converting macromolecular regulatory models from deterministic to stochastic formulation pengyuan...
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Converting Macromolecular Regulatory Models from Deterministic to Stochastic Formulation
Pengyuan Wang, Ranjit Randhawa, Clifford A. Shaffer, Yang Cao, and William T. Baumann
Virginia Tech, Blacksburg VA
The Fundamental Goal of Molecular Cell Biology
The Cell Cycle
Cell Cycle Control Mechanism
Modeling Techniques
One method: Use ODEs that describe the rate at which each protein concentration changes Protein A degrades protein B:
… with initial condition [A](0) = A0.
Parameter c determines the rate of degradation. Sometimes modelers use “creative” rate laws to
approximate subsystems
]A[]B[
cdt
d
Simulation: Budding Yeast Cell Cycle
Table 6. Properties of clb, sic1, and hct1 mutants
mass at birth
mass at
SBF 50%
mass at
DNA repl.
mass at bud ini.
mass at division
TG1
(min)
changed
parameter
Comments
1 wild type
(daughter) 0.71 1.07
(71’) 1.15 (84’)
1.15 (84’)
1.64 (146’)
84 CT 146 min (time of occurrence of event)
2 clb1 clb2
0.71 1.07 1.16 1.16 No mit k's,b2 = 0
k"s,b2 = 0 Surana 1991 Table 1, G2 arrest.
3 clb1 clb2
1X GAL-CLB2 0.65 1.10 1.19 1.19 1.50 105 k's,b2 = 0.1
k"s,b2 = 0 Surana 1993 Fig 4, 1X GAL-CLB2 is OK, 4X GAL-CLB2 (or 1X GAL-CLB2db) causes telophase arrest.
4 clb5 clb6 0.73 1.07
(65’) 1.30 (99’)
1.17 (80’)
1.70 (146’)
99 k's,b5 = 0 k"s,b5 = 0
Schwob 1993 Fig 4, DNA repl begins 30 min after SBF activation.
5 clb5 clb6
GAL-CLB5 0.61 0.93 0.92 0.96 1.41 73 k's,b5 = 0.1
k"s,b5 = 0 Schwob 1993 Fig 6, DNA repl concurrent with SBF activation in both GAL-CLB5 and GAL-CLB5db.
6 sic1 0.66 1.00
(73’) 0.82 (37’)
1.06 (83’)
1.52 (146’)
38 k's,c1 = 0 k"s,c1 = 0
Schneider 1996 Fig 4, sic1 uncouples S phase from budding.
7 sic1 GAL-SIC1 0.80 1.07 1.38 1.17 1.86 94 k's,c1 = 0.1 k"s,c1 = 0
Verma 1997 Fig3B, Nugroho & Mendenhall 1994 Fig 2, most cells are viable.
8 hct1 0.73 1.08 1.17 1.18 1.69 82 k"d,b2 = 0.01 Schwab 1997 Fig 2, viable, size like WT, Clb2 level high
throughout the cycle. 9 sic1 hct1
0.71 No SBF 0.72 No bud No mit k's,c1 = 0
k"d,b2 = 0.01 Visintin 1997, telophase arrest.
10 sic1 GAL-CLB5
first cycle second cycle
0.71 0.52
0.74
0.73
No repl
0.76
1.20
k's,b5 = 0.1 k"s,b5 = 0 k's,c1 = 0
Schwob 1994 Fig 7C, inviable. First cycle OK, DNA repl advanced; but pre-repl complexes cannot form and cell dies after the first cycle.
Expermental Data
Putting it Together
Chen/Tyson Budding Yeast Model Contains over 30 ODEs, some nonlinear. Events can cause concentrations to be reset. About 140 rate constant parameters
Most are unavailable from experiment and must set by the modeler
Fundamental Activities of the Modeler Collect information
Search literature (databases), Lab notebooks Define/modify models
A user interface problem Run simulations
Equation solvers (ODEs, PDEs, deterministic, stochastic)
Compare simulation results to experimental data Analysis
Modeling Process
Stochastic Simulation Motivation
ODE-based (deterministic) models cannot explain behaviors introduced by random nature of the system. Variations in mass of division Variations in time of events Behavior of small numbers (RNA, DNA) Differences in gross outcomes
Gillespie’s Stochastic Simulation Algorithm (SSA) There is a population for each chemical species There is a “propensity” for each reaction, in part
determined by population Each reaction changes population for associated
species Loop:
Pick next reaction (random, propensity) Update populations, propensities
Slow, there are approximations to speed it up
Question
Given an existing deterministic model, how do we convert it to a formulation capable of stochastic simulation? Can this be automated? Is there a fundamental difference in representation?
SSA is known to be CPU-intensive. How much computation resource is really needed to simulate the converted model stochastically?
Relation between the Two Formulations In common: both models describe the same
reaction network. Difference: the reaction rate equation is replaced
by a propensity function describing how likely that the reaction will fire in next unit time.
Connection: although they have different physical meanings, propensity function shares the same expression as corresponding reaction rate equation (written in number of molecules). Caveat: except for the “creative” rate laws
Missing Information
Usually ODE models are written in terms of normalized concentrations.
Thus they need to be converted to models in terms of number of molecules (population).
Some information is missing Characteristic concentration Explicit definition of units Volume of the container.
Conversion The relation between normalized concentration,
real concentration and population of a species:
How Units are Used in the Model
Every parameter and species is assigned the correct unit, scaling factors.
The conversion algorithm follows units to convert the model.
The Challenge
Assigning correct units to species and parameters is difficult because all the species, parameters, and reactions are connected by the whole reaction network.
Once the modeler is forced to provide the “complete” specification, the conversion can be automated
Caveats: “Creative” rate laws Events
Events Need Extra Care
Except for events, all other parts of the model are automatically converted by JigCell.
/*deterministic events*/
If (A>threshold)
Then {event is triggered}.
(Here “>” means rising above a threshold)
/*stochastic events*/
If (A<minimum)
Then {minimum=A}
If (minimum<certain low value AND A>threshold)
Then {event is triggered; minimum=A}.
(we ask for A truly rising from a low value, not happening to rise by oscillation.)
Conversion Tool
Part of the JigCell modeling suite Automatically checks unit consistency inside the
model Every two quantities (a parameter, a species, or
the result of a sub-expression) connected by + or - in the rate law equation must have same units.
All species whose values are changed by the same reaction must have the same units.
The unit of the result from the rate law equation must be equal to the unit of the reaction rate.
The Tool: Entering the Data
The Tool: Error Checking
The Tool: Error Correction
The Tool: Results – Reactions
The Tool: Results – Unit Types
Simulation Experiments: Setup Model:
A simplified cell cycle model A full-sized budding yeast cell cycle model*
Data: 38 of 45 species in full-sized model use realistic
characteristic concentration found in the literature. Cell volume is set to 50fL.
Simulator: StochKit, a C++ stochastic simulator integrated
into JigCell, running SSA.
Distribution of Species on Converted Simplified Model Ensemble result of 10,000 simulations at 200
minutes simulation time.
Simulations on the Converted Full-sized Model The same model (except events) can be simulated
either deterministically or stochastically The interesting cases are where they do not agree
Mass at Birth, Full-sized Model Mean = 1.20, CV = 2.96%. (Compared with 1.21
from deterministic simulation)
Variance of Mass at Birth vs. Simulation Time vs. Population
Simulation Times
Stochastic Time Deterministic TimeModel Wall Total Avg./run
Simplified 145 12305 1.23 0.029
Full-sized 3862 382267 38.2 0.311 Even a single run of the stochastic simulation
takes much more time than the deterministic simulation.
Parallel computing is needed and feasible.
Effect of Random Number Generators
SPRNG random()
Conclusions
Improved support for the conversion process The JigCell conversion tool
Deterministic and stochastic formulations are not fundamentally different Deterministic modelers like to take short cuts
Real experience with stochastic simulations on meaningful models Events Runtimes Approximation results
Future Work
Initial conditions distribution Truly growing volume:
Our previous model had growing mass but fixed volume, which is not realistic
Change to growing volume will change the reaction rate (propensity function)
Simulations on mutants of particular interest