Multi-scale simulations of whole Tyler Earnest / PI: Zan - - PowerPoint PPT Presentation

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Multi-scale simulations of whole Tyler Earnest / PI: Zan - - PowerPoint PPT Presentation

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Multi-scale simulations of whole Tyler Earnest / PI: Zan Luthey-Schulten (UIUC) NCSA Blue Waters Symposium for Petascale Science and yeast cells Beyond: June 6, 2018 Chemical kinetic simulations Earnest, , ZLS Rep. Prog. Phys (2018)

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Multi-scale simulations of whole yeast cells

Tyler Earnest / PI: Zan Luthey-Schulten (UIUC)

NCSA Blue Waters Symposium for Petascale Science and Beyond: June 6, 2018

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Chemical kinetic simulations

Earnest, …, ZLS Rep. Prog. Phys (2018) 10.1088/1361-6633/aaae2c

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Chemical kinetic simulations

Earnest, …, ZLS Rep. Prog. Phys (2018) 10.1088/1361-6633/aaae2c

c(t)

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Chemical kinetic simulations

Earnest, …, ZLS Rep. Prog. Phys (2018) 10.1088/1361-6633/aaae2c

c(x, t)

c(t)

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Chemical kinetic simulations

Earnest, …, ZLS Rep. Prog. Phys (2018) 10.1088/1361-6633/aaae2c

P(n, t)

c(x, t)

c(t)

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Chemical kinetic simulations

Earnest, …, ZLS Rep. Prog. Phys (2018) 10.1088/1361-6633/aaae2c

P(n, x, t) P(n, t) c(x, t) c(t)

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CME/ODE — Well mixed chemical kinetics

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Saccharomyces cerevisiae — Characteristic scales

  • Conc. [µM]
  • Diff. coeff.

[µm2/s]

  • Diff. time [s]

Sugar ~1,000 ~200 0.013 Protein ~1 ~5 0.53 Gene 10-4 10-5 105 4 µm

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Saccharomyces cerevisiae — Characteristic scales

  • Conc. [µM]
  • Diff. coeff.

[µm2/s]

  • Diff. time [s]

Sugar ~1,000 ~200 0.013 Protein ~1 ~5 0.53 Gene 10-4 10-5 105 4 µm Concentration/time scales do not overlap!

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Yeast galactose switch

Ramsey et al. Nat Genet. 2006 10.1038/ng1869

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Yeast galactose switch

107 reactions per second

  • ver 6 hours

Ramsey et al. Nat Genet. 2006 10.1038/ng1869

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Yeast galactose switch

107 reactions per second

  • ver 6 hours

Switch induction result of by single molecule event but

Ramsey et al. Nat Genet. 2006 10.1038/ng1869

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Hybrid CME/ODE simulations

Bianchi, …, TME, …, ZLS. IET Syst. Biol. 2018 10.1049/iet-syb.2017.0070

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Hybrid CME/ODE simulations

Chemical master equation: Gillespie algorithm

Bianchi, …, TME, …, ZLS. IET Syst. Biol. 2018 10.1049/iet-syb.2017.0070

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Hybrid CME/ODE simulations

Chemical master equation: Gillespie algorithm Chemical rate equation: LSODA

Bianchi, …, TME, …, ZLS. IET Syst. Biol. 2018 10.1049/iet-syb.2017.0070

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Hybrid CME/ODE simulations

Chemical master equation: Gillespie algorithm Chemical rate equation: LSODA

ODE

Communication Timestep τ ODE Adaptive Timestep ∆t time

⎧ ⎫

CME updates ODE species counts

⎬

ODE updates CME propensities

CME

Bianchi, …, TME, …, ZLS. IET Syst. Biol. 2018 10.1049/iet-syb.2017.0070

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Results: 40x speed up with limited impact on accuracy

External galactose 0.055 mM 2.0 mM CME (hr) 2.1 47.4 Hybrid (10 s) 0.4 (5.2) 1.1 (43.1) Hybrid (1s) 0.8 (2.6) 1.8 (26.3)

Wall time to simulate 750 min

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RDME/ODE — Spatial resolution

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Reaction-Diffusion Master Equation

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Reaction-Diffusion Master Equation

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Reaction-Diffusion Master Equation

Discretize to lattice

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Reaction-Diffusion Master Equation

Discretize to lattice React within subvolumes Diffuse between subvolumes Particles:

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Reaction-Diffusion Master Equation

Discretize to lattice System state described by particle count

  • f each type at each subvolume

React within subvolumes Diffuse between subvolumes Particles:

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Roberts et al. J. Comput. Chem. 2013

Whole-cell modeling with Lattice Microbes

Designed for CUDA 
 Multiple levels of parallelism GPGPU


Roberts et al. IPDPS (2009) 10.1109/ipdps.2009.5160930

Multi-GPU


Hallock et al. Parallel Comput. 2014 10.1016/j.parco.2014.03.009

MPI


(w.i.p.) 


Extensible through Python

Peterson et al. PyHPC 2013 10.13140/2.1.3207.7440
 ⟹ Hybrid solvers

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Yeast galactose switch — Initial geometry

Cryo-electron tomography

TME, …, E. Villa, ZLS. 10.1021/acs.jpcb.7b00672

2.04 × 1.91 × 0.242 μm3 section of yeast cell 2% of total volume Use tomogram as template to build whole cell geometry

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Use tomogram as template for cell geometry

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Use tomogram as template for cell geometry

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Use tomogram as template for cell geometry

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Use tomogram as template for cell geometry

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G80 is sequestered from nucleus

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New transporters are localized near nucleus

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New transporters are localized near nucleus

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Outlook

Demonstrated CME ⟷ ODE RDME ⟷ ODE Planning RDME ⟷ PDE In progress RDME ⟷ Brownian dynamics

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Outlook

Demonstrated CME ⟷ ODE RDME ⟷ ODE Planning RDME ⟷ PDE In progress RDME ⟷ Brownian dynamics

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Outlook

Goal Whole-cell physico-chemical model

  • f minimal cell

JCVI-syn3A1 400 nm diameter 453 protein coding genes 2 hr doubling time Multi-scale modeling ODE —Metabolism2 RDME — Gene expression3 BD —Ribosomes, DNA, cytoskeleton

2Breuer, TME, …, ZLS 2018 submitted 3TME, …, ZLS. BPJ 2016 10.1016/j.bpj.2015.07.030 1Huchison et al. Science 2016 10.1126/science.aad6253

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Acknowledgements

Zan Luthey-Schulten Joe Peterson Mike Hallock David Bianchi

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Acknowledgements

Lattice Microbes: http://goo.gl/akkSyg Zan Luthey-Schulten Joe Peterson Mike Hallock David Bianchi