1. Practical Application Scenario: Cell Cycle & Kinetochore 2. From Hash Life to Particle Based Simulation 3. Chemical Organization Theory Jan Huwald Peter Dittrich Bio Systems Analysis Group Institute of Computer Science, Friedrich-Schiller-University Jena 06.12.2012 Birmingham, Jan Huwald / Peter Dittrich - FSU Jena 1 HIERATIC
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Practical Application Scenario: Study of Kinetochor Organization and Mitotic Control Jan Huwald / Peter Dittrich - FSU Jena 06.12.2012 Birmingham, HIERATIC 3
http://nobelprize.org/nobel_prizes/medicine/laureates/2001/illpres/introduction.html - • B. Ibrahim Diekmann S, Schmitt E, Dittrich P (2008) In-Silico Modeling of the Mitotic Spindle Assembly Checkpoint. PLoS ONE 3(2): e1555. doi:10.1371/journal.pone.0001555 • B. Ibrahim et al. / Biophysical Chemistry 134 (2008) 93 – 100 • B. Ibrahim et al. / BioSystems 95 (2009) 35 – 50 06.12.2012 Birmingham, HIERATIC Jan Huwald / Peter Dittrich - FSU Jena 4
Wait until all kinetochores are correctly attached WAIT! http://library.thinkquest.org/C004535/mitosis .html 06.12.2012 Birmingham, HIERATIC Jan Huwald / Peter Dittrich - FSU Jena 5
Wait until all kinetochores are correctly attached GO! http://library.thinkquest.org/C004535/mitosis .html 06.12.2012 Birmingham, HIERATIC Jan Huwald / Peter Dittrich - FSU Jena 6
Wait until all kinetochores are correctly attached GO! http://library.thinkquest.org/C004535/mitosis .html 06.12.2012 Birmingham, HIERATIC Jan Huwald / Peter Dittrich - FSU Jena 7
Systems Biology of Mitosis http://nobelprize.org/nobel_prizes/medicine/laureates/2001/illpres/introduction.html • M. Lohel, B. Ibrahim, S. Diekmann, P. Dittrich (2009), The Role of Localization in the Operation of the Mitotic Spindle Assembly Checkpoint, Cell Cycle, 8(16):2650 - 2660, 2009 - • B. Ibrahim Diekmann S, Schmitt E, Dittrich P (2008) In-Silico Modeling of the Mitotic Spindle Assembly Checkpoint. PLoS ONE 3(2): e1555. doi:10.1371/journal.pone.0001555 • B. Ibrahim et al. / Biophysical Chemistry 134 (2008) 93 – 100 • B. Ibrahim et al. / BioSystems 95 (2009) 35 – 50 06.12.2012 Birmingham, HIERATIC Jan Huwald / Peter Dittrich - FSU Jena 8
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The Human Kinetochor 06.12.2012 Birmingham, Jan Huwald / Peter Dittrich - FSU Jena 10 HIERATIC
The Human Kinetochore Cell during mitosis 06.12.2012 Birmingham, HIERATIC Jan Huwald / Peter Dittrich - FSU Jena 11
The Human Kinetochore 06.12.2012 Birmingham, HIERATIC Jan Huwald / Peter Dittrich - FSU Jena 12
Experiments performed by the Diekmann Group (FLI Jena) dynamics structure RICS interaction FRAP EM/AFM Y2H, M2H dynamics neighbourhood in vivo , in situ in vitro cell cycle dependent FRET cell cycle dependent Western blots interaction Pull-down in prepation: MassSpec FCS/FCCS protein amounts dynamics protein modification Jan Huwald / Peter Dittrich - FSU Jena 06.12.2012 Birmingham, HIERATIC 13
Proximities derived from wet experiments (FRET) See: paper: D. Hellwig, S. Emmerth, T: Ulbricht, V: Döring, C. Hoischen, R. Martin, C. P. Samora, A. D. McAinsh, C. W. Carroll, A. F. Straight, P. Meraldi, S. Dekmann, Dynamic binding of CENP- N to the kinetochore through the cell cycle, J. Cell. Sci., 2011, 15;124, pp 3871-83. paper: L. Prendergast, C. v. Vuuren, A. Kaczmarczyk, V. Doering, D. Hellwig, N. uinn, C. Hoischen, S. Diekmann, K. F. Sullivan, Pre-mitotic assembly of CENPs -T and -W switches centromeric chromatin to a mitotic state, PLoS Biology , 2011; 9(6):e1001082, 2011. paper: A. Eskat, W. Deng, A. Hofmeister, S. Rudolphi, S. Emmerth, D. Hellwig,T. Ulbricht, V. Döring, J. M. Bancroft, A. D. McAinsh, M. C.Cardoso, P. Meraldi, C. Hoischen, H. Leonhardt, S. Diekmann, Step-Wise Assembly, Maturation and Dynamic Behavior of the Human CENP-P/O/R/Q/U Kinetochore Sub-Complex, PLoS ONE 7(9): e44717, 2012. paper: S. Dambacher, W Deng, Mahn,, D. Sadic, J.J. Fröhlich, A. Nuber, C. Hoischen, S. Diekmann, Heinrich Leonhardt and Gunnar Schotta, CENP-C facilitates the recruitment of M18BP1 to centromeric chromatin, Nucleus 3:1, 101 – 110; 2012. paper: M. Bui, E. K. Dimitriadis, C. Hoischen, E. An, D. Quénet, S. Giebe A. Nita-Lazar, S. Diekmann, Y. Dalal, Cell-Cycle-Dependent Structural Transitions in the Human CENP-A Nucleosome In Vivo, Cell 150, 317 – 326, 2012. 06.12.2012 Birmingham, HIERATIC Jan Huwald / Peter Dittrich - FSU Jena 14
3-D Rule-Based Model 1. Set of reaction rules like 2. Geometry information: - size of a molecule - angle of bond 06.12.2012 Birmingham, HIERATIC Jan Huwald / Peter Dittrich - FSU Jena 15
Rule-Based Modeling in Space 06.12.2012 Birmingham, HIERATIC Jan Huwald / Peter Dittrich - FSU Jena 16
Example of an infinite reaction network # use the 'kill' modification to delete bonds (used by the next four rules) A(a!1).Pa(a!1~kill) -> A(a) + Pa(a~kill) Pa(a~kill) -> Pa(a~n) B(a!1).Pb(a!1~kill) -> B(a) + Pb(a~kill) Pb(a~kill) -> Pb(a~n) # transform the bonds A(a!2,x!1).B(x!1,a!4).Pa(a!2~n,x!3).Pb(x!3,a!4) -> A(a!2,x!1).B(x!1,a!4).Pa(a!2~kill,x!3).Pb(x!3,a!4) A(a,x!1).B(x!1,a!2).Pb(a!2,x!3).Pa(x!3,a) + A(a,x!1).B(x!1,a) -> A(a,x!1).B(x!1,a!2).Pb(a!2,x!3).Pa(x!3,a!4).A(a!4,x!5).B(x!5,a) A(x!1).B(x!1,a!2).Pb(a!2~n,x!3).Pa(x!3,a!4).A(a!4,x!5).B(x!5) -> A(x!1).B(x!1,a!2).Pb(a!2~kill,x!3).Pa(x!3,a!4).A(a!4,x!5).B(x!5) A(a!+,x!1).B(x!1,a) + Pa(a!+,x!3).Pb(x!3,a) -> A(a!+,x!1).B(x!1,a!2).Pa(a!+,x!3).Pb(x!3,a!2) # attach new motor-proteins to the filaments A(a,x!1).B(x!1,a,o!+) + Pa(a,x!3).Pb(x!3,a) -> A(a!2,x!1).B(x!1,a,o!+).Pa(a!2,x!3).Pb(x!3,a) # release motor-proteins Fin(o!1).B(a!2,o!1).Pa(a,x!3).Pb(x!3,a!2) -> Fin(o!1).B(a,o!1) + Pa(a,x!3).Pb(x!3,a) G. Grünert, B. Ibrahim, T. Lenser, M. Lohel, T. Hinze, P. Dittrich, BMC Bioinformatics , 11:307, 2010 Jan Huwald / Peter Dittrich - FSU Jena 06.12.2012 Birmingham, 17 HIERATIC
Interactions derived from wet experiments (FRET) See: paper: D. Hellwig, S. Emmerth, T: Ulbricht, V: Döring, C. Hoischen, R. Martin, C. P. Samora, A. D. McAinsh, C. W. Carroll, A. F. Straight, P. Meraldi, S. Dekmann, Dynamic binding of CENP- N to the kinetochore through the cell cycle, J. Cell. Sci., 2011, 15;124, pp 3871-83. paper: L. Prendergast, C. v. Vuuren, A. Kaczmarczyk, V. Doering, D. Hellwig, N. uinn, C. Hoischen, S. Diekmann, K. F. Sullivan, Pre-mitotic assembly of CENPs -T and -W switches centromeric chromatin to a mitotic state, PLoS Biology , 2011; 9(6):e1001082, 2011. paper: A. Eskat, W. Deng, A. Hofmeister, S. Rudolphi, S. Emmerth, D. Hellwig,T. Ulbricht, V. Döring, J. M. Bancroft, A. D. McAinsh, M. C.Cardoso, P. Meraldi, C. Hoischen, H. Leonhardt, S. Diekmann, Step-Wise Assembly, Maturation and Dynamic Behavior of the Human CENP-P/O/R/Q/U Kinetochore Sub-Complex, PLoS ONE 7(9): e44717, 2012. paper: S. Dambacher, W Deng, Mahn,, D. Sadic, J.J. Fröhlich, A. Nuber, C. Hoischen, S. Diekmann, Heinrich Leonhardt and Gunnar Schotta, CENP-C facilitates the recruitment of M18BP1 to centromeric chromatin, Nucleus 3:1, 101 – 110; 2012. paper: M. Bui, E. K. Dimitriadis, C. Hoischen, E. An, D. Quénet, S. Giebe A. Nita-Lazar, S. Diekmann, Y. Dalal, Cell-Cycle-Dependent Structural Transitions in the Human CENP-A Nucleosome In Vivo, Cell 150, 317 – 326, 2012. 06.12.2012 Birmingham, HIERATIC Jan Huwald / Peter Dittrich - FSU Jena 18
3-D Rule-Based Model 06.12.2012 Birmingham, HIERATIC Jan Huwald / Peter Dittrich - FSU Jena 19
What we can learn … - Bridge can form - Kinetochore has different structures - Bridge depends on nucleosome distances and molecule concentration Source: R. Henze et al. 06.12.2012 Birmingham, HIERATIC Jan Huwald / Peter Dittrich - FSU Jena 20
Clustering 600 Simulations Source: R. Henze et al. 06.12.2012 Birmingham, HIERATIC Jan Huwald / Peter Dittrich - FSU Jena 21
M-Phase Full Kinetochore (Inner and Outer Kinetochore) Source: R. Henze et al. 06.12.2012 Birmingham, Jan Huwald / Peter Dittrich - FSU Jena 22 HIERATIC
3-D Rule-Based Model Source: R. Henze et al. 06.12.2012 Birmingham, HIERATIC Jan Huwald / Peter Dittrich - FSU Jena 23
Example of an infinite reaction network # use the 'kill' modification to delete bonds (used by the next four rules) A(a!1).Pa(a!1~kill) -> A(a) + Pa(a~kill) Pa(a~kill) -> Pa(a~n) B(a!1).Pb(a!1~kill) -> B(a) + Pb(a~kill) Pb(a~kill) -> Pb(a~n) # transform the bonds A(a!2,x!1).B(x!1,a!4).Pa(a!2~n,x!3).Pb(x!3,a!4) -> A(a!2,x!1).B(x!1,a!4).Pa(a!2~kill,x!3).Pb(x!3,a!4) A(a,x!1).B(x!1,a!2).Pb(a!2,x!3).Pa(x!3,a) + A(a,x!1).B(x!1,a) -> A(a,x!1).B(x!1,a!2).Pb(a!2,x!3).Pa(x!3,a!4).A(a!4,x!5).B(x!5,a) A(x!1).B(x!1,a!2).Pb(a!2~n,x!3).Pa(x!3,a!4).A(a!4,x!5).B(x!5) -> A(x!1).B(x!1,a!2).Pb(a!2~kill,x!3).Pa(x!3,a!4).A(a!4,x!5).B(x!5) A(a!+,x!1).B(x!1,a) + Pa(a!+,x!3).Pb(x!3,a) -> A(a!+,x!1).B(x!1,a!2).Pa(a!+,x!3).Pb(x!3,a!2) # attach new motor-proteins to the filaments A(a,x!1).B(x!1,a,o!+) + Pa(a,x!3).Pb(x!3,a) -> A(a!2,x!1).B(x!1,a,o!+).Pa(a!2,x!3).Pb(x!3,a) # release motor-proteins Fin(o!1).B(a!2,o!1).Pa(a,x!3).Pb(x!3,a!2) -> Fin(o!1).B(a,o!1) + Pa(a,x!3).Pb(x!3,a) G. Grünert, B. Ibrahim, T. Lenser, M. Lohel, T. Hinze, P. Dittrich, BMC Bioinformatics , 11:307, 2010 Jan Huwald / Peter Dittrich - FSU Jena 06.12.2012 Birmingham, 24 HIERATIC
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From Hash Life to Particle Based Simulation Jan Huwald / Peter Dittrich - FSU Jena 06.12.2012 Birmingham, HIERATIC 26
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