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ISSN 1386-6338 (P)
ISSN 1434-3207 (E)
In Silico Biology is a scientific research journal for the advancement of computational models and simulations applied to complex biological phenomena. We publish peer-reviewed leading-edge biological, biomedical and biotechnological research in which computer-based (i.e.,
) modeling and analysis tools are developed and utilized to predict and elucidate dynamics of biological systems, their design and control, and their evolution. Experimental support may also be provided to support the computational analyses.
In Silico Biology aims to advance the knowledge of the principles of organization of living systems. We strive to provide computational frameworks for understanding how observable biological properties arise from complex systems. In particular, we seek for integrative formalisms to decipher cross-talks underlying systems level properties, ultimate aim of multi-scale models.
Studies published in
In Silico Biology generally use theoretical models and computational analysis to gain quantitative insights into regulatory processes and networks, cell physiology and morphology, tissue dynamics and organ systems. Special areas of interest include signal transduction and information processing, gene expression and gene regulatory networks, metabolism, proliferation, differentiation and morphogenesis, among others, and the use of multi-scale modeling to connect molecular and cellular systems to the level of organisms and populations.
In Silico Biology also publishes foundational research in which novel algorithms are developed to facilitate modeling and simulations. Such research must demonstrate application to a concrete biological problem.
In Silico Biology frequently publishes special issues on seminal topics and trends. Special issues are handled by Special Issue Editors appointed by the Editor-in-Chief. Proposals for special issues should be sent to the Editor-in-Chief.
About In Silico Biology
is a pendant to
(in the living system) and
(in the test tube) biological experiments, and implies the gain of insights by computer-based simulations and model analyses.
In Silico Biology (ISB) was founded in 1998 as a purely online journal. IOS Press became the publisher of the printed journal shortly after. Today, ISB is dedicated exclusively to biological systems modeling and multi-scale simulations and is published solely by IOS Press. The previous online publisher, Bioinformation Systems, maintains a website containing studies published between 1998 and 2010 for archival purposes.
We strongly support open communications and encourage researchers to share results and preliminary data with the community. Therefore, results and preliminary data made public through conference presentations, conference proceeding or posting of unrefereed manuscripts on preprint servers will not prohibit publication in ISB. However, authors are required to modify a preprint to include the journal reference (including DOI), and a link to the published article on the ISB website upon publication.
Abstract: Sporulation involves inducing scores of genes in a temporally and spatially coordinated cell development programme. Its initiation is controlled by an expanded two-component signal transduction system, termed a phosphorelay. The Spo0A response regulator is the master control element in the decision to sporulate, consisting of a receiver or phosphoacceptor domain and an effector or transcription activation domain having a high degree of sequence conservation. This study examined long-term Spo0A protein evolution for…determining whether concerted evolution or purifying selection was the major factor in its evolution. The proportion of synonymous (pS) and non-synonymous nucleotide (pN) differences between Spo0A genes from 28 bacterial species was analysed. DIVERGE software was used for evaluating site-specific amino acids before phylogenetic divergence between Bacillus and Clostridium for detecting site-selective constrains operating on the Spo0A protein. Evolutionary Trace software was used for tracing the phylogenetic markers for this protein.
Keywords: Sporulation, phosphorelay, Spo0A, protein evolution, selective constrains, phylogenetic markers
Abstract: Modern high-throughput techniques allow for the identification and quantification of hundreds of metabolites of a biological system which cover central parts of the metabolome. Due to the amount and complexity of obtained data there is an increasing need for the development of appropriate computational interpretation methods. A novel data analysis pipeline designed for high-throughput determined metabolomic data is presented. The combination of principal component analysis (PCA) with emergent self-organizing maps (ESOM)…and hierarchical cluster analysis (HCA) algorithms is used to unravel the structure underlying metabolomic data sets, including the detection of outliers. Observed differences between various analyzed metabolomes are automatically mapped and visualized using KEGG metabolic pathway maps. This way typical metabolic biomarker for data sets from various analyzed growth conditions and genetic backgrounds become visible. In order to validate the described methods we analyzed time resolved metabolomic datasets obtained for Corynebacterium glutamicum cells grown on various carbon sources consisting of 126 different metabolic patterns. The analysis pipeline was implemented in the user-friendly Java software eSOMet. The software was successfully used for the clustering of the metabolome data mentioned above. Metabolic biomarkers typical for the utilized carbon sources and analyzed growth phases were identified.
Keywords: Emergent self-organizing maps, cluster analysis, comparative metabolome data analysis
Abstract: The computational prediction of protein-protein interactions (PPI) is an essential complement to direct experimental evidence. Traditional approaches rely on less available or computationally predicted surface properties, show database-specific performances and are computationally expensive for large-scale datasets. Several sensitivity and specificity issues remain. Here, we report a novel method based on 'Amino-acid Residue Associations' (ARA) among interacting proteins which utilizes the accurate and easily available primary sequence. Large scale PPI datasets…for six model species (from E. coli to human) were studied. The ARA method shows up to 73% sensitivity and 78% specificity. Furthermore, the method performs remarkably well in terms of stability and generalizability. The performance of ARA method benchmarked against existing prediction techniques shows performance improvement up to 25%. Ability of ARA method to predict PPI across species and across databases is also demonstrated. Overall, the ARA method provides a significant improvement over existing ones in correctly identifying large scale protein-protein interactions, irrespective of the data resource, network size or organism.
Abstract: Plasmodium falciparum is the parasite responsible for more than 90% of deaths that occur due to malaria. Organization and mining of 'omic' (genomic, proteomic, transcriptomic, interactomic) data can improve our understanding of P. falciparum biology and help in the fight against malaria. PlasmoID (Plasmodium Information Discovery) is a tool developed for the dynamic exploration of the parasite's 'omic' landscape. Diverse computational and curated P. falciparum protein-protein interaction datasets, as well as binary…relationships involving protein-small molecule entities, manually curated protein-protein relationships derived from the published literature and protein-protein interactions based on metabolic pathways are included in the PlasmoID database. The graphical user interface is designed as a plug-in to Cytoscape, an open-source network visualization tool. Important features of this plug-in include a synchronized tabular representation of any network loaded on the canvas, ability to find the shortest path between a pair of nodes in the database, search and expansion of entities from the database, and the ability to add new entities to the database through the interface. Malaria researchers can now seamlessly interrogate heterogeneous 'omic' datasets as well as add proprietary data to generate and visualize P. falciparum pathway and cell process network models. PlasmoID can be downloaded from http://pfalciparum.atc.tcs.com/PlasmoID.
Keywords: P. falciparum, malaria, systems biology, PlasmoID, interactome
Abstract: Previous evolutionary study of the tumor suppressor Merlin revealed that this protein family was produced by very early metazoans with the exception of some or all flatworm lineages [Golovnina et al., 2005]. We ask whether other tumor-suppressor proteins had also been in existence in these times and focus our attention on Hyperplastic Discs (Hyd) protein, a classic tumor suppressor in Drosophila melanogaster which, when mutated, may cause over-proliferation and malignancy. Phylogenetic analysis of the Hyd…protein indicates that it was present among metazoa by the time Trichoplax adhaerens had emerged from the common unicellular ancestor of the Animalia.
Abstract: Detailed knowledge of the mechanisms of transcriptional regulation is essential in understanding the gene expression in its entirety. Transcription is regulated, among other things, by transcription factors that bind to DNA and can enhance or repress the transcription process. If a transcription factor fails to bind to DNA or binds to a wrong DNA region that can cause severe effects to the gene expression, to the cell and even to the individual. The problems in transcription…factor binding can be caused by alterations in DNA structure which often occurs when parts of the DNA strands are mutated. An increasing number of the identified disease-related mutations occur in gene regulatory sequences. These regulatory mutations can disrupt transcription factor binding sites or create new ones. We have studied effects of mutations on transcription factor binding affinity computationally. We have compared our results with experimentally verified cases where a mutation in a gene regulatory region either creates a new transcription factor binding site or deletes a previously existing one. We have investigated the statistical properties of the changes on transcription factor binding affinity according to the mutation type. Our analysis shows that the probability of a loss of a transcription factor binding site and a creation of a new one varies remarkably by the mutation type. Our results demonstrate that computational analysis provides valuable information about the effect of mutations on transcription factor binding sites. The analysis results also give a useful test set for in vitro studies of regulatory mutation effects.
Abstract: Neisseria gonorrhoeae is responsible for causing gonorrhea, one of the most common sexually transmitted diseases prevailing globally. Although extensive researches are in progress in order to control the transmission of the disease and to develop drug(s) against the pathogen, till date no effective vaccine or specific drug could be developed and only antibiotic treatment is in use. Perhaps, due to excess use of antibiotics, several resistant strains have been found. In the present study, metabolic pathways-related…candidate drug and vaccine targets have been identified in N. gonorrhoeae virulent strain FA 1090 using an in silico subtractive genomics approach. 106 putative drug targets out of 537 essential genes have been predicted. 67 cytoplasmic and 9 membrane enzymes, along with 10 membrane transporters are found to be the potential drug targets from the host-pathogen common metabolic pathways. Among these targets, competence lipoproteins (NGO0277) and cysW have been identified as candidate vaccine targets. 20 drug targets have been identified from pathogen specific unique metabolic pathways. Out of these, 6 enzymes are involved in dual metabolic pathways and 2 are expressed in cell wall and fimbrium. These gonococci-specific proteins are expected to be better possible drug targets. Screening of the functional inhibitors against these novel targets may result in discovery of novel therapeutic compounds that can be effective against antibiotic resistant strains.
Abstract: It is getting familiar that pathway information greatly contributes to elucidate the molecular basis of human disease with large-scale biological data. We developed a pathway database for molecular pathology in periodontitis named 'Pathogenic Pathway Database for Periodontitis'. Periodontitis is an inflammation disease in periodontal tissue and associated with an increased health risk of angina, myocardial infarction, and fetal cardiovascular events. Despite accumulation of biomedical research on periodontitis pathology at the molecular…level, there has been no systematization for biological pathways in periodontitis. We checked 185 reference papers and extracted causal relationships among molecules as well as pathways representing molecular etiology. We also built an ontology that systematizes conceptual terms associated with the pathways. Besides pathways, our ontology provides cellular and tissue specific contextual information that is required to represent pathology at the cellular and tissue specific levels. We implemented in our database an integrated viewer for the association between pathways and ontology. Pathogenic Pathway Database for Periodontitis is freely available at http://bio-omix.tmd.ac.jp/disease/perio/.
Keywords: Pathway database, ontology, pathogenic pathway, periodontitis, alveolar bone resorption
Abstract: Bacteria have developed several defense mechanisms against bacteriophages over evolutionary time, but the concept of prokaryotic RNA interference mediated defense mechanism against phages and other invading genetic elements has emerged only recently. Clustered regularly interspaced short palindromic repeats (CRISPR) together with closely associated genes (cas genes) constitute the CASS system that is believed to provide a RNAi-like defense mechanism against bacteriophages within the host bacterium. However, a CASS mediated RNAi-like pathway…in enteric pathogens such as Vibrio cholerae O395 or Escherichia coli O157 have not been reported yet. This study specifically was designed to investigate the possibility and evolutionary origin of CASS mediated RNAi-like pathway in the genome of a set of enteric pathogens, especially V. cholerae. The results showed that V. cholerae O395 and also other related enteric pathogens have the essential CASS components (CRISPR and cas genes) to mediate a RNAi-like pathway. The functional domains of a V. cholerae Cas3 protein, which is believed to act as a prokaryotic Dicer, was revealed and compared with the domains of eukaryotic Dicer proteins. Extensive homology in several functional domains provides significant evidence that the Cas3 protein has the essential domains to play a vital role in RNAi like pathway in V. cholerae. The secondary structure of the pre-siRNA for V. cholerae O395 was determined and its thermodynamic stability also reinforced the previous findings and signifies the probability of a RNAi-like pathway in V. cholerae O395.
Keywords: CRISPR, cas genes, prokaryotic RNA interference, Vibrio cholerae O395
Abstract: Guanine is the most mutable nucleotide in HIV genes because of frequently occurring G to A transitions, which are caused by cytosine deamination in viral DNA minus strands catalyzed by APOBEC enzymes. Distribution of guanine between three codon positions should influence the probability for G to A mutation to be nonsynonymous (to occur in first or second codon position). We discovered that nucleotide sequences of env genes coding for third variable regions (V3 loops) of…gp120 from HIV1 and HIV2 have different kinds of guanine usage biases. In the HIV1 reference strain and 100 additionally analyzed HIV1 strains the guanine usage bias in V3 loop coding regions (2G>1G≫3G) should lead to elevated nonsynonymous G to A transitions occurrence rates. In the HIV2 reference strain and 100 other HIV2 strains guanine usage bias in V3 loop coding regions (3G>2G>1G) should protect V3 loops from hypermutability. According to the HIV1 and HIV2 V3 alignment, insertion of the sequence enriched with 2G (21 codons in length) occurred during the evolution of HIV1 predecessor, while insertion of the different sequence enriched with 3G (19 codons in length) occurred during the evolution of HIV2 predecessor. The higher is the level of 3G in the V3 coding region, the lower should be the immune escaping mutation occurrence rates. This hypothesis was tested in this study by comparing the guanine usage in V3 loop coding regions from HIV1 fast and slow progressors. All calculations have been performed by our algorithms "VVK In length", "VVK Dinucleotides" and "VVK Consensus" (www.barkovsky.hotmail.ru).
Keywords: HIV1, HIV2, APOBEC, mutational pressure, gp120, V3 loop, guanine usage, fast AIDS progressors, slow AIDS progressors, codon usage bias, immune escaping
Abstract: Molecular dynamics simulations were employed to study the conformational dynamics and thermal stabilities of the large αβ-tubulin dimer systems under various conditions. The αβ-tubulin dimer at ambient and cryogenic temperatures remains stable around the native conformations, and the water solvent molecules tend to stabilize the native conformations through the formation of complex hydrogen-bonding networks. The elevation of temperature severely destroys the native conformations and the bioactivities, especially in aqueous solution. It was…caused by the lack of intra- and inter-molecular interactions and the decrease of water polarity at higher temperatures. The conformational analysis of the selected segment (β15-QIGAKFWEVIS) provides detailed information on the whole proteins. It was revealed that the local structures of proteins at ambient and cryogenic temperatures have obvious differences albeit the overall structures are close to each other. The selected segments under high temperatures are dominated by random coils instead of native helix at ambient and cryogenic temperatures, accompanied by more diversities and faster conversions of conformations. In addition, the temperature or/and the solvent are capable of altering the secondary structures and further the conformations of the segments and the whole proteins. At ambient temperatures, the water solvent helps the proteins to achieve the native conformation with bioactivities. Different from the corresponding segments in proteins, the truncated peptides are endowed with higher structural flexibilities and characterized by random coils even at ambient temperatures, along with the disappearance of helical hydrogen bonds.
Keywords: Protein structures, stability, solvent effects, tubulin segments, molecular dynamics