Dynamic simulation of regulatory networks using SQUAD.
BACKGROUND
The ambition of most molecular biologists is the understanding of the intricate network of molecular interactions that control biological systems. As scientists uncover the components and the connectivity of these networks, it becomes possible to study their dynamical behavior as a whole and discover what is the specific role of each of their components. Since the behavior of a network is by no means intuitive, it becomes necessary to use computational models to understand its behavior and to be able to make predictions about it. Unfortunately, most current computational models describe small networks due to the scarcity of kinetic data available. To overcome this problem, we previously published a methodology to convert a signaling network into a dynamical system, even in the total absence of kinetic information. In this paper we present a software implementation of such methodology.


RESULTS
We developed SQUAD, a software for the dynamic simulation of signaling networks using the standardized qualitative dynamical systems approach. SQUAD converts the network into a discrete dynamical system, and it uses a binary decision diagram algorithm to identify all the steady states of the system. Then, the software creates a continuous dynamical system and localizes its steady states which are located near the steady states of the discrete system. The software permits to make simulations on the continuous system, allowing for the modification of several parameters. Importantly, SQUAD includes a framework for perturbing networks in a manner similar to what is performed in experimental laboratory protocols, for example by activating receptors or knocking out molecular components. Using this software we have been able to successfully reproduce the behavior of the regulatory network implicated in T-helper cell differentiation.


CONCLUSIONS
The simulation of regulatory networks aims at predicting the behavior of a whole system when subject to stimuli, such as drugs, or determine the role of specific components within the network. The predictions can then be used to interpret and/or drive laboratory experiments. SQUAD provides a user-friendly graphical interface, accessible to both computational and experimental biologists for the fast qualitative simulation of large regulatory networks for which kinetic data is not necessarily available.
Swiss Institute of Bioinformatics, Vital-IT Group, Quartier Sorge - Batiment Genopode, CH-1015 Lausanne, Switzerland. alessandro.dicara@merckserono.net
Alessandro
A
Di Cara
Abhishek
A
Garg
Giovanni
G
De Micheli
Ioannis
I
Xenarios
Luis
L
Mendoza
D000818:Animals; D002454:Cell Differentiation; D016000:Cluster Analysis; D003196:Computer Graphics; D003198:Computer Simulation; D003663:Decision Trees; D004798:Enzymes / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D007700:Kinetics; D008954:Models, Biological; D017711:Nonlinear Dynamics; D025941:Protein Interaction Mapping / Q000379:methods; D015398:Signal Transduction; D012984:Software; D049490:Systems Biology / Q000379:methods*; D006377:T-Lymphocytes, Helper-Inducer / Q000502:physiology
D004798:Enzymes