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The Biology of Ageing e-Science Integration and
Simulation System
Tom Kirkwood, Darren Wilkinson,
Richard Boys, Colin Gillespie,
Carole Proctor, Daryl Shanley
GRID-based research node to model/simulate hypotheses about mechanisms of ageing
Accessible and interactive
Nature Reviews Molecular Cell Biology 2003;4: 243 -249
www.basis.ncl.ac.uk
DNA
RNA
PROTEIN
Degradation oraggregation (e.g.amyloid)
Antioxidants
Modelling the ageing processCopying errors,Telomere shortening
Mutationse.g. ROS
Transcription errors
Translation errors
Damage,denaturinge.g. ROS
Chaperones
Refolding
mtDNA
ATP
ROS
ROS
ATP
ROS, etc
Virtual Ageing Cell• Telomere loss and oxidative stress: Proctor & Kirkwood Mech
Ageing Dev 2001.• Mitochondrial mutation: Kowald & Kirkwood J Theor Biol 2000.• Somatic mutation: Kirkwood & Proctor Mech Ageing Dev 2003.• Telomere capping: Proctor & Kirkwood Aging Cell 2003• Extrachromosomal DNA circles: Gillespie et al J Theor Biol
2004 • Genetic pathways: eg Sir2 gene action (in progress)• Protein turnover: Chaperones, ubiquitin-proteasome system
(Proctor et al. Mech Ageing Dev 2004 and in progress)• Antioxidant system: Shanley et al (in progress)• Network models:
• Mitochondrial mutation, oxidative stress, protein turnover (Kowald & Kirkwood Mutation Res 1996)
• Somatic mutation, telomere loss, mitochondrial mutation (oxidative stress (Sozou & Kirkwood JTheor Biol 2001)
A module of the virtual ageing cell: the action of chaperones
and their role in ageing
Proctor et al. 2004 Mechanisms in Ageing and Development
Cellular functions of chaperones
• Folding of nascent proteins• Assist in assembly of protein structures• Refolding of denatured proteins• Transport of proteins through cellular
membranes• Targeting of proteins for degradation• Prevention of protein aggregation
Protein model for quality control
Wickner et al. (1999) Science 286 1888-1893
Hsp90 Model of Regulation of HSF1
Zou et al. (1998) Cell 94:471-480
Steps in building and using a model
1. Draw a diagram of the system.2. Give values to the boxes representing
the number of molecules and to the arrows representing the reaction rates.
3. Use a software tool to translate the diagram into computer code.
4. Use the simulator to discover the dynamic behaviour of the system.
Building a model of the chaperone system
(i) The role of chaperones in preventing protein aggregation
refoldingbinding
aggregation
degradation
synthesis + folding into native state MisP
Hsp90
AggPNatP
ROS
ADP
ATP MisPHsp90
Abbreviations:NatP native proteinMisP misfolded proteinAggP aggregated proteinROS reactive oxygen species
misfolding
(ii) Autoregulation of Hsp90
Abbreviations:Hsf1 heat shock factor-1DIH dimer of Hsf1TriH trimer of Hsf1HSE heat shock element
Hsp90
Hsf1
Hsp90
Hsf1binding
degradation
dimerisation
synthesis
TriHDiH trimerisation
HSEHSE
TriH DNA binding
Model is coded in SBML<sbml xmlns="http://www.sbml.org/sbml/level2" version="1" level="2" ><model id="Hsp90model1" ><listOfCompartments><compartment id="cell" spatialDimensions="3" size=”1” name="cell" /></listOfCompartments><listOfSpecies><species id="NatP" compartment="cell" initialAmount="6000000.0" name=“NatP" /><species id=“Hsp90" compartment="cell" initialAmount=“30000.0" name=" Hsp90 " />
.</listOfSpecies><listOfParameters><parameter id="k1" value="7.04E-8" name=“k1" />
.</listOfParameters><listOfReactions><reaction id="protein_misfolding" reversible="false" ><listOfReactants><speciesReference species=“NatP" ></speciesReference></listOfReactants><listOfProducts><speciesReference species=“MisP" ></speciesReference></listOfProducts>
.</reaction>
.</listOfReactions></model></sbml>
Stochastic simulation
refoldingbinding
aggregation
degradation
synthesis + folding into native state MisP
Hsp90
AggPNatP
ROS
ADP
ATP MisPHsp90
Abbreviations:NatP native proteinMisP misfolded proteinAggP aggregated proteinROS reactive oxygen species
misfolding
• Reactions are picked at random according to their rates.
• After each reaction, the number of each species is updated.
Adding further detail to the model
degraded protein
Ub
Ub
Ub
Ub MisP
Ub
Ub Ub
Ub
ATP ADP
Proteasome
MisP
Ub
Ub
Ub
Ub
Ub = ubiquitin
ATP ADP
Combining models in the BASIS system
• Other components will include models of: the mitochondria; the antioxidant system; damage to nuclear DNA; telomere shortening; and signalling pathways.
• Combining the mitochondria and chaperone model via ROS and ATP
Mitochondriamodel
Chaperonemodel
ROS
ATP
BASIS: architecture
User PC
Internet (GRID)
BASISfile
servere-mail
notification
Web server
CGI scripts
Web browser
BASIS client software
Linux beowulf cluster
Web services
API
Database JobSchedul
er
BASIS: architecture
• Web server is running apache• Condor as a job scheduler• python as an all purpose glue• SBML is parsed and manipulated using
libSBML for C & python• postgresql for the database• graphviz for the visualisation of the SBML
models
BASIS: model repository
• Users have a private space for their models/simulations
• Once a model is made public it cannot be deleted– useful for the publication of models
• Models can be accessed through a web-service interface– other tools can access the models
• Models are referenced using urn’s, e.g. urn:basis.ncl:model:10
Example web-services#To put a model into your space
putModel(SId, sbml)
#Using libSBML & graphviz
visualiseSBMLReaction(sbml, #reaction)
What’s new?
• More interaction with biologists– especially PhD students
• Virtual ageing cell– more computer resources needed – Grid
• Web services– import models from other databases
BASIS TeamTom Kirkwood Darren Wilkinson Richard BoysColin Gillespie Carole Proctor Daryl Shanley
Collaborators at NewcastleThomas von Zglinicki David LydallGabriele SaretzkiTim Cowen (IAH/UCL)Doug TurnbullChris MorrisJohn MathersNeil Wipat
NE E-Science CentrePaul WatsonRob Smith
UnileverJanette JonesJonathan PowellFrans van der OuderaaBerlin (MPI Inst. Mol. Genet.)Axel KowaldUniversity of BolognaClaudio Franceschi Silvana Valensin Paolo TieriINSERM ParisFrancois TaddeiTufts University/USDAJose OrdovasUniversity of LiverpoolBrian MerryUniversity of SemmelweisCsaba SotiOttawa Regional Cancer CentreDoug Gray
Acknowledgements