In Silico Biology - Volume 7, issue 6

Authors: Jaiswal, Kunal

Article Type: Research Article

Abstract: Ubiquitin functions to regulate protein turnover in a cell by closely regulating the degradation of specific proteins. Such a regulatory role is very important, and thus I have analyzed the proteins that are ubiquitin-like, using an artificial neural network, support vector machines and a hidden Markov model (HMM). The methods were trained and tested on a set of 373 ubiquitin proteins and 373 non-ubiquitin proteins, obtained from Entrez protein database. The artificial neural network and support …vector machine are trained and tested using both the physicochemical properties and PSSM matrices generated from PSI-BLAST, while in the HMM based method direct sequences are used for training-testing procedures. Further, the performance measures of the methods are calculated for test sequences, i.e. accuracy, specificity, sensitivity and Matthew's correlation coefficients of the methods are calculated. The highest accuracy of 90.2%, specificity of 87.04% and sensitivity of 94.08% was achieved using the support vector machine model with PSSM matrices. While accuracies of 86.82%, 83.37%, 80.18% and 72.11% were obtained for the support vector machine with physicochemical properties, neural network with PSSM matrices, neural networks with physicochemical properties, and hidden Markov model, respectively. As the accuracy for SVM model is better both using physicochemical properties and the PSSM matrices, it is concluded that kernel methods such as SVM outperforms neural networks and hidden Markov models. Show more

Keywords: Ubiquitin proteins, support vector machine, artificial neural networks, hidden Markov model, physicochemical properties, PSI-BLAST, PSSM Matrices, binary classifier

Citation: In Silico Biology, vol. 7, no. 6, pp. 559-568, 2007

Authors: Chen, Shu | Chinnaswamy, Arunkumar | Biswas, Subhra K. | Goryachev, Andrew B. | Yap, Choon-Kong | Lam, Koi-Yau | Tay, Cheng-Pei | Low, Hong-Sang | Pokhilko, Alexandra | Da-Jun, Toh | Mishra, Santosh K.

Article Type: Research Article

Abstract: The innate immune system is fundamental to the recognition of pathogens, triggering of immune-inflammatory response and host defense. Recent advance in this area has resulted in enormous amount of data, which are stored across different databases. Integrating relevant information from these different data sources is difficult because of their heterogeneous nature and dispersed physical location. We present here a single portal system, Cell Interaction Knowledgebase, with focus on the innate immunity. In particular, …the knowledgebase houses comprehensive information on innate immune cells and cytokines/chemokines which are the principal mediators of communication among the immune cells. Currently the knowledgebase consists of extensive information on 2 major innate immune cell types (Macrophages and Dendritic cells) and 7 6 cytokines/chemokines for both human and mouse. In addition, intra-cellular molecular interactions and inter-cellular interactions involved in the innate immunity are curated and presented in an interactive and dynamic manner by animated pathways and query-driven cell-interaction map respectively. This is one of the first databases that houses extensive phenotypic, signaling, genomic, proteomic and knockout data on both the innate immune cells and their attendant cytokines/chemokines, and is aimed to evolve as a one-stop-shop for immunologists. The first version of database is available at http://cell-interaction.bii.a-star.edu.sg/. Show more

Keywords: Innate immunity, immune cell, cytokine/chemokine, knowledgebase

Citation: In Silico Biology, vol. 7, no. 6, pp. 569-574, 2007

Authors: Kourmpetis, Yiannis A.I. | van der Burgt, Ate | Bink, Marco C.A.M. | ter Braak, Cajo J.F. | van Ham, Roeland C.H.J.

Article Type: Research Article

Abstract: The Gene Ontology (GO) is a widely used controlled vocabulary for the description of gene function. In this study we quantify the usage of multiple and hierarchically independent GO terms in the curated genome annotations of seven well-studied species. In most genomes, significant proportions (6–60%) of genes have been annotated with multiple and hierarchically independent terms. This may be necessary to attain adequate specificity of description. One noticeable exception is Arabidopsis thaliana, …in which genes are much less frequently annotated with multiple terms (6–14%). In contrast, an analysis of the occurrence of InterPro hits in the proteomes of the seven species, followed by a mapping of the hits to GO terms, did not reveal an aberrant pattern for the A. thaliana genome. This study shows the widespread usage of multiple hierarchically independent GO terms in the functional annotation of genes. By consequence, probabilistic methods that aim to predict gene function automatically through integration of diverse genomic datasets, and that employ the GO, must be able to predict such multiple terms. We attribute the low frequency with which multiple GO terms are used in Arabidopsis to deviating practices in the genome annotation and curation process between communities of annotators. This may bias genome-scale comparisons of gene function between different species. GO term assignment should therefore be performed according to strictly similar rules and standards. Show more

Keywords: Gene Ontology, genome annotation, annotation strategies, protein function, gene function prediction, multi-label classification, Arabidopsis genome

Citation: In Silico Biology, vol. 7, no. 6, pp. 575-582, 2007

Authors: Kundu, Sangeeta | Roy, Debjani

Article Type: Research Article

Abstract: Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) of pathogenic protozoa Trichomonas vaginalis (TvGAPDH) is an attractive drug target since this parasite lacks functional citric acid cycle and is dependent solely on glycolysis for its energy requirements. The three dimensional structure of TvGAPDH dimer has been generated by homology modelling based on the crystal structure of human liver GAPDH. Comparison of the NAD^{+} binding pocket of the modeled TvGAPDH with human GAPDH (hGAPDH) reveals the …presence of a hydrophobic pocket near the N-6 position of adenine ring as well as a hydrophobic cleft near O-2' of the adenosine ribose that are absent in the human enzyme. In order to exploit these structural differences adenosine and several adenosine analogs with substitution on N-6 position of adenine ring or 2' position of ribose sugar or both have been studied by docking experiments using the program AutoDock version 3.0.5. Our docking result suggests that bulkier hydrophobic substitution at the N-6 position of the adenine ring could form more stable complexes with TvGAPDH than with hGAPDH. An improvement of binding occurs in TvGAPDH when methoxybenzamido group has been introduced at the O-2' position of the ribose sugar. The combination of N-6 and O-2' substitutions may have produced significantly improved inhibitors. Our study may help in identifying structural elements involved in the origin of selectivity at the NAD^{+} binding pocket of TvGAPDH. This study could further be extended for future anti-trichomonal drug design strategies in order to control trichomoniasis. Show more

Keywords: Trichomonas vaginalis, homology modeling, glyceraldehyde-3-phosphate dehydrogenase, docking, drug-design

Citation: In Silico Biology, vol. 7, no. 6, pp. 583-593, 2007

Authors: Farwer, Jochen | Packer, Martin J. | Hunter, Christopher A.

Article Type: Research Article

Abstract: We announce the release of a web-based tool for DNA structure prediction (PREDICTOR) which allows the calculation of atomic structures of double-helical DNA with up to 150 Watson-Crick base pairs (http://farwer.staff.shef.ac.uk/ PREDICTOR). The semi-empirical method uses computational chemistry to extrapolate knowledge of sequence-dependent DNA structure contained in the X-ray crystal structure database. The properties of the base stacking interactions are treated theoretically, and an empirical model is used to add the conformational …constraints imposed by the backbone. For DNA oligomers in the X-ray crystal structure database that were not used for parameterisation of the model, the method distinguishes A and B form DNA reasonably reliably, and the final structures are accurate to 2 å rmsd. Simulation of a 150mer and a 494mer with experimentally confirmed bending clearly reproduces the bending whereas the predicted structure of a random 150mer does not show any curvature. Calculation times are 90 seconds for an octamer and 7 minutes for a 30mer. Show more

Keywords: DNA conformation, DNA sequence-dependent structure, DNA atomic structure prediction, step parameters, DNA backbone conformation

Citation: In Silico Biology, vol. 7, no. 6, pp. 595-600, 2007

Authors: Sridhar, Jayavel | Rafi, Ziauddin Ahamed

Article Type: Research Article

Abstract: Genome evolution in prokaryotes is assisted by integration of gene pools from phages and plasmids. Regions downstream of tRNAs and tmRNAs are considered as hot spots for the integration of these gene pools or genomic islands. Till date, genomic islands have been identified only at tRNA/tmRNA genes in the enterobacterial genomes. Present work reports 10 distinct small RNAs as potent integration sites for genomic islands. A known tool tRNAcc 1.0 has been used to …identify genomic islands associated with small RNAs c0362, oxyS, ryaA, rybB, rybD, ryeB, ryeE, rtT, sraE and tmRNA. The coordinates of 25 such small RNA associated genomic islands in three E. coli (strains: CFT073, EDL933 and K12) and Shigella flexneri (strain: 301) genomes are presented. Moreover cross-verification of the genomic sequences encoded within the identified genomic islands in horizontal gene transfer database, GenBank annotation features and atypical sequence compositions support our results. Again, all of the identified 25 genomic integration sites do exhibit genomic block rearrangements with respect to the associated small RNA. Similar to tRNAs/tmRNAs, the downstream regions of the small RNAs are found to be hotspots of integration. Show more

Keywords: sRNA, genomic islands, genomic blocks, integration sites, phage elements

Citation: In Silico Biology, vol. 7, no. 6, pp. 601-611, 2007

Authors: Stephan, Martin | Möller, Friedrich | Wiehe, Thomas | Kleffe, Jürgen

Article Type: Research Article

Abstract: The surprisingly low number of about 25,000 genes in the human genome [1] confirmed a fairly accurate estimate given by King and Jukes in 1969 based on population genetical arguments [2]. On the other hand, the number of different transcripts vastly exceeds gene number. This fact intensified the search for alternatively spliced genes. Recent results [1,3,4-7] suggest that more than 60% of the human genes are alternatively spliced, some of them with a myriad of different …splice forms. Alternative splicing is found in all higher eukaryotic species in varying frequency. In this paper we focus on a particular form of alternative splicing, the so-called mutually exclusive exon usage (MEEU). In most known examples mutually exclusive exons are arranged in cassettes of highly similar exons suggesting that they have been derived by exon duplication [8-10]. Since classical gene-finding programs may fail to correctly predict such genes [11-16], we present a method, which is based on local similarity of exons, to detect gene candidates with mutually exclusive exon usage. We have screened the entire genome of D. melanogaster and found five new genes with MEEU in addition to eight previously described cases. Additional 1703 candidate regions of putative mutually exclusive exons were identified. Show more

Keywords: Alternative splicing, mutually exclusive exon usage, gene prediction, exon similarity, exon duplication

Citation: In Silico Biology, vol. 7, no. 6, pp. 613-621, 2007

Authors: Jeong, Euna | Nagasaki, Masao | Saito, Ayumu | Miyano, Satoru

Article Type: Research Article

Abstract: With the rapidly accumulating knowledge of biological entities and networks, there is a growing need for a general framework to understand this information at a system level. In order to understand life as system, a formal description of system dynamics with semantic validation will be necessary. Within the context of biological pathways, several formats have been proposed, e.g., SBML, CellML, and BioPAX. Unfortunately, these formats lack the formal definitions of each term or fail to capture …the system dynamics behavior. Thus, we have developed a new system dynamics centered ontology called Cell System Ontology (CSO). As an exchange format, the ontology is implemented in the Web Ontology Language (OWL), which enables semantic validation and automatic reasoning to check the consistency of biological pathway models. The features of CSO are as follows: (1) manipulation of different levels of granularity and abstraction of pathways, e.g., metabolic pathways, regulatory pathways, signal transduction pathways, and cell-cell interactions; (2) capture of both quantitative and qualitative aspects of biological function by using hybrid functional Petri net with extension (HFPNe); and (3) encoding of biological pathway data related to visualization and simulation, as well as modeling. The new ontology also predefines mature core vocabulary, which will be necessary for creating models with system dynamics. In addition, each of the core terms has at least one standard icon for easy modeling and accelerating the exchangeability among applications. In order to demonstrate the potential of CSO-based pathway modeling, visualization, and simulation, we present an HFPNe model for the ASEL and ASER regulatory networks in Caenorhabditis elegans. Show more

Keywords: Cell system ontology, CSO, biological pathway, data exchange format, HFPNe, dynamic simulation, visualization

Citation: In Silico Biology, vol. 7, no. 6, pp. 623-638, 2007

Authors: Karmaker, Amitava | Kwek, Stephen

Article Type: Research Article

Abstract: DNA copy number aberrations along the genome are vital markers for studying pathogenesis of various diseases including cancers. Array-based Comparative Genome Hybridization (aCGH), which is a high-throughput cytogenetic method, helps in identifying genome-wide copy number aberrations, both gains and losses. Here, we propose a computational technique to analyze aCGH data and to identify potential DNA copy number alterations along the genome. Our technique detects the possible breakpoints by comparing contiguous probe log …ratios, reports the aberrant segments and handles outliers to minimize false discovery rate. Empirically, we tested our algorithm on both prokaryotic (Brucella ovis) and eukaryotic (glioblastoma and colorectal cancer datasets from human) genomes. Our findings complement previous studies; our performance is competitive, sometimes superior, against other popular methods. Show more

Keywords: aCGH, chromosomal aberration, DNA copy number

Citation: In Silico Biology, vol. 7, no. 6, pp. 639-649, 2007

Authors: Tiwari, Abhishek | Panigrahi, Sunil K.

Article Type: Research Article

Abstract: The program HBAT is a tool to automate the analysis of potential hydrogen bonds and similar type of weak interactions like halogen bonds and non-canonical interactions in macromolecular structures, available in Brookhaven Protein Database (PDB) file format. HBAT is written using PERL and TK languages. The program generates an MSOFFICE Excel compatible output file for statistical analysis. HBAT identify potential interactions based on geometrical criteria. A series of analysis reports like frequency tables, …geometry distribution tables, furcations list are generated. A user friendly GUI offers freedom to select several parameters and options. Graphviz based visualization of hydrogen bond networks in 2D helps to study the cooperativity and anticooperativity geometry in hydrogen bond. HBAT supports post docking interaction analysis between PDB files for any target/receptor (in PDB files) and docked ligands/poses (in SDF). This tool can be implemented in active site interaction analysis, structure based drug design and molecular dynamics simulations. Show more

Keywords: Hydrogen bond, software, geometrical analysis, water, cooperativity

Citation: In Silico Biology, vol. 7, no. 6, pp. 651-661, 2007