In Silico Biology - Volume 6, issue 1-2

Authors: Doi, Atsushi | Nagasaki, Masao | Matsuno, Hiroshi | Miyano, Satoru

Article Type: Research Article

Abstract: MDM2 and p19ARF are essential proteins in cancer pathways forming a complex with protein p53 to control the transcriptional activity of protein p53. It is confirmed that protein p53 loses its transcriptional activity by forming the functional dimer with protein MDM2. However, it is still unclear that protein p53 keeps its transcriptional activity when it forms the trimer with proteins MDM2 and p19ARF. We have observed mutual behaviors among genes p53, MDM2, p19ARF and their products …on a computational model with hybrid functional Petri net (HFPN) which is constructed based on information described in the literature. The simulation results suggested that protein p53 should have the transcriptional activity in the forms of the trimer of proteins p53, MDM2, and p19ARF. This paper also discusses the advantages of HFPN based modeling method in terms of pathway description for simulations. Show more

Keywords: Hybrid functional Petri net, p53, biological pathway, simulation

Citation: In Silico Biology, vol. 6, no. 1-2, pp. 1-13, 2006

Authors: Konieczny, Leszek | Brylinski, Michal | Roterman, Irena

Article Type: Research Article

Abstract: The model adopting the three-dimensional Gauss function to express the hydrophobicity distribution in proteins is presented in this paper. The tendency to create the hydrophobic center during protein folding is expressed in form of an external force field of the form of three-dimensional Gauss function which directs the folding polypeptide to locate the hydrophobic residues in a central part of the molecule and hydrophilic ones exposed toward the molecular surface. The decrease of the differences between …hydrophobicity distribution as it appears at each step of the folding simulation and the expected hydrophobicity distribution (three-dimensional Gauss function) is the convergence criterion together with traditional non-bonding interaction optimization. The model was applied to fold the hypothetical membrane protein (target protein in CASP6) TA0354_69_121 from Thermoplasma acidophilum. Show more

Keywords: Protein folding, hydrophobicity, hydrophobic collapse, Gauss function, CASP, protein structure prediction

Citation: In Silico Biology, vol. 6, no. 1-2, pp. 15-22, 2006

Authors: Khan, Imtiaz A. | Mort, Matthew | Buckland, Paul R. | O'Donovan, Michael C. | Cooper, David N. | Chuzhanova, Nadia A.

Article Type: Research Article

Abstract: DNA sequence features were sought that could be used for the in silico ascertainment of the likely functional consequences of single nucleotide changes in human gene promoter regions. To identify relevant features of the local DNA sequence context, we transformed into consensus tables the nucleotide composition of sequences flanking 101 promoter SNPs of type C↔T or A↔G, defined empirically as being either 'functional' or 'non-functional' on the basis of a standardised reporter …gene assay. The similarity of a given sequence to these consensus tables was then measured by means of the Shapiro-Senapathy score. A decision rule with the potential to discriminate between empirically ascertained functional and non-functional SNPs was proposed that potentiated discrimination between functional and non-functional SNPs with a sensitivity of 80% and a specificity of 20%. Two further datasets (viz. disease-associated SNPs of types A↔G and C↔T (N=75) and pathological promoter mutations (transitions, N=114)) were retrieved from the Human Gene Mutation Database (HGMD; http://www.hgmd.org/) and analyzed using consensus tables derived from the functional and non-functional promoter SNPs; ∼70% were correctly recognized as being of probable functional significance. Complexity analysis was also used to quantify the regularity of the local DNA sequence environment. Functional SNPs/mutations of type C↔T were found to occur in DNA regions characterized by lower average sequence complexity as measured with respect to symmetric elements; complexity values increased gradually from functional SNPs and pathological mutations to functional disease-associated SNPs and non-functional SNPs. This may reflect the internal axial symmetry that frequently characterizes transcription factor binding sites. Show more

Keywords: Promoter, polymorphism, mutation, functional significance, discriminant analysis, DNA sequence complexity

Citation: In Silico Biology, vol. 6, no. 1-2, pp. 23-34, 2006

Authors: Matute, Daniel R. | Barreto-Hernandez, Emiliano | Falquet, Laurent

Article Type: Research Article

Abstract: Automatically finding new protein domains is a challenge when using the complete collection of known proteins (i.e., UniProt). By limiting the taxonomic range to class insecta, including two full proteomes (A. gambiae and D. melanogaster), we reduced the size of the search space in the hope of finding taxon-specific domains. The MKDOM2 program (http://prodes.toulouse.inra.fr/prodom/xdom/mkdom2.html) was used to cluster the insect proteins into potential domains that were analyzed manually in a second step. …We analyzed 219 potential domains, of which 2 were insect-specific. We show that it is possible to find new domains or to extend known domains using a semi-automated method; however the goal to detect class-specific domains was only partially achieved in the sense that the new domains we found were not all insect-specific domains. The files used as input and the resulting output files, as well as extensive descriptions of the domains, are available as supplementary data from http://bioinf.ibun.unal.edu.co/insecta/. Show more

Keywords: Domains, insect, ProDom, Prosite, HMM, MKDOM

Citation: In Silico Biology, vol. 6, no. 1-2, pp. 35-42, 2006

Authors: Dutta, Anirban | Singh, Shashi Kr. | Ghosh, Payel | Mukherjee, Runni | Mitter, Sayak | Bandyopadhyay, Debashis

Article Type: Research Article

Abstract: Availability of genome sequences of pathogens has provided a tremendous amount of information that can be useful in drug target and vaccine target identification. One of the recently adopted strategies is based on a subtractive genomics approach, in which the subtraction dataset between the host and pathogen genome provides information for a set of genes that are likely to be essential to the pathogen but absent in the host. This approach has been used successfully in …recent times to identify essential genes in Pseudomonas aeruginosa. We have used the same methodology to analyse the whole genome sequence of the human gastric pathogen Helicobacter pylori. Our analysis revealed that out of the 1590 coding sequences of the pathogen, 40 represent essential genes that have no human homolog. We have further analysed these 40 genes by the protein sequence databases to list some 10 genes whose products are possibly exposed on the pathogen surface. This preliminary work reported here identifies a small subset of the Helicobacter proteome that might be investigated further for identifying potential drug and vaccine targets in this pathogen. Show more

Keywords: Helicobacter, comparative microbial genomics, subtractive genomics, novel drug targets, putative vaccine targets, surface proteins

Citation: In Silico Biology, vol. 6, no. 1-2, pp. 43-47, 2006

Authors: Arakawa, Kazuharu | Nakayama, Yoichi | Tomita, Masaru

Article Type: Research Article

Abstract: In view of the recent explosion in genome sequence data, and the 200 or more complete genome sequences currently available, the importance of genome-scale bioinformatics analysis is increasing rapidly. However, computational genome informatics analyses often lack a statistical assessment of their sensitivity to the completeness of the functional annotation. Therefore, a pre-analysis method to automatically validate the sensitivity of computational genome analyses with regard to genome annotation completeness is useful for this …purpose. In this report we developed the Gene Prediction Accuracy Classification (GPAC) test, which provides statistical evidence of sensitivity by repeating the same analysis for five different gene groups (classified according to annotation accuracy level), and for randomly sampled gene groups, with the same number of genes as each of the five classified groups. Variability in these results is then assessed, and if the results vary significantly with different data subsets, the analysis is considered "sensitive" to annotation completeness, and careful selection of data is advised prior to the actual in silico analysis. The GPAC test has been applied to the analyses of Sakai et al., 2001, and Ohno et al., 2001, and it revealed that the analysis of Ohno et al. was more sensitive to annotation completeness. It showed that GPAC could be employed to ascertain the sensitivity of an analysis. The GPAC benchmarking software is freely available in the latest G-language Genome Analysis Environment package, at http://www.g-language.org/. Show more

Keywords: Bioinformatics, genome analysis, software, annotation, genome informatics

Citation: In Silico Biology, vol. 6, no. 1-2, pp. 49-60, 2006

Authors: Wessel, Ralf | Foos, Volker | Aspelmeier, Allan | Jürgens, Martin | Graessmann, Adolf | Klein, Andreas

Article Type: Research Article

Abstract: CorrXpression is a stand-alone desktop application for the identification of significant genes within collections of microarrays. The software combines three methods in two steps of analysis: correspondence analysis (CA), ratio analysis and correlation analysis. The graphical interface of CorrXpression visualizes the result of the CA with a biplot and the expression of selected genes in dependency of the experiments as bar diagrams. The CA-plot is an excellent tool for visualization and evaluation of data and …results of ratio analysis and correlation analysis. The input data are selected from a database or from appropriate ASCII files. Show more

Keywords: Microarray, correspondence analysis, correspondence plot, principal component analysis, gene expression, database, breast cancer

Citation: In Silico Biology, vol. 6, no. 1-2, pp. 61-70, 2006

Authors: Kumar, Lokesh | Futschik, Matthias | Herzel, Hanspeter

Article Type: Research Article

Abstract: Genomic DNA sequences contain a wealth of information about the bendability and curvature of the DNA molecule. For example, the well-known 10–11 bp periodicities within genomes can be attributed to supercoiled structures or wrapping around nucleosomes. Such periodic signals have previously been examined mainly based on mono- or dinucleotide correlations. In this study, we generalize this approach and analyze correlation functions of longer motifs such as tetramers or poly(A) sequences. Periodically placed …motifs may indicate regular protein binding or curvature signals. We detected various periodic signals e.g. strong 10–11 bp oscillations of periodically placed poly(A), poly(T) or poly(W) stretches. These observations lead to a new view on the intensively studied 10–11 bp periodicities. Show more

Keywords: Genomic DNA, periodicities, supercoiling, nucleosomes, motif, correlation, C. elegans, DNA bendability, poly(A) sequences

Citation: In Silico Biology, vol. 6, no. 1-2, pp. 71-78, 2006

Authors: Komura, Daisuke | Nishimura, Kunihiro | Ishikawa, Shumpei | Panda, Binaya | Huang, Jing | Nakamura, Hiroshi | Ihara, Sigeo | Hirose, Michitaka | Jones, Keith W. | Aburatani, Hiroyuki

Article Type: Research Article

Abstract: Genomic copy number change is one of the important phenomenon observed in cancer and other genetic disorders. Recently oligonucleotide microarrays have been used to analyze changes in the copy number. Although high density microarrays provide genome wide useful data on copy number, they are often associated with substantial amount of experimental noise that could affect the performance of the analyses. We used the high density oligonucleotide genotyping microarrays in our experiments that uses redundant …probe tiling approach for individual SNPs. We found that the noise in the genotyping microarray data is associated with several experimental steps during target preparation and devised an algorithm that takes into account those experimental parameters. Additionally, defective probes that do not hybridize well to the target and therefore could not be modified inherently were detected and omitted automatically by using the algorithm. When we applied the algorithm to actual datasets, we could reduce the noise substantially without compressing the dynamic range. Additionally, combinatorial use of our noise reduction algorithm and conventional breakpoint detection algorithm successfully detected a microamplification of c-myc which was overlooked in the raw data. The algorithm described here is freely available with the software upon request to all non-profit researchers. Show more

Keywords: Gene dosage, genotyping microarray, noise reduction

Citation: In Silico Biology, vol. 6, no. 1-2, pp. 79-92, 2006

Authors: Gambin, Anna | Lasota, Sıawomir | Rutkowski, Michaı

Article Type: Research Article

Abstract: We introduce and formally define the notion of a stationary state for Petri nets. We also propose a fully automatic method for finding such states. The procedure makes use of the Presburger arithmetic to describe all the stationary states. Finally we apply this novel approach to find stationary states of a gene regulatory network describing the flower morphogenesis of A. thaliana. This shows that the proposed method can be successfully applied in the study of biological …systems. Show more

Keywords: Petri net, stationary state, gene regulatory network, Presburger arithmetic, flower morphogenesis, Arabidopsis thaliana

Citation: In Silico Biology, vol. 6, no. 1-2, pp. 93-109, 2006

Authors: Kaur, Harpreet | Raghava, Gajendra Pal Singh

Article Type: Research Article

Abstract: In this study, an attempt has been made to develop a method for predicting weak hydrogen bonding interactions, namely, C^{α} -H·O and C^{α} -H·π interactions in proteins using artificial neural network. Both standard feed-forward neural network (FNN) and recurrent neural networks (RNN) have been trained and tested using five-fold cross-validation on a non-homologous dataset of 2298 protein chains where no pair of sequences has more than 25% sequence identity. It …has been found that the prediction accuracy varies with the separation distance between donor and acceptor residues. The maximum sensitivity achieved with RNN for C^{α} -H·O is 51.2% when donor and acceptor residues are four residues apart (i.e. at Δ_{D-A} =4) and for C^{α} -H·π is 82.1% at Δ_{D-A} =3. The performance of RNN is increased by 1–3% for both types of interactions when PSIPRED predicted protein secondary structure is used. Overall, RNN performs better than feed-forward networks at all separation distances between donor-acceptor pair for both types of interactions. Based on the observations, a web server CHpredict (available at http://www.imtech.res.in/raghava/chpredict/) has been developed for predicting donor and acceptor residues in C^{α} -H·O and C^{α} -H·π interactions in proteins. Show more

Keywords: Weak hydrogen bonds, donor, acceptor, prediction, neural network, secondary structure

Citation: In Silico Biology, vol. 6, no. 1-2, pp. 111-125, 2006

Authors: Seshasayee, Aswin Sai Narain

Article Type: Research Article

Abstract: Protein-protein interaction networks are useful in contextual annotation of protein function and in general to achieve a system-level understanding of cellular behavior. This work reports on the social behavior of the yeast protein-protein interaction network and concludes that it is non-random. This work, while providing an analysis of organization of genes into functional societies, can potentially be useful in assessing the accuracy of contextual gene annotation based on such interaction networks.

Keywords: Protein-protein interaction, small world, clustering coefficient, pathway, contextual annotation

Citation: In Silico Biology, vol. 6, no. 1-2, pp. 127-130, 2006

Authors: Bock, Christoph | Hesser, Jürgen

Article Type: Research Article

Abstract: High sequence identity between two proteins (e.g. > 60% is a strong evidence for high structural similarity. However, internal shifts in one of the two proteins can sometimes give rise to unexpectedly high structural differences. This, in turn, causes unreliable structure predictions when two such proteins are used in homology modeling. Here, we perform a computational analysis of helix shifts and we show that their occurrence can be predicted with statistical learning methods. Our …results indicate that helix shifts increase the RMS error by factor 2.6 compared to those protein pairs without a helix shift. Although helix shifts are rare (1.6% of helices and a commensurately higher number of proteins are affected), they therefore pose a significant problem for reliable structure prediction systems. In this paper, we prototype a new approach for model quality assessment and demonstrate that it can successfully warn against helix shifts. A support vector machine trained on a wide range of sequence and structure properties predicts the occurrence of helix shifts with a sensitivity of 74.2% and a specificity of 83.6%. On an equalized test dataset, this corresponds to an accuracy of 78.9%. Projected to the full dataset, it translates to an accuracy of 83.4%. Our analysis shows that helix shift detection is a valuable building block for highly reliable structure prediction systems. Furthermore, the statistical learning based approach to helix shift detection that we employ here is orthogonal to well-established model quality assessment methods (which use geometric constraint checking or mean force potentials). Therefore, a further increase of prediction accuracy is expected from the combination of these methods. Show more

Keywords: Comparative modeling, homology modeling, error sources, MQAP, helix movement, secondary structure

Citation: In Silico Biology, vol. 6, no. 1-2, pp. 131-145, 2006

Authors: Mizuta, Satoshi | Munakata, Hikaru | Aimaiti, Abulimiti | Oya, Ichitaro | Oosawa, Kenji | Shimizu, Toshio

Article Type: Research Article

Abstract: Genomes contain various types of repetitive sequences. They may be used as probes for seeking genome rearrangements because they are rather free from the natural selection if they are located in the intergenic regions. In this study, we searched for tandem repeats (TRs) in 44 prokaryotic genomes by the color-coding method and sought the signs of genome rearrangements by detailed analysis of the detected TRs. We found 13,542 tandem repeats from 44 prokaryotic genomes in total …ranging from several tens to one thousand per genome. The results of statistical analysis show that TRs tend to exist on high base composition bias regions in some genomes. Moreover, we recognized the characteristic distribution patterns of equivalent TR-pairs in 12 genomes, which are expected to indicate the occurrence of whole-genome duplication (WGD) on the genomes. It is demonstrated that TRs could indeed be used for seeking genome rearrangements. Although it has not been made clear at this time whether or not WGD had occurred in prokaryotic genomes, the results of the analyses of equivalent TR-pairs in this study are thought to be evidences of WGD in these genomes. Show more

Keywords: Tandem repeats, color-coding, genome rearrangement, prokaryotes

Citation: In Silico Biology, vol. 6, no. 1-2, pp. 147-159, 2006