Article

Lumpability abstractions of rule-based systems

Theoretical Computer Science (Impact Factor: 0.49). 01/2012; 431:137--164. DOI:10.1016/j.tcs.2011.12.059
Source: OAI

ABSTRACT The induction of a signaling pathway is characterized by transient complex formation and mutual posttranslational modification of proteins. To faithfully capture this combinatorial process in a mathematical model is an important challenge in systems biology. Exploiting the limited context on which most binding and modification events are conditioned, attempts have been made to reduce the combinatorial complexity by quotienting the reachable set of molecular species, into species aggregates while preserving the deterministic semantics of the thermodynamic limit. Recently we proposed a quotienting that also preserves the stochastic semantics and that is complete in the sense that the semantics of individual species can be recovered from the aggregate semantics.
In this paper we prove that this quotienting yields a sufficient condition for \emph{weak lumpability} and that it gives rise to a backward Markov bisimulation between the original and aggregated transition system. We illustrate the framework on a case study of the EGF/insulin receptor crosstalk.

0 0
 · 
0 Bookmarks
 · 
210 Views
  • Source
    [show abstract] [hide abstract]
    ABSTRACT: Biochemical networks are used in computational biology, to model mechanistic details of systems involved in cell signaling, metabolism, and regulation of gene expression. Parametric and structural uncertainty, as well as combinatorial explosion are strong obstacles against analyzing the dynamics of large models of this type. Multiscaleness, an important property of these networks, can be used to get past some of these obstacles. Networks with many well separated time scales, can be reduced to simpler models, in a way that depends only on the orders of magnitude and not on the exact values of the kinetic parameters. The main idea used for such robust simplifications of networks is the concept of dominance among model elements, allowing hierarchical organization of these elements according to their effects on the network dynamics. This concept finds a natural formulation in tropical geometry. We revisit, in the light of these new ideas, the main approaches to model reduction of reaction networks, such as quasi-steady state (QSS) and quasi-equilibrium approximations (QE), and provide practical recipes for model reduction of linear and non-linear networks. We also discuss the application of model reduction to the problem of parameter identification, via backward pruning machine learning techniques.
    Frontiers in Genetics 01/2012; 3:131.
  • Source
    [show abstract] [hide abstract]
    ABSTRACT: In this paper we present a formalism based on stochastic automata to describe the stochastic dynamics of signal transduction networks that are specified by rule-sets. Our formalism gives a modular description of the underlying stochastic process, in the sense that it is a composition of smaller units, agent-views. The view of an agent is an automaton that identifies all local modification changes of that agent (internal state modifications, binding and unbinding), but also those of interacting agents, which are tested within the same rule. We show how to represent the generator matrix of the underlying Markov process of the whole rule-set as Kronecker sums of the rate matrices belonging to individual view-automata. In the absence of birth the automata are finite, since the number of different contexts in which one agent can appear in a
    01/2011;
  • Source
    [show abstract] [hide abstract]
    ABSTRACT: In this paper, we present a method for reducing a regular, discrete-time Markov chain (DTMC) to another DTMC with a given, typically much smaller number of states. The cost of reduction is defined as the Kullback-Leibler divergence rate between a projection of the original process through a partition function and the a DTMC on the correspondingly partitioned state space. Finding the reduced model with minimal cost is computationally expensive, as it requires exhaustive search among all state space partitions, and exact evaluation of the reduction cost for each candidate partition. In our approach, we optimize an upper bound on the reduction cost instead of the exact cost; The proposed upper bound is easy to compute and it is tight in the case when the original chain is lumpable with respect to the partition. Then, we express the problem in form of information bottleneck optimization, and we propose the agglomerative information bottleneck algorithm for finding a locally optimal solution. The theory is illustrated with examples and one application scenario in the context of modeling bio-molecular interactions.
    04/2013;

Full-text (2 Sources)

View
14 Downloads
Available from
Nov 14, 2013