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