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PubMedDate not supplied

An innovative application of the "flexible" GRID/PCA computational method: study of differences in selectivity between PGAs from Escherichia coli and a Providentia rettgeri mutant.

The original GRID/PCA technique was adapted for the development of a tool potentially useful for the plan of a research strategy in rational enzyme design. The use of the MOVE directive of GRID made it possible to partially take into account protein flexibility, and the multivariate analysis was used as an instrument for focusing only on relevant information related to the differences in enzyme substrate selectivities. The comparison of two different penicillin G acylases, from Escherichia coli and from Providentia rettgeri, was used as a case study; these enzymes are very similar and their reported selectivities differ only for a couple of mutations around the active site. The "flexible" GRID/PCA method was able to correctly predict the observed selectivity differences caused not only by mutations of residues of the active site but also by long range effects on substrate selectivity due to sequence mutations on residues not directly involved in substrate recognition.

Bacteria↗
PubMed2002

Second-generation mimics of ganglioside GM1 oligosaccharide: a three-dimensional view of their interactions with bacterial enterotoxins by NMR and computational methods.

As a step to delineate a strategy of ligand design for cholera toxin (CT), NMR studies were performed on several mimics of the GM1 ganglioside oligosaccharide. The conformation of these analogues was investigated first in solution and then upon binding to cholera toxin by transferred nuclear Overhauser effect (TR-NOE) measurements. It was demonstrated that CT selects a conformation similar to the global minima of the free saccharides from the ensemble of presented conformations. No evidence of major conformational distortions was obtained, but one or two of the available conformers of the hydroxyacid side chain appear to be selected in the bound state. The NMR data were interpreted with the aid of computer models, generated and analyzed by using a combination of different approaches (MacroModels' MC/EM and MC/SD, Autodock, and GRID). Analysis of the NMR data supported by computational studies allowed us to interpret the experimental observations and to derive workable models of the ligand:toxin complexes. These models suggest that the higher affinity of the (R)-lactic acid derivative 3 may stem from lipophilic interactions with a hydrophobic area in the toxin binding site located in the vicinity of the sialic acid side chain binding region of the CT:GM1 complex, and formed by the side chain of Ile-58 and Lys-34. Thus, the models obtained have allowed us to make useful design suggestions for the improvement of ligand affinity.

Journal Article↗
PubMed2002

Second-generation mimics of ganglioside GM1 oligosaccharide: a three-dimensional view of their interactions with bacterial enterotoxins by NMR and computational methods.

As a step to delineate a strategy of ligand design for cholera toxin (CT), NMR studies were performed on several mimics of the GM1 ganglioside oligosaccharide. The conformation of these analogues was investigated first in solution and then upon binding to cholera toxin by transferred nuclear Overhauser effect (TR-NOE) measurements. It was demonstrated that CT selects a conformation similar to the global minima of the free saccharides from the ensemble of presented conformations. No evidence of major conformational distortions was obtained, but one or two of the available conformers of the hydroxyacid side chain appear to be selected in the bound state. The NMR data were interpreted with the aid of computer models, generated and analyzed by using a combination of different approaches (MacroModels' MC/EM and MC/SD, Autodock, and GRID). Analysis of the NMR data supported by computational studies allowed us to interpret the experimental observations and to derive workable models of the ligand:toxin complexes. These models suggest that the higher affinity of the (R)-lactic acid derivative 3 may stem from lipophilic interactions with a hydrophobic area in the toxin binding site located in the vicinity of the sialic acid side chain binding region of the CT:GM1 complex, and formed by the side chain of Ile-58 and Lys-34. Thus, the models obtained have allowed us to make useful design suggestions for the improvement of ligand affinity.

Binding Sites↗
PubMed2000

Computational methods for gene expression-based tumor classification.

Gene expression profiles may offer more or additional information than classic morphologic- and histologic-based tumor classification systems. Because the number of tissue samples examined is usually much smaller than the number of genes examined, efficient data reduction and analysis methods are critical. In this report, we propose a principal component and discriminant analysis method of tumor classification using gene expression profile data. Expression of 2000 genes in 40 tumor and 22 normal colon tissue samples is used to examine the feasibility of gene expression-based tumor classification systems. Using this method, the percentage of correctly classified normal and tumor tissue was 87.0%. The combined approach using principal components and discriminant analysis provided superior sensitivity and specificity compared to an approach using simple differences in the expression levels of individual genes.

Analysis of Variance↗
PubMed1979

[Tangential pendulum irradiation of the thoracic wall with co-60 during radiation therapy of surgically treated cancers of the breast: comparison of measurement and computation methods for irradiation planning (author's transl)].

The irradiation technique for tangential pendulum 60-Co-irradiation of the thoracic wall is described, and the possibility of a homogeneous irradiation of the thoracic region of interest by means of individual irradiation planning together with a careful, but practicable, technique of positioning and adjustment is shown. The radiation load to the lung can be kept on a moderate level. Phantom measurements with thermoluminescence probes, films and an ionization chamber have been performed for three typical forms of the thorax. Dose distributions thus obtained show a satisfying accordance with calculated values of the dose, the deviations amounting to 3 to 8%. The EDP program applied, COMRAD, thus permits computation of individual pendulum isodoses with sufficient accuracy in practice, and therefore, may be used regularly.

Breast Neoplasms↗
PubMed2000

Computational method for general multicenter electronic structure calculations.

Here a three-dimensional fully numerical (i.e., chemical basis-set free) method [P. F. Batcho, Phys. Rev. A 57, 6 (1998)], is formulated and applied to the calculation of the electronic structure of general multicenter Hamiltonian systems. The numerical method is presented and applied to the solution of Schrödinger-type operators, where a given number of nuclei point singularities is present in the potential field. The numerical method combines the rapid "exponential" convergence rates of modern spectral methods with the multiresolution flexibility of finite element methods, and can be viewed as an extension of the spectral element method. The approximation of cusps in the wave function and the formulation of multicenter nuclei singularities are efficiently dealt with by the combination of a coordinate transformation and a piecewise variational spectral approximation. The complete system can be efficiently inverted by established iterative methods for elliptical partial differential equations; an application of the method is presented for atomic, diatomic, and triatomic systems, and comparisons are made to the literature when possible. In particular, local density approximations are studied within the context of Kohn-Sham density functional theory, and are presented for selected subsets of atomic and diatomic molecules as well as the ozone molecule.

Computer Simulation↗
PubMed2004

A computational method for assessing peptide- identification reliability in tandem mass spectrometry analysis with SEQUEST.

High-throughput protein identification in mass spectrometry is predominantly achieved by first identifying tryptic peptides by a database search and then by combining the peptide hits for protein identification. One of the popular tools used for the database search is SEQUEST. Peptide identification is carried out by selecting SEQUEST hits above a specified threshold, the value of which is typically chosen empirically in an attempt to separate true identifications from false ones. These SEQUEST scores are not normalized with respect to the composition, length and other parameters of the peptides. Furthermore, there is no rigorous reliability estimate assigned to the protein identifications derived from these scores. Hence, the interpretation of SEQUEST hits generally requires human involvement, making it difficult to scale up the identification process for genome-scale applications. To overcome these limitations, we have developed a method, which combines a neural network and a statistical model, for normalizing SEQUEST scores, and also for providing a reliability estimate for each SEQUEST hit. This method improves the sensitivity and specificity of peptide identification compared to the standard filtering procedure used in the SEQUEST package, and provides a basis for estimating the reliability of protein identifications.

Algorithms↗
PubMedDate not supplied

[Computer method for evaluating disorders in sense of color].

A new method for evaluating disorders in the sense of color has been developed and offered for practice. A total of 340 patients with diseases of the retina and optic nerve and 80 normal subjects were examined. The results indicate that different conditions of examination, selection of combination by the color, brightness, and deepness of the stimulus and background allow detection of decreased sensitivity of one, two, or three color perceptors (disorders in sense of color--color blindness) and permit a quantitative evaluation of functional disorders in the color channels of visual system. The new method can be used in the diagnosis of the initial pathological processes of different origin, involving the cone system at any level of visual route and associated with acquired disorders in color vision.

Color Perception↗
PubMed1994

Overview of significant challenges in molecular biology amenable to computational methods.

Many challenging but significant opportunities exist for the development of theoretical approaches in modern Cell and Molecular Biology. The creation of data bases which contain extremely large amounts of information has proven to be an unexpectedly important facto-tin gaining acceptance and respectability for theoretical work that builds on nothing more than what is in the data base itself, such as theoretical work involving the analysis of known protein structures, or the development of more powerful homology searches. Other opportunities, not yet accepted by a broad community, involve work on complex networks (metabolic, genetic, immunologic and neural networks) and work on the "physics of how things work." The DOE National Laboratory System represents the ideal institution that would be well suited to the role of being an "incubator" for the creation of a theoretical and computational discipline within modern biology.

Adenosine Triphosphatases↗
PubMed2001

Computational method to assign microbial genes to pathways.

We present techniques that mine fully sequenced microbial genomes for functional relationships between genes. We show that genes related by one of four techniques are more likely to belong to the same cellular pathways. Furthermore, we demonstrate that the pathway of an uncharacterized gene may be inferred from those of its functionally related partners. Therefore, we are now able to assign most of the genes within bacteria to cellular pathways.

Computational Biology↗
PubMed2004

Computational methods for generating models of denatured and partially folded proteins.

Partially folded and denatured proteins can give important insights into protein folding, misfolding, and aggregation. Such non-native states of proteins are however very difficult to characterise in detail as they are dynamic, heterogeneous systems comprising of ensembles of interconverting conformers. This article describes methods that produce models for non-native proteins in atomic detail. A variety of molecular dynamics based protocols are discussed together with some recent procedures that include restraints from experimental data. These models provide an important framework for interpreting experimental data from studies of non-native states using nuclear magnetic resonance spectroscopy, fluorescence, circular dichroism, and small angle scattering techniques.

Animals↗
PubMedDate not supplied

A computer method for the comparison or the quantitative similarity between normal and abnormal collagen or between sequence data and experimental data.

In this paper, a method is described to correlate collagen structural data obtained by electron microscopy with chemical sequence data, or to compare two experimental sets of data. In this respect, collagen provides a valuable model system, firstly for studying the chemical basis of ultrastructure and the mechanisms of various treatments on a protein, and secondly for detecting and locating the alterations in collagen fibril structure produced by a collagen disorder.

Amino Acid Sequence↗
PubMedDate not supplied

Estimating viral concentrations from dilution counts: a reliable computation method programmed on a pocket calculator.

A program for a Hewlett-Packard 41C calculator is described, applying the maximum likelihood method for the estimation of the density of a suspension of infective particles when counts are available for a number of independent dilutions of the original suspension. An unbiased estimate for the variance of the density, a suitable confidence interval and its corresponding confidence level are also given by the program. Moreover, after testing for the presence of overcrowding and/or clumping, the selection of suitable dilutions is fully automated so as to avoid recourse to statistical tables.

Computers↗
PubMed2003

Disulfide by Design: a computational method for the rational design of disulfide bonds in proteins.

SUMMARY: Disulfide by Design is a program for the design of novel disulfide bonds in proteins. Protein structure files in PDB format are analyzed to identify residue pairs that are likely to form a disulfide bond if the respective amino acids are mutated to cysteines. The output displays residue pairs having the appropriate geometric characteristics for disulfide formation and provides automated generation of modified PDB files including modeled disulfides. Validation demonstrates a high level of accuracy for the algorithm. AVAILABILITY: http://www.ehscenter.org/dbd/ SUPPLEMENTARY INFORMATION: http://www.ehscenter.org/dbd/

Algorithms↗
PubMed2002

Computational method for muscle-path representation in musculoskeletal models.

This paper presents a new and efficient method to calculate the line-of-action of a muscle as it wraps over bones and other tissues on its way from origin to insertion. The muscle is assumed to be a one-dimensional, massless, taut string, and the surfaces of bones that the muscle may wrap around are approximated by cross-sectional boundaries obtained by slicing geometrical models of bones. Each cross-sectional boundary is approximated by a series of connected line segments. Thus, the muscle path to be calculated is piecewise linear with vertices being the contact points on the cross-sectional boundaries of the bones. Any level of geometric accuracy can be obtained by increasing the number of cross sections and the number of line segments in each cross section. The algorithm is computationally efficient even for large numbers of cross sections.

Algorithms↗
PubMed2003

Structural genomics: computational methods for structure analysis.

The success of structural genomics initiatives requires the development and application of tools for structure analysis, prediction, and annotation. In this paper we review recent developments in these areas; specifically structure alignment, the detection of remote homologs and analogs, homology modeling and the use of structures to predict function. We also discuss various rationales for structural genomics initiatives. These include the structure-based clustering of sequence space and genome-wide function assignment. It is also argued that structural genomics can be integrated into more traditional biological research if specific biological questions are included in target selection strategies.

Amino Acid Motifs↗
PubMedDate not supplied

[The role of computer methods in the diagnosis of mono- and multifactorial traumatic compression of the brain].

A scheme of differential diagnosis of mono- and multifactor compression of the brain was formed on the grounds of 18 most frequently encountered signs of the injury. The work is based on 693 cases which were verified on operation. The results were checked on a large independent selection. Accuracy of recognition was 87.5%. The Table suggested by the authors may prove valuable in emergency situations when the patients are admitted in a serious condition, in impetuous development of the compression syndrome, and when there is lack of time for carrying out instrumental examination.

Adult↗