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BIOLOGICAL SYSTEMS SIMULATIONS BASED ON NEGATIVE FEEDBACK
EUROPEAN UNIONEUROPEAN REGIONAL
DEVELOPMENT FUND
The work was co-funded by the European Regional Development Fund as part of the Innovative Economy program.
Jakub Wach3, Marian Bubak1,3, Leszek Konieczny2, Irena Roterman-Konieczna2
1AGH University of Science and Technology, Department of Computer Science, Kraków, Poland
2Jagiellonian University, Department of Bioinformatics and Telemedicine, Kraków, Poland
3Academic Computer Centre Cyfronet AGH, Kraków, Poland
http://dice.cyfronet.pl
PROBLEM DESCRIPTION
Biological system Anything alive (enzyme, virus, cell, ….) Mulitple levels – from a single enzyme to whole organism
Need for simulation Novel treatments Insight into details (structure and function preciction)
Existing simulation methods Approximate (based on PDEs) Precise (Stanford cell model)
NFS APPROACHThe idea L. Konieczny, I. Roterman, P. Spolnik : “Systems
biology” Model function, not structure Use negative-feedback systems (NFSs), simplest
regulator as building blocks
Negative Feedback System Effector
Delivers a product Output regulated by Receptor
Receptor Delivers signal regulating Effector Signal output is regulated by product level
Effector
Substrate
Outflow
Receptor
NFS APPROACH - SYSTEMS Biological system – composition of building blocks Organized Systems – OS – composition of connected NFSs
OS - COOPERATION Cooperation connection
Product of one NFS is substrate of another one Receptor is not aware of the change – it’s a local
(Effector) relation Example – enzymatic cascade, where one
enzyme delivers substrate to another, e.g. glycolysis
OS - COORDINATION Coordiation connection
One NFS can change regulation threshold of another NFS Whole NFS is affected – it’s a global (Receptor) relation Example – allosteric control of enzymes
OS – HIERARCHY Component hierarchy
One NFS can be coupled with a Receptor
Higher – level NFS is created this way Multiple „nesting” levels possible Example – hormonal regulation
APPLICATION
Multiple modules available
Implements OS model with all of the relations Allows both bounded (cooperation) and unbounded (unlimited source)
NFSs Allows space-time constraints by introducing delay parameter Simple iterative simulation algorithm Sophisticated, real product diffusion model
http://crick.cm-uj.krakow.pl:8080/nfs/
APPLICATION - PLAYGROUND
JSON definition of an OS Graphical parameters editor
APPLICATION - PLAYGROUND
Real time OS model visualization in SVG (already presented)
Simulation run results charts Archivable and exportable
APPLICATION - MANAGEMENT
Provides exercise management Allows for creating, editing and deleting
exercises Allows for user (student) assignment Allows date / time constraints for
exercises
Provides task management Allows for OS definition for a task User can add name and description for a
task
WORKFLOW INTEGRATION
Models can be very complex, even for typical scenarios Hundreds of parameters for optimization Search for appropriate structure and values