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PubMed1982

RSITE: a computer program to predict the recognition sequence of a restriction enzyme.

A computer program (RSITE) was developed which predicts the recognition sequence of a restriction endonuclease. The sizes of fragments experimentally determined on cleavage of a DNA of known sequence were input. Possible recognition sequences producing fragments of sizes matching those determined empirically were printed out. The program faithfully predicted the specificity of restriction enzymes of known recognition sequence and also determined the recognition sequence of a new restriction enzyme from Haemophilus influenzae GU (HinGU II).

Base Sequence↗

PubMed1997

Regional vascular mechanical properties by 3-D intravascular ultrasound with finite-element analysis.

A method employing intravascular ultrasound (IVUS) and simultaneous hemodynamic measurements, with resultant finite element analysis (FEA) of accurate three-dimensional IVUS reconstructions (3-DR), was developed to estimate the regional distribution of arterial elasticity. Human peripheral arterial specimens (iliac and femoral, n = 7) were collected postmortem and perfused at three static transmural pressures: 80, 120, and 160 mmHg. At each pressure, IVUS data were collected at 2.0-mm increments through a 20.0-mm segment and used to create an accurate 3-DR. Mechanical properties were determined over normotensive and hypertensive ranges. An FEA and optimization procedure was implemented in which the elemental elastic modulus was scaled to minimize the displacement error between the computer-predicted and actual deformations. The "optimized" elastic modulus (Eopt) represents an estimate of the component element material stiffness. A dimensionless variable (beta), quantifying structural stiffness, was computed. Eopt of nodiseased tissue regions (n = 80) was greater than atherosclerotic regions (n = 88) for both normotensive (Norm) and hypertensive (Hyp) pressurization: Norm, 9.3 +/- 0.98 vs. 3.5 +/- 0.30; Hyp, 11.3 +/- 0.72 vs. 8.5 +/- 0.47, respectively (mean +/- SE x 10(6) dyn/cm2; P < 0.01 vs. nondiseased). No differences in beta between nondiseased and atherosclerotic tissue were noted at Norm pressurization. With Hyp pressurization, beta of atherosclerotic regions were greater than nondiseased regions: 21.5 +/- 2.21 vs. 14.0 +/- 2.11, respectively (P < 0.03). This method provides a means to identify regional in vivo variations in mechanical properties of arterial tissue.

Arteriosclerosis↗

PubMed2005

Strategies and computational tools for improving randomized protein libraries.

In the last decade, directed evolution has become a routine approach for engineering proteins with novel or altered properties. Concurrently, a trend away from purely 'blind' randomization strategies and towards more 'semi-rational' approaches has also become apparent. In this review, we discuss ways in which structural information and predictive computational tools are playing an increasingly important role in guiding the design of randomized libraries: web servers such as ConSurf-HSSP and SCHEMA allow the prediction of sites to target for producing functional variants, while algorithms such as GLUE, PEDEL and DRIVeR are useful for estimating library completeness and diversity. In addition, we review recent methodological developments that facilitate the construction of unbiased libraries, which are inherently more diverse than biased libraries and therefore more likely to yield improved variants.

Algorithms↗

PubMed2005

From genome to drug lead: identification of a small-molecule inhibitor of the SARS virus.

Virtual screening, a fast, computational approach to identify drug leads [Perola, E.; Xu, K.; Kollmeyer, T. M.; Kaufmann, S. H.; Prendergast, F. G. J. Med. Chem.2000, 43, 401; Miller, M. A. Nat. Rev. Drug Disc.2002, 1 220], is limited by a known challenge in crystallographically determining flexible regions of proteins. This approach has not been able to identify active inhibitors of the severe acute respiratory syndrome-associated coronavirus (SARS-CoV) using solely the crystal structures of a SARS-CoV cysteine proteinase with a flexible loop in the active site [Yang, H. T.; Yang, M. J.; Ding, Y.; Liu, Y. W.; Lou, Z. Y. Proc. Natl. Acad. Sci. U.S.A.2003, 100, 13190; Jenwitheesuk, E.; Samudrala, R. Bioorg. Med. Chem. Lett.2003, 13, 3989; Rajnarayanan, R. V.; Dakshanamurthy, S.; Pattabiraman, N. Biochem. Biophys. Res. Commun.2004, 321, 370; Du, Q.; Wang, S.; Wei, D.; Sirois, S.; Chou, K. Anal. Biochem.2005, 337, 262; Du, Q.; Wang, S.; Zhu, Y.; Wei, D.; Guo, H. Peptides2004, 25, 1857; Lee, V.; Wittayanarakul, K.; Remsungenen, T.; Parasuk, V.; Sompornpisut, P. Science (Asia)2003, 29, 181; Toney, J.; Navas-Martin, S.; Weiss, S.; Koeller, A. J. Med. Chem.2004, 47, 1079; Zhang, X. W.; Yap, Y. L. Bioorg. Med. Chem.2004, 12, 2517]. This article demonstrates a genome-to-drug-lead approach that uses terascale computing to model flexible regions of proteins, thus permitting the utilization of genetic information to identify drug leads expeditiously. A small-molecule inhibitor of SARS-CoV, exhibiting an effective concentration (EC50) of 23 microM in cell-based assays, was identified through virtual screening against a computer-predicted model of the cysteine proteinase. Screening against two crystal structures of the same proteinase failed to identify the 23-microM inhibitor. This study suggests that terascale computing can complement crystallography, broaden the scope of virtual screening, and accelerate the development of therapeutics to treat emerging infectious diseases such as SARS and Bird Flu.

Aminobenzoates↗

PubMed1986

Conformational study of thyrotrophin-releasing hormone. I. Aspects of importance in the design of novel TRH analogues.

The solution conformations of thyrotrophin-releasing hormone (TRH), a biologically-active tripeptide, have been predicted computationally using a method which represents solution effects as a dielectric continuum surrounding the molecule throughout energy minimisation; this is described as the reaction field contribution. The predicted conformations have been compared with previous experimental and theoretical studies. Favoured conformations of TRH under other simulated conditions have also been examined, including the behaviour of the cis isomer, and have been related to possible interactions with intermediates and with specific receptors. The relevance of these predictions to the design of biologically-active analogues of TRH has been analysed.

Hydrogen-Ion Concentration↗

PubMed2005

PSORTdb: a protein subcellular localization database for bacteria.

Information about bacterial subcellular localization (SCL) is important for protein function prediction and identification of suitable drug/vaccine/diagnostic targets. PSORTdb (http://db.psort.org/) is a web-accessible database of SCL for bacteria that contains both information determined through laboratory experimentation and computational predictions. The dataset of experimentally verified information (approximately 2000 proteins) was manually curated by us and represents the largest dataset of its kind. Earlier versions have been used for training SCL predictors, and its incorporation now into this new PSORTdb resource, with its associated additional annotation information and dataset version control, should aid researchers in future development of improved SCL predictors. The second component of this database contains computational analyses of proteins deduced from the most recent NCBI dataset of completely sequenced genomes. Analyses are currently calculated using PSORTb, the most precise automated SCL predictor for bacterial proteins. Both datasets can be accessed through the web using a very flexible text search engine, a data browser, or using BLAST, and the entire database or search results may be downloaded in various formats. Features such as GO ontologies and multiple accession numbers are incorporated to facilitate integration with other bioinformatics resources. PSORTdb is freely available under GNU General Public License.

Bacterial Proteins↗

PubMed2005

Analysing the outer membrane subproteome of Methylococcus capsulatus (Bath) using proteomics and novel biocomputing tools.

High-resolution two-dimensional gel electrophoresis and mass spectrometry has been used to identify the outer membrane (OM) subproteome of the Gram-negative bacterium Methylococcus capsulatus (Bath). Twenty-eight unique polypeptide sequences were identified from protein samples enriched in OMs. Only six of these polypeptides had previously been identified. The predictions from novel bioinformatic methods predicting beta-barrel outer membrane proteins (OMPs) and OM lipoproteins were compared to proteins identified experimentally. BOMP ( http://www.bioinfo.no/tools/bomp ) predicted 43 beta-barrel OMPs (1.45%) from the 2,959 annotated open reading frames. This was a lower percentage than predicted from other Gram-negative proteomes (1.8-3%). More than half of the predicted BOMPs in M. capsulatus were annotated as (conserved) hypothetical proteins with significant similarity to very few sequences in Swiss-Prot or TrEMBL. The experimental data and the computer predictions indicated that the protein composition of the M. capsulatus OM subproteome was different from that of other Gram-negative bacteria studied in a similar manner. A new program, Lipo, was developed that can analyse entire predicted proteomes and give a list of recognised lipoproteins categorised according to their lipo-box similarity to known Gram-negative lipoproteins ( http://www.bioinfo.no/tools/lipo ). This report is the first using a proteomics and bioinformatics approach to identify the OM subproteome of an obligate methanotroph.

Bacterial Outer Membrane Proteins↗

PubMed1985

Differentiation of malignant from benign adrenal masses: predictive indices on computed tomography.

CT findings in 43 adrenal masses were analyzed to see which features correlated most significantly with malignancy. Size, contrast enhancement, and consistency emerged as important discriminators of malignant from benign adrenal masses. These three factors were further analyzed by logistic regression technique to examine the joint influence of computed tomographic (CT) features in prediction of malignancy. As a result of logistic regression analysis, a table of estimated probability of malignancy as a function of tumor size alone and another table of estimated probability as a joint function of size and contrast enhancement were developed. Given a similar patient sample and by using the data given, it would be possible to predict chances of malignancy in an adrenal mass if its CT features are known; for example, a 5-cm adrenal mass without enhancement has a 0.31 probability of malignancy; with enhancement, a 0.68 probability.

Adenoma↗

PubMed2006

Genome-wide identification of peroxisome proliferator response elements using integrated computational genomics.

Peroxisome proliferator-activated receptor (PPAR) agonists are currently used therapeutically in humans, even though many of their direct gene targets are unknown. Because PPARs can directly regulate gene expression through peroxisome proliferator response elements (PPREs), we pursued the computational prediction of PPREs on a genome-wide scale. Contrary to current hypotheses, PPREs are not isotype-specific, nor do flanking nucleotides confer additional information. However, a position weight matrix-based search for PPREs within upstream conserved elements yielded sufficient selectivity for a genome-wide search. Additionally, a novel motif occurring with greater prevalence than PPREs was revealed. Microarray and gene ontology analyses further validated our search technique and provided new functional clusters of genes that were not previously known to be directly regulated by PPARs (e.g., chromatin remodeling, DNA damage response, Wnt, and mitogen-activated protein kinase signaling). This first genome-wide library of high-confidence predicted PPAR target genes will be a valuable resource to PPAR biologists.

Animals↗

PubMed2004

New horizons in mouse immunoinformatics: reliable in silico prediction of mouse class I histocompatibility major complex peptide binding affinity.

Quantitative structure-activity relationship (QSAR) analysis is a main cornerstone of modern informatic disciplines. Predictive computational models, based on QSAR technology, of peptide-major histocompatibility complex (MHC) binding affinity have now become a vital component of modern day computational immunovaccinology. Historically, such approaches have been built around semi-qualitative, classification methods, but these are now giving way to quantitative regression methods. The additive method, an established immunoinformatics technique for the quantitative prediction of peptide-protein affinity, was used here to identify the sequence dependence of peptide binding specificity for three mouse class I MHC alleles: H2-D(b), H2-K(b) and H2-K(k). As we show, in terms of reliability the resulting models represent a significant advance on existing methods. They can be used for the accurate prediction of T-cell epitopes and are freely available online ( http://www.jenner.ac.uk/MHCPred).

Algorithms↗

PubMed1982

An interactive technique for the display of nucleic acid secondary structure.

The ability to visualize nucleic acid secondary structure has become quite important since the advent of computer prediction and biochemical techniques that depict such structures. Manually drawing the conformations can be quite time consuming and tedious. Thus, the ability to draw with the aid of a computer the secondary structure of nucleic acid molecules is quite advantageous. This paper describes an interactive algorithm that permits one to generate such drawings which may then be used for further analysis and/or publications.

Animals↗

PubMed2006

Using pseudo-amino acid composition and support vector machine to predict protein structural class.

As a result of genome and other sequencing projects, the gap between the number of known protein sequences and the number of known protein structural classes is widening rapidly. In order to narrow this gap, it is vitally important to develop a computational prediction method for fast and accurately determining the protein structural class. In this paper, a novel predictor is developed for predicting protein structural class. It is featured by employing a support vector machine learning system and using a different pseudo-amino acid composition (PseAA), which was introduced to, to some extent, take into account the sequence-order effects to represent protein samples. As a demonstration, the jackknife cross-validation test was performed on a working dataset that contains 204 non-homologous proteins. The predicted results are very encouraging, indicating that the current predictor featured with the PseAA may play an important complementary role to the elegant covariant discriminant predictor and other existing algorithms.

Amino Acid Sequence↗

PubMed1977

The evaluation of clinical predictions. A method and initial application.

Clinical predictions are never certain but are inherently probablisitc. The accuracy coefficient, a measure of probabilistic accuracy based on probability assigned to outcomes that occur, was used to assess the skill of clinical rheumatologists in predicting patient outcomes. Physicians' scores correlated well with degree of clinical experience. An approach to evaluation based on the measure provides a sensitive assessment of marginal benefit of technologies such as laboratory tests, diagnostic procedures or computer consultations. Most currently used methods of computer prediction were not as accurate as the best physicians tested. By allowing measurement of ability to individualize predictions to each patient's unique characteristics, the accuracy-coefficient approach has potential use in physician assessment.

Bayes Theorem↗

PubMed1987

A simple scoring system for evaluating symptoms, history and urine dipstick testing in the diagnosis of urinary tract infection.

Patients presenting with symptoms suggestive of urinary tract infection were recruited in a general practice survey aimed at measuring the predictive value of symptoms, history and urine dipstick testing for diagnosing the presence of bacterial infection. Urine specimens were obtained from 87% of the 521 patients recruited. A diagnosis of infection was established by urine culture producing a colony count in a pure culture exceeding 100 000 organisms per ml or between 10 000 and 100 000 organisms per ml plus a minimum of 100 leucocytes per mm(3).Occurrence rates for symptoms and other items of information in infected and non-infected groups were used to derive their positive and negative predictive values in making the diagnosis. The predictive value of volunteered symptoms was compared with that of elicited and volunteered symptoms combined. The positive predictive value of symptoms was increased where elicited symptoms were included but this was achieved at the cost of diminishing the negative predictive value. The occurrence rates were used to derive a mathematical model for diagnosing infection. The symptoms-history-urinalysis (SHU) score generated in this model compared well with a computer predicted probability. Both were substantially better than the assessment and action (decision to prescribe an antibiotic) of the recording doctor.The scoring method described has been demonstrated in urinary tract infection but may be applied to any symptom combination related to a diagnosis for which there is an agreed definition.

Adolescent↗

PubMed2005

Molecular modeling of phosphorylation sites in proteins using a database of local structure segments.

A new bioinformatics tool for molecular modeling of the local structure around phosphorylation sites in proteins has been developed. Our method is based on a library of short sequence and structure motifs. The basic structural elements to be predicted are local structure segments (LSSs). This enables us to avoid the problem of non-exact local description of structures, caused by either diversity in the structural context, or uncertainties in prediction methods. We have developed a library of LSSs and a profile--profile-matching algorithm that predicts local structures of proteins from their sequence information. Our fragment library prediction method is publicly available on a server (FRAGlib), at http://ffas.ljcrf.edu/Servers/frag.html . The algorithm has been applied successfully to the characterization of local structure around phosphorylation sites in proteins. Our computational predictions of sequence and structure preferences around phosphorylated residues have been confirmed by phosphorylation experiments for PKA and PKC kinases. The quality of predictions has been evaluated with several independent statistical tests. We have observed a significant improvement in the accuracy of predictions by incorporating structural information into the description of the neighborhood of the phosphorylated site. Our results strongly suggest that sequence information ought to be supplemented with additional structural context information (predicted with our segment similarity method) for more successful predictions of phosphorylation sites in proteins.

Amino Acid Sequence↗

PubMed2005

Alternative splicing of conserved exons is frequently species-specific in human and mouse.

In this article, we provide evidence that a frequent source of diversity between mammalian transcripts occurs as a consequence of species-specific alternative splicing (AS) of conserved exons. Using a highly predictive computational method, we estimate that >11% of human and mouse cassette alternative exons undergo skipping in one species but constitutively splicing in the other. These species-specific AS events are predicted to modify conserved domains in proteins more frequently than other classes of AS events. The results thus provide evidence that species-specific AS of conserved exons constitutes an additional potential source of complexity and species-specific differences between mammals.

Alternative Splicing↗

PubMed2001

Modelling sedimentation processes in a constructed stormwater wetland.

The design and operation of constructed wetlands for the treatment of stormwater relies heavily on promoting sedimentation, and being able to predict accurately the expected effectiveness of the pond in removing material from the inflows. A study of sediment behaviour has been carried out in a stormwater wetland in Adelaide, Australia where computer predictions, based on solving the hydrodynamic equations and the transport equation, have been compared to deposition patterns observed in the field. The long-term residence time distribution has been shown to be useful in predicting overall sediment removal rates. Comparisons between the model and field observations indicate generally good agreement. Sources of potential error identified include the variable nature of the runoff concentrations entering the pond and the sediment size distribution. The importance of the transient nature of the flow events was highlighted by the spread of sediment throughout the whole pond.

Conservation of Natural Resources↗

PubMed2001

Transcriptional activity of multiple copies of a subtelomerically located olfactory receptor gene that is polymorphic in number and location.

We report here on the transcriptional activity of multiple copies of a subtelomerically located olfactory receptor (OR) gene, OR-A. Due to recent duplication events, both the copy number and chromosomal location of OR-A vary among humans. Sequence analyses of 180 copies of this gene, derived from 12 chromosome ends in 22 individuals, show that the main coding exon of all but one copy is an intact open reading frame with 0-5 predicted amino acid differences. We detected transcription of OR-A in both olfactory epithelium and testis tissue using RT-PCR amplification with primers designed on the basis of a computationally predicted gene structure. Two alternatively spliced forms of transcripts, one encoding an isoform with an extended N-terminus, were found in both tissues. A third transcript, derived from a second promoter, was also observed in testes. The start methionine is predicted in all transcripts to lie in an upstream exon rather than the main coding exon, as is typical for most other OR genes. By examining sequence variants among transcripts, we show that transcription of this gene occurs at multiple chromosomal locations. Our results lend credence to the idea that OR diversity could be generated in rearrangement-prone subtelomeric regions and show that polymorphism in subtelomeric regions could lead to individual-to-individual variation in the expressed repertoire of OR genes.

Alternative Splicing↗