ongoing computational work at the molecular sciences...
TRANSCRIPT
Ongoing computational work at the MolecularSciences Institute and the CQGF supportingquantitative understanding of cell signaling
Steve Andrewsthe Molecular Sciences Institute
Berkeley, California, USA
Centers of Excellence in Genomic ScienceCaltech
October 17, 2008
Smoldyn: a spatial stochastic biochemical simulator
Smoldyn: Smoluchowski dynamics• Space is 3-dimensional and continuous• Stochastic: molecules move by Brownian motion• Reactions occur when molecules collide• Realistic molecule-membrane interactions
A general purpose toolFor more information and to download:http://www.smoldyn.org
Why simulate space and stochasticity?• signal transduction• macromolecular crowding• diffusion in membranes
100 nm
Dose response alignment
Figure: Wang and Dohlman, Science, 306:1508, 2004.
Yeast mating pheromone signaling pathway
α
PRM1
Dose response alignmentYeast mating pheromone signaling pathway
α
PRM1
We observe dose-responsealignment at many stages
Why?How?
Simulating effects of different pathway architectures
α
Ai Aa
Bi
kAakAi
kαAa
Ba
kBakBi
kABa
kDAi
Ca
kCakCi
kBCa
Da
kDakDi
kCDa
Ci
Di
α A B C D
Concept
Precise definition
HillSim• finds steady-state activities• finds dose-response curves• fits them to Hill functions
amplitude
EC50
baseline
Hillcoeff.
simulated
Simulating effects of different pathway architectures
α
Ai Aa
Bi
kAakAi
kαAa
Ba
kBakBi
kABa
kDAi
Ca
kCakCi
kBCa
Da
kDakDi
kCDa
Ci
Di
α A B C D
Concept
Precise definition
HillSim• finds steady-state activities• finds dose-response curves• fits them to Hill functions• optimizes alignment
score =actualn, p ! targetn, p
" n, p
#
$%
&
'(
2
Hillparameters
)nodes
)
amplitude
EC50
baseline
Hillcoeff.
simulated
target
Achieving dose response alignment
α A B C D
α A B C D
α A B C D
α A B C D
Linear Multi-input feedforward
Negative feedback Pull-up / pull-down
Acknowledgements
SmoldynDennis BrayKaren LipkowUpi BhallaDylan MorrisTom ShimizuAdam ArkinRoger Brent
Signaling architectureRoger BrentRichard YuGustavo PesceAlejandro Colman-LernerOrna ResnekovAndrew Gordon