Showing papers in "Bioinformatics in 1986"

A discrete model of bacterial metabolism

Abstract: This paper describes a computer model of the intermediary metabolism of bacteria during steady-state growth and during adaptations, e.g. to new carbon sources. Metabolic regulation is represented as a process of optimisation, in which the trend is towards improved metabolic performance. The model uses linear programming techniques for the optimisation. The implementation falls into four phases: (i) assembly of model parameters; (ii) calculations; (iii) storage of solutions and (iv) projection of solutions. The use of a commercial database and a commercial spreadsheet has proved to be of great assistance in the first and third phases. A metabolic map format, with the optional addition of conversion values, names of enzymes or co-factors has been used to project the results in a form convenient for inspection.

Peptide sequencing program

Abstract: A computer program has been devised to automate rationalization of peptide fragmentation patterns. The program systematically generates all possible linear amino acid sequences which might be attributable to a peptide with a known amino acid composition. The generated sequences are then searched to find those that most closely match the spectrum of an unknown sequence.

Steady-state modelling of metabolic pathways: a guide for the prospective simulator.

Abstract: Steady-state modelling and control analysis by means of computer simulation provides valuable insight into the behavior of metabolic pathways. This review, which is aimed at the newcomer to this field, discusses the objectives of steady-state modelling and the steady-state properties of the four basic metabolic structures, namely linear and branched chains, loops and cycles. It is shown how the model definition in terms of stoichiometric reactions and rate equations leads to a set of balance equations from which the conservation constraints and flux relationships can be deduced, either informally or through a rigorous analysis of the stoichiometric matrix. The initial analysis of a steady-state metabolic model is summarized in an algorithm. Key references to the literature on metabolic modelling are given.

A package of computer programs for handling taxonomic databases.

Abstract: A package of programs is described which processes taxonomic data, suitable to use when preparing monographs, handbooks, Floras or Faunas, in which species or other taxa are described and identified. There is also an interactive program for specimen identification, and conversion routines which prepare data for numerical taxonomy (clustering and cladistics). The programs are equally suitable for botany or for zoology, or even for non-biological data.

METAMOD: software for steady-state modelling and control analysis of metabolic pathways on the BBC microcomputer

Abstract: METAMOD, a BBC microcomputer-based software package for steady-state modelling and control analysis of model metabolic pathways, is described, The package consists of two programs. METADEF allows the user to define the pathway in terms of reactions, rate equations and initial concentrations of metabolites. METACAL uses one of two algorithms to calculate the steady-state concentrations and fluxes. One algorithm uses the current ratio of production and consumption rates of variable metabolites to adjust iteratively their concentrations in such a way that they converge towards the steady state. The other algorithm solves the roots of the system equations by means of a quasi-Newtonian procedure. Control analysis allows the calculation of elasticity, control and response coefficients, by means of finite difference approximation. METAMOD is interactive and easy to use, and suitable for teaching and research purposes.

IBM microcomputer programs that analyze DNA sequences for tRNA genes.

Abstract: A set of four computer programs that search DNA sequence data files for transfer RNA genes have been written in IBM (Microsoft) BASIC for the IBM personal computer. These programs locate and plot predicted secondary structures of tRNA genes in the cloverleaf conformation. The set of programs are applicable to eukaryotic tRNA genes, including those containing intervening sequences, and to prokaryotic and mitochondrial tRNA genes. In addition, two of the programs search up to 150 residues downstream of tRNA gene sequences for possible eukaryotic RNA polymerase III termination sites comprised of at least four consecutive T residues. Molecular biologists studying a variety of gene sequence and flanking regions can use these programs to search for the additional presence of tRNA genes. Furthermore, investigators studying tRNA gene structure-to-function relationships would not need to do extensive restriction mapping to locate tRNA gene sequences within their cloned DNA fragments.

The elucidation of protein function from its amino acid sequence.

Abstract: This review gives an outline of how computers may be used to determine the function of a protein, when only its primary structure is known. The current programming methods are outlined in general terms before their detailed application is discussed, and the common ways of predicting protein structure are also introduced. Identification is usually by database searching and sequence alignment, though a collection of motifs relating sequence to function are also described.

A Pascal microcomputer program for prediction of protein secondary structure and hydropathic segments

Abstract: This paper describes a simple Pascal microcomputer program for prediction of protein secondary structure according to the Chou and Fasman algorithm. In addition, it performs an analysis of the hydropathic character of the residues for prediction of external/internal regions of the polypeptide chain. Also it searches for probable glycosylation and phosphorylation sites.

Compression of nucleic acid and protein sequence data.

Abstract: This paper describes the application of text compression methods to machine-readable files of nucleic acid and protein sequence data. Two main methods are used to reduce the storage requirements of such files, these being n-gram coding and run-length coding. A Pascal program combining both of these techniques resulted in a compression figure of 74.6% for the GenBank data-base and a program that used only n-gram coding gave a compression figure of 42.8% for the Protein Identification Resource database.

A rapid computer technique for analysing molecular interactions.

Abstract: A rapid method for analysing enzyme-substrate interactions using a discriminant analysis program is described. This technique identifies the structural features of substrate molecules which are important in determining metabolic activity. Two model systems, nucleoside diphosphatase activity of Golgi membranes and the interaction of yeast hexokinase with a range of D-sugars, are used as illustrations of the technique. The conclusions from both models are consistent with those previously obtained from analytical techniques.

DNAMAT: an efficient graphic matrix sequence homology algorithm and its application to structural analysis.

Abstract: We present a fast algorithm to produce a graphic matrix representation of sequence homology. The algorithm is based on lexicographical ordering of fragments. It preserves most of the options of a simple naive algorithm with a significant increase in speed. This algorithm was the bais for a program, called DNAMAT, that has been extensively tested during the last three years at the Weizmann Institute of Science and has proven to be very useful. In addition we suggest a way to extend our approach to analyse a series of related DNA or RNA sequences, in order to determine certain common structural features. The analysis is done by 'summing' a set of dot-matrices to produce an overall matrix that displays structural elements common to most of the sequences. We give an example of this procedure by analysing tRNA sequences.

Quantitative computer analysis of signal sequence homologies in DNA

Abstract: Homologies to prokaryotic recognition sites for RNA polymerase, ribosomes, and cyclic-AMP receptor protein (CRP), are analyzed by a new computer program using weighting factors to account for the statistical variation at each position of the consensus. Known signal sequence sites are easily detected by this algorithm, and other sites with equally strong homology are found whose biological function is still unknown. Some sites are biologically active even though they have very weak homology. No arbitrary 'cutoff score' can distinguish active recognition sites from inactive homologies; experiments must determine why certain weak homologies are able to function while others are not.

Monte Carlo simulation program for ecosystems

Abstract: A Monte Carlo computer simulation program is designed in order to describe the spatial and time evolution of a population of living individuals under preassigned environmental conditions of energy. The simulation is inspired by previous techniques developed in physics--in particular, in molecular dynamics and simulations of liquids--and it already provides some new insights regarding macroscopic deterministic models in ecology and concerning eventual control of artificial biomass production plants.

A new representation of protein structure: vector diagram.

Abstract: A vector diagram was devised for representation of protein structure. This was done by giving each nucleic acid triplet a corresponding vector, and expressing a protein as a set of vectors which were aligned in the order of peptide sequence. The magnitude of each vector was made to reflect the hydrophilicity of amino acid, and the direction of the vector was chosen so that similar amino acids had similar directions. The diagram not only shows the primary sequence but suggests the folding structure of proteins.

A computer program for selecting animals for control and experimental groups in biochemical studies.

Abstract: The standard method for selecting experimental animals for control and experimental groups is by a randomization process in which each animal is placed into one of the groups without looking at any of its individual differences. An alternative, active matching process is proposed by which three to five animals are chosen to form 'experimental units' that are closely matched with respect to average weight and with respect to distribution of weights (standard distribution values). Several such units are then randomly assigned to each control or treatment group and, at the end of the experiment, the animals within each unit are pooled prior to analysis. The merits of this approach and a computer algorithm for making the selections are described.

Computer-aided analysis of infrared, circular dichroism and absorption spectra.

Abstract: Marquardt and Powell optimization methods without constraints on the optimized spectral parameters were employed for decomposition of complex i.r., c.d. and absorption spectra into component bands. The procedure resolved experimental spectra into eight component bands and it can be easily adjusted for a larger set of component bands. The CPU time required for achievement of satisfactory convergence of parameters for eight component bands is rather large even when using mainframe computers and therefore division of spectra into a few non-overlapped parts is advisable. The program also can be used for calculation of absorption, c.d. and difference spectra from formatted raw spectral data.

Analysis of repeating oligonucleotide sequences in ribonucleic acids using an Apple II microcomputer.

Abstract: A simple computer program has been developed to locate repeating subsequences of all possible lengths in a given nucleic acid. The observed number of repeats of subsequences was compared with the expected number of such repeats in several RNAs. The analysis showed that, in the case of rRNAs, there are no constraints in the choice of the fourth and the higher order nucleotides, while the selection is maximum at the level of nearest neighbour. This is, however, not true for RNAs coding for proteins, where the constraints are also found at the level of nucleotides containing five or more bases.

Computer monitoring, capture and analysis of gas/liquid chromatograph traces.

Abstract: The work described here is effectively the computerization of a gas/liquid chromatograph of the pen recorder type using a BBC microcomputer. The output from the g.l.c. can be captured by the computer in accordance with a series of parameters. The sampling rate can be altered, as can an averaging facility to reduce noise, and a threshold level to eliminate the storage of irrelevant and space-consuming data. The unprocessed readings are initially stored on the computer's floppy disk, then later retrieved and cut into smaller sections to allow maximum resolution for on-screen analysis. In the main analysis stage of the system all processing is shown graphically on the computer monitor at all stages. The principal steps in analysis involve the mathematical modelling and elimination of the solvent peak, the fixing of the retention time for each subsequent peak and its disentangling from any following peaks, and finally the calculation of the area under each individual peak. Several alternative methods are made available for disentangling peaks, which can be tried successively on a single peak then each printed out with comments for comparison later. All readings and results in table form and screen dumps of all trace images are available via a dot matrix printer.

Protein graphics: historical development, future directions and microcomputer applications.

Abstract: Designers in the macroscopic world of highrise buildings, spacecraft and robots can see the relationship between structure and function in their designs. This is not possible for protein chemists. Yet the relationship between structure and function is just as critical in the unseen world of molecules as it is in the world that we can touch and see. Engineering graphics in computer-aided design and manufacturing has increased efficiency in conventional design and made possible design of complex systems such as industrial robots. The new design possibilities opened to engineers by interactive computer graphics are indeed revolutionary, but they still may be superseded by graphics in protein research and engineering. Although the capability to visualize simple molecular structures in and of itself often gives biologists important clues as to the function of proteins, computer graphics also has given biologists a tool that they can use to calculate structural properties of proteins. Predictions from the modeling studies can be tested experimentally, providing a continual interplay between theory and practice. Unfortunately, at present, only about 100 of the over 4000 proteins with known amino acid sequences can be displayed even though, in principle, the complete three-dimensional structure of a protein is determined by the minimum energy configuration of its amino acid sequence. Only 100 or so proteins have known atomic coordinates because currently the only means of determining these coordinates experimentally is by X-ray crystallography, an expensive method that usually takes about 5 years from start to finish. Even though the set of proteins with known atomic coordinates is growing and the time required to solve protein structures using X-ray crystallography is being reduced, a dramatic improvement in the understanding of protein structure and function requires a synergy of techniques that bring together all the information on protein structure and function. These techniques include interactive graphics, molecular mechanics, distance geometry, quantum mechanics and analysis of experimental observations using expert systems.

Computer-assisted mathematical analysis of sigmoid biological events

Abstract: A program in BASIC is described which allows accurate quantification of some numerical parameters that can be objectively correlated to biological indexes in sigmoid biological events. Attention was focused on the polymerization process of actin (a muscle protein with a mol. wt of 42,000 daltons) studied as the variation in the OD360 index with time. The experimental points, if plotted, can be well approximated by a rational function of the type delta OD360 = f(t), which passes through the origin and can be represented graphically by a sigmoid curve. The program was very helpful in comparing the experimental curves and in analysing significant parameters, such as maximum velocity and asymptote, that characterize these curves and whose interpretation would otherwise be purely subjective.

Lap computers in the laboratory.

Abstract: The acquisition of data from laboratory instruments and the automatic control of experimental apparatus is facilitated by the use of small, inexpensive battery-powered microcomputers ('lap computers'). Useful capabilities and features of currently available lap computers are summarized. A general strategy for data acquisition from laboratory instruments is outlined, and three illustrative examples of particular applications of lap computers in data acquisition and experimental control are described.

An improved FORTRAN 77 recombinant DNA database management system with graphic extensions in GKS.

Abstract: We have improved an existing clone database management system written in FORTRAN 77 and adapted it to our software environment. Improvements are that the database can be interrogated for any type of information, not just keywords. Also, recombinant DNA constructions can be represented in a simplified 'shorthand', whereafter a program assembles the full nucleotide sequence from the contributing fragments, which may be obtained from nucleotide sequence databases. Another improvement is the replacement of the database manager by programs, running in batch to maintain the databank and verify its consistency automatically. Finally, graphic extensions are written in Graphical Kernel System, to draw linear and circular restriction maps of recombinants. Besides restriction sites, recombinant features can be presented from the feature lines of recombinant database entries, or from the feature tables of nucleotide databases. The clone database management system is fully integrated into the sequence analysis software package from the Pasteur Institute, Paris, and is made accessible through the same menu. As a result, recombinant DNA sequences can directly be analysed by the sequence analysis programs.

An effective approach to the identification of subclones of a DNA of known nucleotide sequence.

Abstract: The problem of subclone identification for DNA fragments of a known nucleotide sequence has been considered. We suggest a strategy for rapid identification of a large number of subclones based on: (i) partial sequencing of the subclone DNA (single nucleotide track); (ii) representation of the result in the form of a numeric code showing the distribution of the chosen nucleotide along the sequence; and (iii) identification of the subclone sequence using this code in a catalogue compiled and printed for a whole DNA sequence. The same approach is applicable when the subclones are expected to have homology with known sequences.

A demonstration of pharmacokinetics and physiological modelling using a microcomputer for data capture and analysis.

Abstract: We describe a simple and inexpensive demonstration of mass transport and exchange using dye clearance from a hydrodynamic model. A microcomputer was used for data acquisition and storage, non-linear least squares curve fitting, compartmental analysis and parameter estimation. The system is useful for demonstrating the indicator-dilution technique for fluid volume measurement and compartmental analysis in pharmacokinetics.

Four spreadsheet templates for the laboratory

Abstract: Four spreadsheet templates have been devised to ease certain laboratory operations, namely preparing buffers by mixing solutions, calculating required rotor speeds to achieve particular g-values, preparing and utilising isokinetic gradients to determine sedimentation coefficients, and calculating purification tables. Their use in designing experiments is described briefly.

A microcomputer program for hydropathic analysis of proteins with I/O through word processing and graphics software.

Abstract: A BASIC program has been devised for the hydropathic analysis of protein sequences according to the method of Kyte and Doolittle (1982). The program uses sequence data from input files that are created with a word processor and produces two types of output file: one contains a bar graph of the hydropathic profile in a format that can be easily edited; the other is a tabulation of hydropathic indices along a protein's sequence that can be used as input by the program for the production of a bar graph or as input into other graphics and analysis software. An MS-DOS microcomputer, operating under IBM BASICA or GWBASIC and a dot matrix printer with block graphics capabilities are the only hardware requirements for graphic display of hydropathy profiles. The program is capable of unattended analysis from a list of up to 15 input files.

Solving algebraic equations on a microcomputer.

Abstract: Equation-solving programs for microcomputers make the numerical solution of algebraic equations an easy task. It is no longer necessary to learn or to program algorithms for the solution of many different types of equations. A single equation or a set of simultaneous equations may simply be entered into the computer and numerically solved for unknowns without concern as to whether the equations are linear or non-linear. Several examples of possible applications of equation-solving programs are discussed. Solution times for these examples are given for SEQS on the Apple II and Macintosh computers. The example sets of equations, which include chemical equilibrium and enzyme kinetics problems, have been chosen to demonstrate important aspects of the uses and limitations of equation solving. The four examples discussed are: a two-compartment pharmacokinetic model, citric acid ionization in aqueous solution, an enzyme inhibition model, and an example of the application of an equation-solving program in doing a simple non-linear regression problem.

Microcomputer simulation of steady-state enzyme kinetics for educational purposes

Abstract: A BASIC program to assist the instruction of steady-state enzyme kinetics has been developed for the IBM PC microcomputer. Its purpose is to simulate laboratory experiments in order to minimize the time required to obtain kinetic data from which students deduce kinetic mechanisms and determine kinetic constants of enzyme-catalyzed reactions. The program randomly selects a kinetic scheme from various sequential, ping pong, and iso reaction sequences as well as values for the kinetic constants. The scheme and kinetic constants are unknown to the student at this time; the only thing he or she knows is the stoichiometry of the catalyzed reaction which can have two or three substrates and products. The student is prompted to enter values for concentrations of substrates and products; several different concentrations for each substrate and product can be entered in a single experiment. The program then calculates, displays and prints (if desired) the corresponding initial steady-state velocities. The student can perform as many experiments as desired until enough information is obtained to determine the kinetic mechanism and to calculate values for the kinetic constants.