This guide describes the JWS Online system that is freely available over the internet from the main site located at the Stellenbosch University4 (South Africa) and inter-
national mirrors at the Free University of Amsterdam5 (Netherlands) and the Virginia
Bioinformatics Institute6 (U.S.A).
7.2.1
Navigating the JWS Online web site
All JWS Online web sites have the same basic design. When accessing the site root, the home page displays the site logo and latest news. The site information page contains information about the site, software, contact details and licence. Throughout the site forum links refer to online bulletin boards hosted on the main server. Forum topics include discussions about models, JWS Online software and developer news.
The database page
The core of any JWS Online site is the database page, Fig. 7.1, which consists of three tables containing all the models available on the site (Fig. 7.1 b – e ). The largest group of models are the ‘silicon cell’ or detailed models which are based on experimentally
4 http://jjj.biochem.sun.ac.za 5 http://www.jjj.bio.vu.nl 6 http://jjj.vbi.vt.edu
observed data. Alternatively, the ‘core’ models are representations of a specific pathway and can illustrate a certain type of behaviour (e.g. [181]), while ‘demo’ models illustrate a generic metabolic motif, for example a branched pathway. JWS Online already contains a variety of detailed kinetic models, describing a number of metabolic pathways, from a variety of organisms.
• Saccharomyces cerevisiae: glycolysis [182] and glycerol synthesis [183].
• Enteric bacteria: phosphotransferase system [184] and tryptophan operon [185]. • Cell cycle models [186].
• Signal transduction models [187].
Aside from the basic model information such as name, author and year published, the database table has links to pages (the info links) containing extended bibliographic information such as the abstract and reference. We have started a collaboration with the Systems Biology Workbench (SBW) group [121] and it is possible to download certain models in SBML format7 which allows them to be run using an SBML compatible
application. Following the model link loads the page containing the online model.
A model page
Besides the standard navigation bar on top of the page a JWS Online model page is divided into three main parts as shown in Fig. 7.2. These three sections contain the basic information needed to study the requested model, namely, Fig. 7.2 a , the web based Java interface to the model repository, Fig. 7.2 b , an HTML image map that describes the model reaction network and c a rate equation panel. Panel Fig. 7.2 c dynamically displays the rate equation of the reaction step selected in panel Fig. 7.2 b . A reaction step is selected by positioning the mouse pointer over the oval representing an enzyme.
a
b
c
d
e
f
Fig. 7.1 The JWS Online database page. a model category selection, b column containing published article’s title and link to the online model, c author and year of publication, d link to a page containing bibliographic information and a downloadable SBML file (if available), e if the model was added as part of a journal collaboration, the collaborating journal name is shown here and f is a menu listing the available JWS Onlineservers.
7.2.2
Using the JWS Online applets
In order to run the Java applet, which acts as a graphical interface to the JWS Online system, an internet connection, web browser and compatible Java Runtime Environ- ment8 (JRE version 1.3 or newer) needs to be installed. The client has been successfully
used on a variety of operating systems9 and browsers.
• Microsoft Windows 98, 2000, XP using Mozilla 1.4+ and Internet Explorer 5.0 and 6.0
• Mandrake Linux 9.2 and 10.0, RedHat Linux 9.0 using either Mozilla or Galeon
7
http://www.sbw-sbml.org/ModelsWebPages/ModelRepository.htm
8
Available from http://www.java.com
9
a b
c
Fig. 7.2 A JWS Online model page. a the Java client applet, b an image map of the model reaction scheme which shows the rate equation in the lower panel, c when the pointer is moved over the relevant enzyme. This scheme based on the model presented in [188].
• Apple Macintosh OS X using Safari
Looking at the client interface, as shown in Fig. 7.3, it can be seen that the applet is divided into five main components. On the left side of the applet, Fig. 7.3 a , is a scrollable table of parameter values. This table contains the following columns:
• column one: the parameter number. This can be used for quick referencing of input parameters.
• column two: the parameter name. Parameter names are used as in the literature although additionally the initial values of the time simulation are displayed as parameter+i.
a
b
c
d
e
Fig. 7.3 A typical JWS Online client applet. a input table, b analysis selection panels, c Evaluate model button, d connection status panel and connection status e utility buttons.
read-only the values in this column can be changed and set to the desired value. The input table’s behaviour is similar to commonly used spreadsheet applications and it is necessary to ‘enter’ new data in a cell before the value is accepted as changed. In practice, this means pressing the action key (equivalent to the PC’s <enter> key) or clicking on another cell in the table. If invalid data is entered into the value column, the default value is used for evaluation and ERROR is displayed in the cell. At any time, if the Reset button (Fig. 7.3 e ) is pressed, the parameters are reset to their default values. When changing model parameters, it is important to be aware of any moiety conserved cycles. In order to display any moiety conservation in a model, the Cons
button (Fig. 7.3 e ) can be used. Once the applet is started, the connection to the server or applet status is displayed in the message window (Fig. 7.3 d ). Displayed messages are colour coded where green is normal, yellow is a warning message and red indicates a serious error. In the case of serious errors, a suggested action or error code is displayed. When an evaluation is started with the Evaluate model button (Fig. 7.3 c ) the message window border should flash yellow to green, this indicates that the evaluation is proceeding normally.
The evaluation selection panels (Fig. 7.3 b ) allow three different types of analysis to be performed. Highlighting a tab on the panel automatically selects the relevant analysis type which can be either, a time simulation (Sim), steady-state analysis (State) or metabolic control analysis (MCA) [60, 61].
a
b
c
Fig. 7.4 The three JWS Online applet, analysis types. a simulation panel, b steady-state panel with structural analysis options and c control analysis panel.
All three analysis panels are simultaneously shown in Fig. 7.4. To begin with, the time simulation panel, Fig. 7.4 a , allows one to set the simulation start and end times and has various output formatting options. Next, either the metabolite concentrations (Metabolites) or reaction rates (Rates) evolution over time can be selected as output.
Once this selection has been made, the individual rates or concentrations to be displayed on the graph can be selected from the table. The selection table has three columns, an index, variable name and checkbox column, when either Metabolites or Rate is initially selected the relevant concentration or reaction rate is automatically brought into focus. In Fig. 7.4 b the steady-state panel is shown which contains options to either display the steady-state fluxes and concentrations or structural properties of the system. These structural properties are displayed as either the stoichiometric (N), kernel (K) or link (L) matrices [78, 82]. The system stability can be investigated by way of the Jacobian matrix and eigenvalues. The final panel, as shown in Fig. 7.4 c , contains options to calculate either the metabolite elasticities or the flux and concentration control coefficients of the system. All elasticities and control coefficients are scaled to the current steady state.
a
b
Fig. 7.5 JWS Online output. a shows the output of a time simulation, while b shows the results of a steady-state analysis.
Once the analysis type and and output options have been set the model can be run and processed by the server. When the evaluation is complete the results are displayed, as an image, in a separate result window. Fig. 7.5 a shows the result of a time simulation. The results of a steady-state analysis (Fig. 7.5 b ) contains the steady-state metabolite concentrations, fluxes and stability (stable or unstable). Fig. 7.6 shows a K matrix and a section of an elasticity matrix. The result of each evaluation is displayed in a separate window and can be quickly resized using the property menu that can be accessed by
right clicking anywhere on the result window.
a
b
Fig. 7.6 JWS Online output. a is an example of a K matrix [82], while b shows a section of an elasticity matrix.