Depend on Proliferation in Rheumatoid Arthritis

Christian A. Seemayer, Stefan Kuchen, Peter Kuenzler, Veronika Řihošková, Janine Rethage, Wilhelm K. Aicher, Beat A. Michel, Renate E. Gay, Diego Kyburz, Michel Neidhart, Steffen Gay
2003 American Journal of Pathology  
The aim of the study was to investigate the relationship between invasion and proliferation in rheumatoid arthritis synovial fibroblasts (RASFs). In vitro, RASFs, normal synovial fibroblasts (NSFs), and RASFs transformed with SV40 T-antigen (RASF SV40 ) were analyzed for the expression of cell surface markers (Thy1, VCAM-1, ICAM-1, CD40, CD44) and their proliferation by flow cytometry. Furthermore, colonyforming unit assays were performed and the expression of matrix metalloproteinases (MMP)-14
more » ... and cathepsin K mRNA were determined by real-time polymerase chain reaction. In vivo, in the severe combined immunodeficiency (SCID) mouse co-implantation model, RASFs, NSFs, and RASF SV40 were tested for cartilage invasion, cellular density, and for their expression of the cell cycle-associated protein Ki67. In the SCID mouse co-implantation model, RASFs invaded significantly stronger into the cartilage than NSFs and RASF SV40 . Of note, RASF SV40 cells formed tumor-like tissues, and the cellular density adjacent to the cartilage was significantly higher than in RASFs or NSFs. In turn, the proliferation marker Ki67 was strongly expressed in the SV40-transformed synoviocytes in SCID mice, but not in RASFs, and specifically not at sites of cartilage invasion. Using the colony-forming unit assay, RASFs and NSFs did not form colonies, whereas RASF SV40 lost contact inhibition. In vitro, the proliferative rate of RASFs was low (4.3% S phase) in contrast to RASF SV40 (24.4%). Expression of VCAM-1 was significantly higher, whereas of ICAM-1 was significantly lower, in RASFs than in RASF SV40 . CD40 was significantly stronger expressed in RASF SV40 , whereas CD44 and AS02 were present at the same degree in almost all synoviocytes. Expres-Supported by the Swiss National Science Foundation (to C. A. S., D. K. and grants 32-64142.00 to S. G. and 32-58904.99 to D. K.); and the EMDO foundation (to C. A. S., S. K., and V. Ř .).
doi:10.1016/s0002-9440(10)64289-7 pmid:12707039 pmcid:PMC1851181 fatcat:exwgjjln2neojmo5iziaohbgae

Homology-based inference sets the bar high for protein function prediction

Tobias Hamp, Rebecca Kassner, Stefan Seemayer, Esmeralda Vicedo, Christian Schaefer, Dominik Achten, Florian Auer, Ariane Boehm, Tatjana Braun, Maximilian Hecht, Mark Heron, Peter Hönigschmid (+8 others)
2013 BMC Bioinformatics  
doi:10.1186/1471-2105-14-s3-s7 pmid:23514582 pmcid:PMC3584931 fatcat:gwjjghihvrffdluv6lvlyzqoqu

Page 35 of Diabetes Metabolism Research and Reviews Vol. 8, Issue 1 [page]

1992 Diabetes Metabolism Research and Reviews  
Issa-Chergui B, Guttmann RD, Seemayer TA, Kelley VE, and Colle E: The effect of diet on the spontaneous insulin dependent diabetic syn¬ drome in the rat. Diabetes Res 9:81-86, 1988. 271.  ...  Stefan Y, Meda P, Neufeld M, and Orci L: Stimulation of insulin secretion reveals hetero¬ geneity of pancreatic B cells in vivo. ] Clin Invest 80:175-183, 1987. 251.  ... 

ConKit: a python interface to contact predictions

Felix Simkovic, Jens M H Thomas, Daniel J Rigden, Janet Kelso
2017 Bioinformatics  
Acknowledgements The authors would like to acknowledge Stefan Seemayer for the provision of helpful software libraries.  ...  ., 2012) ; CCMpred (Seemayer et al., 2014) ; PSICOV (Jones et al., 2012) ; and bbcontacts (Andreani and Sö ding, 2015) .  ... 
doi:10.1093/bioinformatics/btx148 pmid:28369168 pmcid:PMC5870551 fatcat:325qtszb4vdqvighue5hbo7rr4

A large-scale evaluation of computational protein function prediction

Predrag Radivojac, Wyatt T Clark, Tal Ronnen Oron, Alexandra M Schnoes, Tobias Wittkop, Artem Sokolov, Kiley Graim, Christopher Funk, Karin Verspoor, Asa Ben-Hur, Gaurav Pandey, Jeffrey M Yunes (+90 others)
2013 Nature Methods  
Automated annotation of protein function is challenging. As the number of sequenced genomes rapidly grows, the overwhelming majority of protein products can only be annotated computationally. if computational predictions are to be relied upon, it is crucial that the accuracy of these methods be high. here we report the results from the first large-scale community-based critical assessment of protein function annotation (CAFA) experiment. Fifty-four methods representing the state of the art for
more » ... rotein function prediction were evaluated on a target set of 866 proteins from 11 organisms. two findings stand out: (i) today's best protein function prediction algorithms substantially outperform widely used first-generation methods, with large gains on all types of targets; and (ii) although the top methods perform well enough to guide experiments, there is considerable need for improvement of currently available tools. The accurate annotation of protein function is key to understanding life at the molecular level and has great biomedical and pharmaceutical implications. However, with its inherent difficulty and expense, experimental characterization of function cannot scale up to accommodate the vast amount of sequence data already
doi:10.1038/nmeth.2340 pmid:23353650 pmcid:PMC3584181 fatcat:7rqgsz4wgfa45lb4iirt2sa4ai

p53 in rheumatoid arthritis synovial fibroblasts at sites of invasion

C A Seemayer
2003 Annals of the Rheumatic Diseases  
Christian A Seemayer was supported by the Swiss National Science Foundation (grant 32-64142.00 to Steffen Gay), Christian A Seemayer, Stefan Kuchen, and Veronika Řihošková were supported by the EMDO foundation  ... 
doi:10.1136/ard.2003.007401 pmid:14644850 pmcid:PMC1754413 fatcat:xcnz3swn4raufd5orklp77dozm

bbcontacts: prediction of β -strand pairing from direct coupling patterns

Jessica Andreani, Johannes Söding
2015 Computer applications in the biosciences : CABIOS  
Acknowledgements We thank Stefan Seemayer and Susann Vorberg for stimulating discussions and Stefan Seemayer and Armin Meier for feedback on the paper draft.  ...  Finally, bbcontacts was compared with general contact prediction methods: CCMpred (Seemayer et al., 2014) , PhyCMAP (Wang and Xu, 2013) and PconsC2 (Skwark et al., 2014) .  ...  Direct coupling predictions were obtained with CCMpred (Seemayer et al., 2014) , a fast implementation of the state-of-the-art methods by Kamisetty et al. (2013) and Ekeberg et al. (2013) .  ... 
doi:10.1093/bioinformatics/btv041 pmid:25618863 fatcat:shcddmghdvd7rjr5nss37thh6y

Bullous emphysema – Not always nicotine-related!

Camilla Lüttecke-Hecht, Tim O. Hirche
2014 Respiratory Medicine Case Reports  
Stefan Seemayer, Wiesbaden, Germany, for the support regarding the professional contents of this case report.  ... 
doi:10.1016/j.rmcr.2014.04.002 pmid:26029539 pmcid:PMC4061440 fatcat:6urn5wo23neztnmvvpn7e2l2e4

Epigenetic Modifications: Are we Closer to Clinical Applicability?

Frederique Ponchel, Agata N Burska
2016 Journal of Pharmacogenomics & Pharmacoproteomics  
Kuchen S, Seemayer CA, Rethage J, von Knoch R, Kuenzler P, et al. (2004) The L1 retroelement-related p40 protein induces p38delta MAP kinase. Autoimmunity 37: 57-65. 32.  ...  Stefan M, Zhang W, Concepcion E, Yi Z, Tomer Y (2014) DNA methylation profiles in type 1 diabetes twins point to strong epigenetic effects on etiology. J Autoimmun 50: 33-37. 40.  ... 
doi:10.4172/2153-0645.1000158 fatcat:lku5hog3effd3fpytre52kwvai

Page 29 of Diabetes Metabolism Research and Reviews Vol. 19, Issue 1 [page]

Diabetes Metabolism Research and Reviews  
Stefan Y, Malaisse-Lagae F, Yoon JW, Notkins AL, Orci L. Vims-induced diabetes in mice: a quantitative evaluation of islet cell population by immunofluorescence technique.  ...  Numazaki K, Goldman H, Seemayer TA, Wong I, Wain¬ berg MA. Infection by human cytomegalovirus and rubella virus of cultured human fetal islets of Langerhans. In Vivo 1990; 4: 49-54. 105.  ... 

AMTLICHE MITTEILUNGEN

Verkündungsblatt Der, Fachhochschule Düsseldorf
unpublished
Dr. 1 Vertretung Weinert, Stefan, Prof. Dr. 1 Vertretung Graetz, Jörg, Prof.  ...  §13 Abs. 2 HG 15 gewählt Kruse, Oliver, Prof. 13 gewählt Korschildgen, Stefan, Prof. 13 gewählt Stahl, Wilhelm, Prof.  ... 
fatcat:shgy6gb3ujedteo5q5x2nprgwm
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