QSSPN: dynamic simulation of molecular interaction networks describing gene regulation, signalling and whole-cell metabolism in human cells.
BACKGROUND
Dynamic simulation of genome-scale molecular interaction networks will enable the mechanistic prediction of genotype-phenotype relationships. Despite advances in quantitative biology, full parameterization of whole-cell models is not yet possible. Simulation methods capable of using available qualitative data are required to develop dynamic whole-cell models through an iterative process of modelling and experimental validation.


RESULTS
We formulate quasi-steady state Petri nets (QSSPN), a novel method integrating Petri nets and constraint-based analysis to predict the feasibility of qualitative dynamic behaviours in qualitative models of gene regulation, signalling and whole-cell metabolism. We present the first dynamic simulations including regulatory mechanisms and a genome-scale metabolic network in human cell, using bile acid homeostasis in human hepatocytes as a case study. QSSPN simulations reproduce experimentally determined qualitative dynamic behaviours and permit mechanistic analysis of genotype-phenotype relationships.


METHODS
The model and simulation software implemented in C++ are available in supplementary material and at http://sysbio3.fhms.surrey.ac.uk/qsspn/.
Faculty of Health and Medical Sciences, School of Biosciences and Medicine, University of Surrey, Guildford, Surrey GU2 7XH, UK.
Ciarán P
CP
Fisher
Nicholas J
NJ
Plant
J Bernadette
JB
Moore
Andrzej M
AM
Kierzek
D000465:Algorithms; D001647:Bile Acids and Salts / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D019295:Computational Biology / Q000379:methods*; D003198:Computer Simulation; D005240:Feasibility Studies; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D056726:Genetic Association Studies; D015894:Genome, Human; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D006801:Humans; D053858:Metabolic Networks and Pathways; D008954:Models, Biological; D009010:Monte Carlo Method; D025941:Protein Interaction Mapping; D015398:Signal Transduction; D012984:Software
D001647:Bile Acids and Salts; D002784:Cholesterol