Computational models of neuronal biochemistry

Transcription

1 Computational models of neuronal biochemistry Melanie I Stefan Centre for Discovery Brain Sciences, University of Edinburgh 25 August 2017 melanie.stefan@ed.ac.uk Models of neuronal biochemistry 25 August / 24

2 Stefan lab, University of Edinburgh Models of neuronal biochemistry 25 August / 24

3 Modelling neuronal protein signalling Outline 1 Modelling neuronal protein signalling 2 Space affects chemical signalling 3 Chemical signalling affects space melanie.stefan@ed.ac.uk Models of neuronal biochemistry 25 August / 24

4 Modelling neuronal protein signalling Calcium signalling in (early) LTP Models of neuronal biochemistry 25 August / 24

5 Modelling neuronal protein signalling Calcium signalling in (early) LTP Models of neuronal biochemistry 25 August / 24

6 Modelling neuronal protein signalling Calcium signalling in (early) LTP Models of neuronal biochemistry 25 August / 24

7 Modelling neuronal protein signalling Calcium signalling in (early) LTP Models of neuronal biochemistry 25 August / 24

8 Modelling neuronal protein signalling Calcium signalling in (early) LTP Models of neuronal biochemistry 25 August / 24

9 Modelling neuronal protein signalling Calcium signalling in (early) LTP Models of neuronal biochemistry 25 August / 24

10 Modelling neuronal protein signalling Calcium signalling in (early) LTP Models of neuronal biochemistry 25 August / 24

11 Modelling neuronal protein signalling Of course, it s more complicated Kennedy et al. Nat Rev Neurosci, melanie.stefan@ed.ac.uk Models of neuronal biochemistry 25 August / 24

12 Space affects chemical signalling Outline 1 Modelling neuronal protein signalling 2 Space affects chemical signalling 3 Chemical signalling affects space melanie.stefan@ed.ac.uk Models of neuronal biochemistry 25 August / 24

13 Space affects chemical signalling Space affects chemical signalling Kennedy et al. Nat Rev Neurosci, Biochemistry in small compartments Biological compartments are not well-mixed Ligand concentration can be small There is competition This can lead to counter-intuitive biochemical behaviours One example is the high-dose hook effect Models of neuronal biochemistry 25 August / 24

14 Space affects chemical signalling But first... Models of neuronal biochemistry 25 August / 24

15 Space affects chemical signalling But first... Models of neuronal biochemistry 25 August / 24

16 Space affects chemical signalling But first... Consider this game All available Panini cards are distributed among N players A player wins if they have a full Austria set melanie.stefan@ed.ac.uk Models of neuronal biochemistry 25 August / 24

17 Space affects chemical signalling But first... Consider this game All available Panini cards are distributed among N players A player wins if they have a full Austria set How many winners can there be? melanie.stefan@ed.ac.uk Models of neuronal biochemistry 25 August / 24

18 Space affects chemical signalling But first... Consider this game All available Panini cards are distributed among N players A player wins if they have a full Austria set How many winners can there be? How could we increase the number of winners? melanie.stefan@ed.ac.uk Models of neuronal biochemistry 25 August / 24

19 Space affects chemical signalling How to win a game melanie.stefan@ed.ac.uk Models of neuronal biochemistry 25 August / 24

20 Space affects chemical signalling How to win a game melanie.stefan@ed.ac.uk Models of neuronal biochemistry 25 August / 24

21 Space affects chemical signalling OK, but why should I care? melanie.stefan@ed.ac.uk Models of neuronal biochemistry 25 August / 24

22 Space affects chemical signalling OK, but why should I care? Calmodulin Ranjita Dutta Roy Karolinska Insitutet, Stockholm, Charité, Berlin Dutta-Roy et al. BMC Sys Biol, melanie.stefan@ed.ac.uk Models of neuronal biochemistry 25 August / 24

23 Space affects chemical signalling Calmodulin is an allosteric protein Stefan et al. PNAS, Models of neuronal biochemistry 25 August / 24

24 Space affects chemical signalling Wild-type calmodulin shows a hook effect melanie.stefan@ed.ac.uk Models of neuronal biochemistry 25 August / 24

25 Space affects chemical signalling Non-cooperative mutant shows a stronger hook effect melanie.stefan@ed.ac.uk Models of neuronal biochemistry 25 August / 24

26 Space affects chemical signalling More is not always better (for allosteric activators) Models of neuronal biochemistry 25 August / 24

27 Space affects chemical signalling More is not always better (for allosteric activators) Models of neuronal biochemistry 25 August / 24

28 Chemical signalling affects space Outline 1 Modelling neuronal protein signalling 2 Space affects chemical signalling 3 Chemical signalling affects space melanie.stefan@ed.ac.uk Models of neuronal biochemistry 25 August / 24

29 Chemical signalling affects space Chemical signalling affects space Actin cytoskeleton confers structural stability and strength Actin monomers assemble into branched strands Calcium signalling changes actin dynamics Models of neuronal biochemistry 25 August / 24

30 Chemical signalling affects space How does the spine cytoskeleton grow and change? Kadri Pajo Pajo and Stefan submitted Models of neuronal biochemistry 25 August / 24

31 Chemical signalling affects space MCell MCell Agent-based spatial stochastic simulator (Kerr et al. SIAM J Sci Comput., 2008) Allows for modelling of multi-state molecules (Stefan et al. PLoS Comp Biol, 2014) Available at Integration with blender for model definition and visualisation melanie.stefan@ed.ac.uk Models of neuronal biochemistry 25 August / 24

32 Chemical signalling affects space Modelling actin cytoskeleton dynamics Models of neuronal biochemistry 25 August / 24

33 Chemical signalling affects space Modelling actin cytoskeleton dynamics Models of neuronal biochemistry 25 August / 24

34 Chemical signalling affects space Modelling actin cytoskeleton dynamics Models of neuronal biochemistry 25 August / 24

35 Chemical signalling affects space Modelling actin cytoskeleton dynamics Models of neuronal biochemistry 25 August / 24

36 Chemical signalling affects space Take-home messages Stefan et al. PLoS Comp Biol, 2014 Subcellular space is not a test-tube The biochemistry of cellular compartments is often non-intuitive New tools allow us to create spatial models of biochemical signalling We can model structural change and chemical interactions on the same platform melanie.stefan@ed.ac.uk Models of neuronal biochemistry 25 August / 24

37 Chemical signalling affects space Come and say hi! Stefan Lab Isla Smith - High-dose hook effect in diagnostic testing Jana Finz gar - mglur-nmdar interactions Lewis Strachan, Richard Fitzpatrick - Pathway modelling in autism spectrum disorders Salvador Garcı a Gonza lez - Learning analytics software Susana Roma n Garcı a - CaMKII interactions with NMDA receptors Tara O Driscoll - CaMKII autoactivation Zale Cao - Neuronal networks in C. elegans Alumni Excellence Ogunbayo - Components of a minimal memory sytem Kadri Pajo - Actin cytoskeleton remodelling Yubin Xie - Multi-scale modelling of plasticity in the MVN melanie.stefan@ed.ac.uk Models of neuronal biochemistry 25 August / 24