Computational Biology
Simmune Software
Simmune consists of three components:
- Simmune modeler (short: 'simmod')
- simulator (short: 'simmune')
- signaling network browser.
Here, we provide a brief overview of the Simmune package which comes with extensive documentation and tutorial movies. To request Simmune (executables for Windows (tm), MacOS (tm) and most Unix (tm) platforms) send an email to software@simmune.org. Simmune is free for non-commercial research. Licenses for commercial research can be obtained as well. Commercial licenses will currently be handled by NIAID's Office of Technology Development.
The Simmune Modeler
The Simmune modeler, Simmod, has five main windows for the definition of:
At the fundamental scale (in the molecule window), the modeler defines molecules by specifying their types (receptors, enzymes, adaptors etc.) and their properties, such as the number of binding sites, enzymatically active sites and diffusion coefficients. Simmod then creates graphical representations of the molecules and allows the modeler to define interactions between their binding sites simply by using the mouse to draw connections between them. Once a connection (binding possibility) is established, the modeler can define the association and dissociation rates of the interaction.
In addition to defining the interaction kinetics the modeler can specify whether a binding or debinding event induces changes in the properties of the interacting molecules. The classical example for such a situation is the induction of conformational changes to the cytoplasmic domain of a receptor upon ligation by its extracellular ligand. Such changes then render certain binding sites (like, e.g., the enzymatically active domains of RTKs (receptor tyrosine kinases)) more or less available for their binding partners.
By defining these interactions (plus enzymatic transformations, described below) between pairs of molecules the modeler provides the information the software needs to construct the full network of all molecular complexes that are possible in the system.
At the next scale, the scale of molecular complexes, the modeler uses the graphical molecule symbols from the molecule definition window to 'build' those molecule complexes that should be tracked in space and time during simulations and / or that have enzymatic activity. Complexes are build simply by double-clicking the binding possibilities indicated by lines between binding sites.
Important Note
Based on the modeler's definition of molecular binding possibilities and enzymatic transformations Simmune automatically builds the complete network of molecules, molecule complexes and their reactions. If, for example, the modeler has specified a binding possibility between a molecule A and a molecule B the software will automatically include the formation (and dissociation) of the complex A:B into the construction of the reaction network. The network is constructed upon user request or, automatically, during a simulation. The definition of molecule complexes 'by hand' is necessary only for those complexes for which i) the modeler wishes to investigate concentrations and locations during simulations and/or for which ii) the modeler wishes to define enzymatic action on other molecular species.
The molecule complex symbols created in the complex window are used in the cell definition window to specify the initial biochemistry (distribution of complexes in the membrane and the cytosol) of cells. This completes the biochemistry part of the model. Based on the user's inputs the software can calculate - during a simulation run, see below - the time evolution of the concentrations and spatial distributions of all complexes. It also can automatically generate graphical representations of the signaling network (see below) and show how the concentrations of its components and the reaction flows in the different regions of a simulated cell change over time.
Mechanisms of Cellular Behavior
Models of cellular behavior may incorporate components on multiple spatial and temporal scales. A model of a collection of interacting cells could, for example, be simulated with a detailed simulation of signaling processes leading to the activation and translocation to the nucleus of messengers that induce cell division. One the other hand, one might, in the model's context, perhaps not be interested in the details of the division process itself, just in the result: a delayed appearance of an additional cell in the system. To make such scale-hybrid models and simulations possible Simmune allows the modeler to connect the detailed intracellular biochemistry to 'stimulus-response' mechanisms: Presence or absence of threshold amounts of user-defined molecular complexes can be defined as conditions ('stimulus') for the cell to perform actions ('response') like division, expression of additional molecules (intracellularly) or on the membrane, directed secretion of molecules, directed movement or death. In this case, the biochemical details of how the actions themselves are executed need not be simulated - only the build-up of stimuli and the consequences are.
Extracellular Space
With Simmune, cells can be simulated in 2D space, pseudo 2D (a thin slice of 3D space that eliminates most of the artifacts 2D models suffer from) and 3D space. Currently, only rectangular pieces of space with variable dimensions can be defined as the extracellular compartment. We are working on the possibility to define more complex topologies.
Defining Simulations
After the model components have been defined, the parameters for the simulations of the model can be specified in the simulation definition window. Besides being an interface for technical settings (like random generator seed etc.) this window allows the modeler to specify protocols for simulated experiments: when and at which space points should cells and molecules be introduced to the simulated system. While Simmune makes it possible to run fully interactive simulations during which the modeler can add, modify or inspect agents at any time (see below) simulation protocols make it possible to study the behavior of the simulated model through sequences of exactly defined (and easily reproducible) manipulations.
The Simmune Simulator
Once the model and the simulation parameters have been defined the model can be investigated through simulation with the Simmune simulator ('simmune'). The simulator is usually started from the simulation definition window of Simmod. It offers three different views of the simulated extracellular space: i) a concentration over time view that lists all extracellular agent types (molecule types, cells) and how their (spatial) average concentration or total number changes as the simulated time progresses, ii) a pseudo 3D view of the simulated extracellular compartment with (depending on their types, differently colored) dots representing the cells in the system, and iii) a 'slice' view that shows a 2D cut through the extracellular compartment and in addition to being able to visualize molecule concentration gradients (See gradient screenshot) can be used to select single cells for detailed inspections of their intracellular biochemistry (See Single Cell Screenshot). The single-cell inspection mode also allows the user to save the time course of the biochemistry of the selected cells for inspection with the network browser (see below).
The Network Browser
Usually, software for the construction of signaling pathways requires the modeler to specify each single reaction between the molecular complexes involved in the model and then perform a layout of the graphical representation of the pathway by hand.
As described above, Simmune automatically constructs the complete signaling network of interacting complexes based on the specifications of bi-molecular binding possibilities. Moreover, during a simulation of the behavior of cells that contain such signaling networks the modeler can save the detailed behavior of the cellular biochemistry. The modeler can then use the network browser to investigate the dynamics of the signaling processes with the help of automatically generated graphical representations of the networks.
These graphical representations use color saturation levels to indicate the relative concentrations of molecular species and visualize the reaction flows between them. The modeler can 'replay' the simulated experiment and follow the dynamics of the signal flow far easier and more intuitively than with conventional approaches. At the same time, the browser offers full access to the quantitative details: clicking on molecular complex symbol allows the modeler to query all relevant properties (molecular components, binding sites involved in formation of the complex etc.) and the exact concentration at any point in time and at different locations in the simulated cell.
Simmune Project Overview
Simmune Contacts
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