Stochastic Modeling and Simulation of Multiscale Biochemical Systems

Numerous challenges arise in modeling and simulation as biochemical networks are discovered with increasing complexities and unknown mechanisms. With the improvement in experimental techniques, biologists are able to quantify genes and proteins and their dynamics in a single cell, which calls for quantitative stochastic models for gene and protein networks at cellular levels that match well with the data and account for cellular noise. This dissertation studies a stochastic spatiotemporal model of the Caulobacter crescentus cell cycle. A two-dimensional model based on a Turing mechanism is investigated to illustrate the bipolar localization of the protein PopZ. However, stochastic simulations are often impeded by expensive computational cost for large and complex biochemical networks. The hybrid stochastic simulation algorithm is a combination of differential equations for traditional deterministic models and Gillespie's algorithm (SSA) for stochastic models. The hybrid method can significantly improve the efficiency of stochastic simulations for biochemical networks with multiscale features, which contain both species populations and reaction rates with widely varying magnitude. The populations of some reactant species might be driven negative if they are involved in both deterministic and stochastic systems. This dissertation investigates the negativity problem of the hybrid method, proposes several remedies, and tests them with several models including a realistic biological system. As a key factor that affects the quality of biological models, parameter estimation in stochastic models is challenging because the amount of empirical data must be large enough to obtain statistically valid parameter estimates. To optimize system parameters, a quasi-Newton algorithm for stochastic optimization (QNSTOP) was studied and applied to a stochastic budding yeast cell cycle model by matching multivariate probability distributions between simulated results and empirical data. Furthermore, to reduce model complexity, this dissertation simplifies the fundamental cooperative binding mechanism by a stochastic Hill equation model with optimized system parameters. Considering that many parameter vectors generate similar system dynamics and results, this dissertation proposes a general α-β-γ rule to return an acceptable parameter region of the stochastic Hill equation based on QNSTOP. Different objective functions are explored targeting different features of the empirical data.

Name thesis:degree_name

Doctor of Philosophy

Level thesis:degree_level

doctoral

Discipline thesis:degree_discipline

Computer Science and Applications

Department dc:contributor.department

Computer Science

Grantor dc:publisher

Virginia Tech

Year dc:date.issued

2019

Author dc:creator

• Chen, Minghan

Chairs dc:contributor.committeechair

• Cao, Young
• Watson, Layne T.

Committee members dc:contributor.committeemember

• Tyson, John J.
• Kang, Hye Won
• Sandu, Adrian

• Caulobacter cell cycle model
• hybrid stochastic simulation algorithm
• stochastic parameter optimization

Statement dc:rights

• In Copyright

Licence dc:rights.uri

• http://rightsstatements.org/vocab/InC/1.0/

Dc Identifier Other

vt_gsexam:20659

OAI identifier oai:identifier

oai:vtechworks.lib.vt.edu:10919/90898