BRAGI: A comprehensive protein modeling program system

A protein modeling program package has been developed. The user friendly system is implemented on high performance graphic devices and facilitates the modeling of a protein with an unknown three-dimensional structure out of that of a homologous one or the design of new variants. A wide range of features can be used by the researcher for this purpose. The system is written in FORTRAN 77 and E&S GSR functions or the HP implementation of the PHIGS standard, respectively.     

NeuralEnsembles: a neural network based ensemble forecasting program for habitat and bioclimatic suitability analysis

NeuralEnsembles is an integrated modeling and assessment tool for predicting areas of species habitat/bioclimatic suitability based on presence/absence data. This free, Windows based program, which comes with a friendly graphical user interface, generates predictions using ensembles of artificial neural networks. Models can quickly and easily be produced for multiple species and subsequently be extrapolated either to new regions or under different future climate scenarios. An array of options is provided for optimizing the construction and training of ensemble models. Main outputs of the program include text files of suitability predictions, maps and various statistical measures of model performance and accuracy.     

Development of a system to classify 3D structural character of RNA.

We are developing a computational system to extract structural character of RNA. We made a program that classifies conformers by recognizing the hydrogen bonding patterns. The program was applied to a set of 279 conformers and they were classified into about 40 groups. The system is expected to be useful for searching structural motifs of RNA and classifying large number of generated conformers in structural modeling process.     

Binding site analysis of full-length alpha1a adrenergic receptor using homology modeling and molecular docking

The recent availability of crystal structure of bovine rhodopsin offers new opportunities in order to approach the construction of G protein coupled receptors. This study focuses the attention on the modeling of full-length alpha(1a) adrenergic receptor (alpha(1a)-AR) due to its biological role and significant implications in pharmacological treatment of benign prostate hyperplasia. This work could be considered made up by two main steps: (a) the construction of full structure of alpha(1a)-AR, through homology modeling methods; (b) the automated docking of an endogenous agonist, norepinephrine, and of an antagonist, WB-4101, using BioDock program. The obtained results highlight the key residues involved in binding sites of both agonists and antagonists, confirming the mutagenesis data and giving new suggestions for the rational design of selective ligands.     

TRITON: a graphical tool for ligand-binding protein engineering

The new version of the TRITON program provides user-friendly graphical tools for modeling protein mutants using the external program MODELLER and for docking ligands into the mutants using the external program AutoDock. TRITON can now be used to design ligand-binding proteins, to study protein-ligand binding mechanisms or simply to dock any ligand to a protein. Availability: Executable files of TRITON are available free of charge for academic users at http://ncbr.chemi.muni.cz/triton/     

Tek FRODO: A new version of FRODO for Tektronix graphics stations

A new version of the molecular graphics program FRODO was developed to allow the range of Tektronix graphics stations to be used for molecular modeling and crystallographic applications. The work was divided into two parts: first, the universal molecular modeling graphic package (Tek_MMGP) was written to enable basic modeling operations for Tektronix stations. Second, all routines of FRODO involving computer graphics were modified to fit the new hardware environment, and linked with Tek_MMGP. The resulting package, Tek_FRODO, has been used successfully for crystallographic refinement in several projects. The program, written in FORTRAN, is ready to be ported to any of Tektronix 3D graphics stations; it is available from the authors on request.     

Biological systems modeling and analysis: a biomolecular technique of the twenty-first century.

It is proposed that computational systems biology should be considered a biomolecular technique of the twenty-first century, because it complements experimental biology and bioinformatics in unique ways that will eventually lead to insights and a depth of understanding not achievable without systems approaches. This article begins with a summary of traditional and novel modeling techniques. In the second part, it proposes concept map modeling as a useful link between experimental biology and biological systems modeling and analysis. Concept map modeling requires the collaboration between biologist and modeler. The biologist designs a regulated connectivity diagram of processes comprising a biological system and also provides semi-quantitative information on stimuli and measured or expected responses of the system. The modeler converts this information through methods of forward and inverse modeling into a mathematical construct that can be used for simulations and to generate and test new hypotheses. The biologist and the modeler collaboratively interpret the results and devise improved concept maps. The third part of the article describes software, BST-Box, supporting the various modeling activities.     

Bugs in computational chemistry software and their consequences: the importance of the source code

The increase in computer power and the development of new mathematical concepts implemented in software have allowed computational chemistry to emerge as a new research field. Although programs were freely distributed during the "golden age" of this discipline, today they are usually copyrighted and have become easier and easier to use through sophisticated graphical interfaces. This "democratization" is a vector of success for this discipline. Nowadays, non-theoreticians can use such programs more easily and solve chemistry-related problems with the computer. The number of program offerings has rapidly grown and private companies specialized in molecular modeling have appeared and compete to sell their products. Thus, numerous software packages, often presenting similar capabilities, are now available on the market. Within this context, the availability of the program source code remains, in our opinion, an important criterion for program selection.     

Analysis of ligand-receptor binding by the difference method

A new method has been proposed for analysis of experimental data on ligand-receptor binding at equilibrium. This method makes it possible to detect heterogeneity of a receptor system in cases where the contribution of the high-affinity site to total binding is rather small and the problem of graphic discrimination of a model cannot be solved unambiguously by other methods. The difference method permits us to exclude experiments on measuring nonspecific binding. A computer program for analysis of ligand-receptor binding has been worked out in which the difference method and traditional methods of binding isotherm analysis are realized. Numerical modeling has shown that the best strategy in experimental data processing is the treatment of total binding isotherms by both the difference method and regression analysis, including the nonspecific binding constant as one of the regression parameters.     

All are not equal: a benchmark of different homology modeling programs

Modeling a protein structure based on a homologous structure is a standard method in structural biology today. In this process an alignment of a target protein sequence onto the structure of a template(s) is used as input to a program that constructs a 3D model. It has been shown that the most important factor in this process is the correctness of the alignment and the choice of the best template structure(s), while it is generally believed that there are no major differences between the best modeling programs. Therefore, a large number of studies to benchmark the alignment qualities and the selection process have been performed. However, to our knowledge no large-scale benchmark has been performed to evaluate the programs used to transform the alignment to a 3D model. In this study, a benchmark of six different homology modeling programs- Modeller, SegMod/ENCAD, SWISS-MODEL, 3D-JIGSAW, nest, and Builder-is presented. The performance of these programs is evaluated using physiochemical correctness and structural similarity to the correct structure. From our analysis it can be concluded that no single modeling program outperform the others in all tests. However, it is quite clear that three modeling programs, Modeller, nest, and SegMod/ ENCAD, perform better than the others. Interestingly, the fastest and oldest modeling program, SegMod/ ENCAD, performs very well, although it was written more than 10 years ago and has not undergone any development since. It can also be observed that none of the homology modeling programs builds side chains as well as a specialized program (SCWRL), and therefore there should be room for improvement.     

Determination of the sedimentation coefficient distribution by least-squares boundary modeling

A new method is presented for the calculation of apparent sedimentation coefficient distributions g*(s) for the size-distribution analysis of polymers in sedimentation velocity experiments. Direct linear least-squares boundary modeling by a superposition of sedimentation profiles of ideal nondiffusing particles is employed. It can be combined with algebraic noise decomposition techniques for the application to interference optical ultracentrifuge data at low loading concentrations with significant systematic noise components. Because of the use of direct boundary modeling, residuals are available for assessment of the quality of the fits and the consistency of the g*(s) distribution with the experimental data. The method can be combined with regularization techniques based on F statistics, such as used in the program CONTIN, or alternatively, the increment of s values can be adjusted empirically. The method is simple, has advantageous statistical properties, and reveals precise sedimentation coefficients. The new least-squares ls-g*(s) exhibits a very high robustness and resolution if data acquired over a large time interval are analyzed. This can result in a high resolution for large particles, and for samples with a high degree of heterogeneity. Because the method does not require a high frequency of scans, it can also be easily used in experiments with the absorbance optical scanning system. Published 2000 John Wiley & Sons, Inc.     

Analysis and implementation of a neural extended Kalman filter for target tracking

Having a better motion model in the state estimator is one way to improve target tracking performance. Since the motion model of the target is not known a priori, either robust modeling techniques or adaptive modeling techniques are required. The neural extended Kalman filter is a technique that learns unmodeled dynamics while performing state estimation in the feedback loop of a control system. This coupled system performs the standard estimation of the states of the plant while estimating a function to approximate the difference between the given state-coupling function model and the behavior of the true plant dynamics. At each sample step, this new model is added to the existing model to improve the state estimate. The neural extended Kalman filter has also been investigated as a target tracking estimation routine. Implementation issues for this adaptive modeling technique, including neural network training parameters, were investigated and an analysis was made of the quality of performance that the technique can have for tracking maneuvering targets.     

A study on a vibratory model of a human body

This paper is concerned with the modeling of the human body as a spring mass system. Based on certain assumptions, an analysis for evaluating the mass and stiffness values of the model is developed. As an illustration of the modeling procedure, a 15-degree-of-freedom model of a male body is considered. The computed natural frequencies of the model are found to be within the range of available experimental values.     

Implementing a community-supported school-based influenza immunization program

School-based influenza immunization programs are increasingly recognized as a key component of community-based efforts to control annual influenza epidemics. Computer modeling suggests that immunizing 70% of schoolchildren could protect an entire community from the flu. Most of the school-based influenza immunization programs described in the literature have had support from industry or federal grants. This article describes a program that used only community resources to administer live, attenuated influenza vaccine supplied by the state health department. Beginning in 2006, the Alachua County Health Department and school system, working in collaboration with the University of Florida, began exploration of a non-mandatory community-wide school-based influenza immunization program, with the goal of achieving high levels of immunization of the ~22,000 public and private pre-K through grade 8 students in the county. In 2009-10 the program was repeated. This report describes the procedures developed to achieve the goal, the barriers that were encountered, and solutions to problems that occurred during the implementation of the program. Preliminary data suggest that the crude immunization rate in the schools was approximately 55% and that at least 10% more students were immunized by their health providers. At an operational level, it is possible to achieve high immunization rates if the stakeholders share a common vision and there is extensive community involvement.     

Computer simulation of biological systems

The current status of mathematical models of biological systems is reviewed. Advances in supercomputer hardware allows more complex models to be constructed. The new generation of microcomputers are quite adequate for many computer simulations of biological systems. A theory of modeling is being developed to improve the relationship between the real biological system and the model. Deterministic models, stochastic models and applications of control theory and optimization methods are discussed. Examples given include models of molecular structure, of experimental techniques, and of biochemical reactions. It is recommended that experimental biologists consider the use of microcomputers to model the system under study as a part of their research program.     

NMπ—improved re‐implementation of NM+, a software for estimating gene dispersal and mating patterns

This study introduces the NMπ computer program designed for estimation of plant mating system and seed and pollen dispersal kernels. NMπ is a re‐implementation of the NM+ program and provides new features such as support for multicore processors, explicit treatment of dioecy, the possibility of incorporating uniparentally cytoplasmic markers, the possibility of assessing assortative mating due to phenotypic similarity and inference about offspring genealogies. The probability model of parentage (the neighbourhood model) accounts for missing data and genotyping errors, which can be estimated along with regular parameters of the mating system. The program has virtually no restrictions with respect to a number of individuals, markers or phenotypic characters. A console version of NMπ can be run under a wide variety of operating systems, including Windows, Linux or Mac OS. For Windows users, a graphical user interface is provided to facilitate operating the software. The program, user manual and example data are available on http://www.ukw.edu.pl/pracownicy/plik/igor_chybicki/3694/ .     

Dose finding - a challenge in statistics

A good understanding and characterization of the dose response relationship of any new compound is an important and ubiquitous problem in many areas of scientific investigation. This is especially true in the context of pharmaceutical drug development, where it is mandatory to launch safe drugs which demonstrate a clinically relevant effect. Selecting a dose too high may result in unacceptable safety problems, while selecting a dose too low may lead to ineffective drugs. Dose finding studies thus play a key role in any drug development program and are often the gate-keeper for large confirmatory studies. In this overview paper we focus on definitive and confirmatory dose finding studies in Phase II or III, reviewing relevant statistical design and analysis methods. In particular, we describe multiple comparison procedures, modeling approaches, and hybrid methods combining the advantages of both. An outlook to adaptive dose finding methods is also given. We use a real data example to illustrate the methods, together with a brief overview of relevant software.