Thomas Wilhelm

Super Natural II--a database of natural products.

Natural products play a significant role in drug discovery and development. Many topological pharmacophore patterns are common between natural products and commercial drugs. A better understanding of the specific physicochemical and structural features of natural products is important for corresponding drug development. Several encyclopedias of natural compounds have been composed, but the information remains scattered or not freely available. The first version of the Supernatural database containing ∼50 000 compounds was published in 2006 to face these challenges. Here we present a new, updated and expanded version of natural product database, Super Natural II (http://bioinformatics.charite.de/supernatural), comprising ∼326 000 molecules. It provides all corresponding 2D structures, the most important structural and physicochemical properties, the predicted toxicity class for ∼170 000 compounds and the vendor information for the vast majority of compounds. The new version allows a template-based search for similar compounds as well as a search for compound names, vendors, specific physical properties or any substructures. Super Natural II also provides information about the pathways associated with synthesis and degradation of the natural products, as well as their mechanism of action with respect to structurally similar drugs and their target proteins.

Bacterial Rotary Export ATPases Are Allosterically Regulated by the Nucleotide Second Messenger Cyclic-di-GMP

Background: AAA+ ATPase proteins play integral roles in the export apparatus of many bacterial organelles. Results: The second messenger cyclic di-GMP binds specifically to multiple export ATPases at a highly conserved binding site. Conclusion: Cyclic di-GMP binding is central to the function of many different bacterial export complexes. Significance: This profoundly affects our understanding of numerous important bacterial organelles, including flagella, type III, and type VI secretion systems. The widespread second messenger molecule cyclic di-GMP (cdG) regulates the transition from motile and virulent lifestyles to sessile, biofilm-forming ones in a wide range of bacteria. Many pathogenic and commensal bacterial-host interactions are known to be controlled by cdG signaling. Although the biochemistry of cyclic dinucleotide metabolism is well understood, much remains to be discovered about the downstream signaling pathways that induce bacterial responses upon cdG binding. As part of our ongoing research into the role of cdG signaling in plant-associated Pseudomonas species, we carried out an affinity capture screen for cdG binding proteins in the model organism Pseudomonas fluorescens SBW25. The flagella export AAA+ ATPase FliI was identified as a result of this screen and subsequently shown to bind specifically to the cdG molecule, with a KD in the low micromolar range. The interaction between FliI and cdG appears to be very widespread. In addition to FliI homologs from diverse bacterial species, high affinity binding was also observed for the type III secretion system homolog HrcN and the type VI ATPase ClpB2. The addition of cdG was shown to inhibit FliI and HrcN ATPase activity in vitro. Finally, a combination of site-specific mutagenesis, mass spectrometry, and in silico analysis was used to predict that cdG binds to FliI in a pocket of highly conserved residues at the interface between two FliI subunits. Our results suggest a novel, fundamental role for cdG in controlling the function of multiple important bacterial export pathways, through direct allosteric control of export ATPase proteins.

The ancient mammalian KRAB zinc finger gene cluster on human chromosome 8q24.3 illustrates principles of C2H2 zinc finger evolution associated with unique expression profiles in human tissues

BackgroundExpansion of multi-C2H2 domain zinc finger (ZNF) genes, including the Krüppel-associated box (KRAB) subfamily, paralleled the evolution of tetrapodes, particularly in mammalian lineages. Advances in their cataloging and characterization suggest that the functions of the KRAB-ZNF gene family contributed to mammalian speciation.ResultsHere, we characterized the human 8q24.3 ZNF cluster on the genomic, the phylogenetic, the structural and the transcriptome level. Six (ZNF7, ZNF34, ZNF250, ZNF251, ZNF252, ZNF517) of the seven locus members contain exons encoding KRAB domains, one (ZNF16) does not. They form a paralog group in which the encoded KRAB and ZNF protein domains generally share more similarities with each other than with other members of the human ZNF superfamily. The closest relatives with respect to their DNA-binding domain were ZNF7 and ZNF251. The analysis of orthologs in therian mammalian species revealed strong conservation and purifying selection of the KRAB-A and zinc finger domains. These findings underscore structural/functional constraints during evolution. Gene losses in the murine lineage (ZNF16, ZNF34, ZNF252, ZNF517) and potential protein truncations in primates (ZNF252) illustrate ongoing speciation processes. Tissue expression profiling by quantitative real-time PCR showed similar but distinct patterns for all tested ZNF genes with the most prominent expression in fetal brain. Based on accompanying expression signatures in twenty-six other human tissues ZNF34 and ZNF250 revealed the closest expression profiles. Together, the 8q24.3 ZNF genes can be assigned to a cerebellum, a testis or a prostate/thyroid subgroup. These results are consistent with potential functions of the ZNF genes in morphogenesis and differentiation. Promoter regions of the seven 8q24.3 ZNF genes display common characteristics like missing TATA-box, CpG island-association and transcription factor binding site (TFBS) modules. Common TFBS modules partly explain the observed expression pattern similarities.ConclusionsThe ZNF genes at human 8q24.3 form a relatively old mammalian paralog group conserved in eutherian mammals for at least 130 million years. The members persisted after initial duplications by undergoing subfunctionalizations in their expression patterns and target site recognition. KRAB-ZNF mediated repression of transcription might have shaped organogenesis in mammalian ontogeny.

DiProGB: the dinucleotide properties genome browser

Motivation: DiProGB is an easy to use new genome browser that encodes the primary nucleotide sequence by thermodynamical and geometrical dinucleotide properties. The nucleotide sequence is thus converted into a sequence graph. This visualization, supported by different graph manipulation options, facilitates genome analyses, because the human brain can process visual information better than textual information. Also, DiProGB can identify genomic regions where certain physical properties are more conserved than the nucleotide sequence itself. Most of the DiProGB tools can be applied to both, the primary nucleotide sequence and the sequence graph. They include motif and repeat searches as well as statistical analyses. DiProGB adds a new dimension to the common genome analysis approaches by taking into account the physical properties of DNA and RNA. Availability and Implementation: Source code and binaries are freely available for download at http://diprogb.fli-leibniz.de, implemented in C++ and supported on MS Windows and Linux (using e.g. WineHQ). Contact: maikfr@fli-leibniz.de; thomas.wilhelm@bbsrc.ac.uk

Power-law distributions resulting from finite resources

An elementary stochastic model, termed the normalization model, is put forward which does demonstrate that power-laws generically occur in systems with finite resources. The model is capable to exhibit power-law distributions with arbitrary power law exponents; nevertheless, for a large fraction of the parameter space power law exponents near unity are obtained.

DASS-GUI

Summary: Many large ‘omics’ datasets have been published and many more are expected in the near future. New analysis methods are needed for best exploitation. We have developed a graphical user interface (GUI) for easy data analysis. Our discovery of all significant substructures (DASS) approach elucidates the underlying modularity, a typical feature of complex biological data. It is related to biclustering and other data mining approaches. Importantly, DASS-GUI also allows handling of multi-sets and calculation of statistical significances. DASS-GUI contains tools for further analysis of the identified patterns: analysis of the pattern hierarchy, enrichment analysis, module validation, analysis of additional numerical data, easy handling of synonymous names, clustering, filtering and merging. Different export options allow easy usage of additional tools such as Cytoscape. Availability: Source code, pre-compiled binaries for different systems, a comprehensive tutorial, case studies and many additional datasets are freely available at http://www.ifr.ac.uk/dass/gui/. DASS-GUI is implemented in Qt. Contact: jehol@psb.vib-ugent.be; thomas.wilhelm@bbsrc.ac.uk Supplementary information: Supplementary data are available at Bioinformatics online.

The decomposition tree for analyses of boolean functions

We present a new data structure, called a Decomposition Tree (DT), for analysing Boolean functions, and demonstrate a variety of applications. In each node of the DT, appropriate bit-string decomposition fragments are combined by a logical operator. The DT has 2k nodes in the worst case, which implies exponential complexity for problems where the whole tree has to be considered. However, it is important to note that many problems are simpler. We show that these can be handled in an efficient way using the DT. Nevertheless, many problems are of exponential complexity and cannot be made any simpler: for example, the calculation of prime implicants. Using our general DT structure, we present a new worst case algorithm to compute all prime implicants. This algorithm has a lower time complexity than the well-known Quine–McCluskey algorithm and is the fastest corresponding worst case algorithm so far.