In this thesis we study stochastic modeling and simulation methods for biochemical systems. The thesis is focused on systems with multi-state and multi-scale features and divided into two parts. In the first part, we propose new algorithms that improve existing multi-state simulation methods. We first compare the well known Gillespie\\\'s stochastic simulation algorithm (SSA) with the StochSim, an agent-based simulation method. Based on the analysis, we propose a hybrid method that possesses the advantages of both methods. Then we propose two new methods that extend the Network-Free Algorithm (NFA) for rule-based models. Numerical results are provided to show the performance improvement by our new methods. In the second part, we investigate two simulation schemes for the multi-scale feature: Haseltine and Rawlings\\\' hybrid method and the quasi-steady-state stochastic simulation method. We first propose an efficient partitioning strategy for the hybrid method and an efficient way of building stochastic cell cycle models with this new partitioning strategy. Then, to understand conditions where the two simulation methods can be applied, we develop a way to estimate the relaxation time of the fast sub-network, and compare it with the firing interval of the slow sub-network. Our analysis are verified by numerical experiments on different realistic biochemical models. / Ph. D.

Gillespie's stochastic simulation algorithm (SSA) has been a conventional method for stochastic modeling and simulation of biochemical systems. However, its population-based scheme faces the challenge from multi-state situations in many biochemical models. To tackle this problem, Morton-Firth and Bray's stochastic simulator (StochSim) was proposed with a particle-based scheme. The thesis first provides a detailed comparison between these two methods, and then proposes improvements on StochSim and a hybrid method to combine the advantages of the two methods. Analysis and numerical experiment results demonstrate that the hybrid method exhibits extraordinary performance for systems with both the multi-state feature and a high total population. In order to deal with the combinatorial complexity caused by the multi-state situation, the rules-based modeling was proposed by Hlavacek's group and the particle-based Network-Free Algorithm (NFA) has been used for its simulation. In this thesis, we improve the NFA so that it has both the population-based and particle-based features. We also propose a population-based method for simulation of the rule-based models. The bacterial chemotaxis model has served as a good biological example involving multi-state species. We implemented different simulation methods on this model. Then we constructed a graphical interface and compared the behaviors of the bacterium under different mechanisms, including simplified mathematical models and chemically reacting networks which are simulated stochastically. / Master of Science

By increasing the level of abstraction in the representation of regulatory network models, we can hope to allow modelers to create models that are beyond the threshold of what can currently be expressed reliably. As hundreds of reactions are difficult to understand, maintain, and extend, thousands of reactions become next to impossible without any automation or aid. Using the multistate-species concept we can reduce the number of reactions needed to represent certain systems and thus, lessen the cognitive load on modelers. A multistate species is an entity with a defined range for state variables, which refers to a group of different forms for a specific species. A multistate reaction involves one or more multistate species and compactly represents a group of similar single reactions. In this work, we have extended JCMB (the JigCell Model Builder) to comply with multistate species and reactions modeling and presented a proposal for enhancing SBML (the Systems Biology Markup Language) standards to support multistate models. / Master of Science

Le comportement d'une cellule dépend de sa capacité à recevoir, propager et intégrer des signaux, constituant ainsi des voies de signalisations. Les protéines s'associent entre elles sur des sites de liaisons, puis modifient la structure spatiale des protéines voisines, ce qui a pour effet de cacher ou de découvrir leurs autres sites de liaisons, et donc d'empêcher ou de faciliter d'autres interactions. En raison du grand nombre de différents complexes bio-moléculaires, nous ne pouvons pas écrire ou générer les systèmes différentiels sous-jacents. Les langages de réécritures de graphes à sites offrent un bon moyen de décrire ces systèmes complexes. Néanmoins la complexité combinatoire resurgit lorsque l'on cherche à calculer de manière effective ce comportement. Ceci justifie l'utilisation d'abstractions. Nous proposons deux méthodes pour réduire la taille des modèles de voies de signalisation, décrits en Kappa. Ces méthodes utilisent respectivement la présence de symétries parmi certains sites et le fait que certaines corrélations entre l'état de différentes parties des complexes biomoléculaires n'ont pas d'impact sur la dynamique du système global. Des sites qui ont la même capacité d'interaction sont liés par une relation de symétrie. Nous montrons que cette relation induit une bisimulation qui peut être utilisée pour réduire la taille du modèle initial. L'analyse du flot d'information détecte les parties du système qui influencent le comportement de chaque site. Ceci nous autorise à couper les espèces moléculaires en petits morceaux pour écrire un nouveau système. Enfin, nous montrons comment raffiner cette analyse pour tenir compte d'information contextuelle. Les deux méthodes peuvent être combinées. La solution analytique du modèle réduit est la projection exacte de la solution originelle. Le calcul du modèle réduit se fait au niveau des règles, en évitant l'exécution du modèle initial. / The behaviour of a cell is driven by its capability to receive, propagate and communicate signals. Proteins can bind together on some binding sites. Post-translational modifications can reveal or hide some sites, so new interactions can be allowed or existing ones can be inhibited. Due to the huge number of different bio-molecular complexes, we can no longer derive or integrate ODE models. A compact way to describe these systems is supplied by rule-based languages. However combinatorial complexity raises again when one attempt to describe formally the behaviour of the models. This motivates the use of abstractions. We propose two methods to reduce the size of the models, that exploit respectively the presence of symmetries between sites and the lack of correlation between different parts of the system. The symmetries relates pairs of sites having the same capability of interactions. We show that this relation induces a bisimulation which can be used to reduce the size of the original model. The information flow analysis detects, for each site, which parts of the system influence its behaviour. This allows us to cut the molecular species in smaller pieces and to write a new system. Moreover we show how this analysis can be tuned with respect to a context. Both approaches can be combined. The analytical solution of the reduced model is the exact projection of the original one. The computation of the reduced model is performed at the level of rules, without the need of executing the original model.