Stochastic Simulation of Process Calculi for Biology

Biological systems typically involve large numbers of components with complex, highly parallel interactions and intrinsic stochasticity. To model this complexity, numerous programming languages based on process calculi have been developed, many of which are expressive enough to generate unbounded numbers of molecular species and reactions. As a result of this expressiveness, such calculi cannot rely on standard reaction-based simulation methods, which require fixed numbers of species and reactions. Rather than implementing custom stochastic simulation algorithms for each process calculus, we propose to use a generic abstract machine that can be instantiated to a range of process calculi and a range of reaction-based simulation algorithms. The abstract machine functions as a just-in-time compiler, which dynamically updates the set of possible reactions and chooses the next reaction in an iterative cycle. In this short paper we give a brief summary of the generic abstract machine, and show how it can be instantiated with the stochastic simulation algorithm known as Gillespie's Direct Method. We also discuss the wider implications of such an abstract machine, and outline how it can be used to simulate multiple calculi simultaneously within a common framework.Comment: In Proceedings MeCBIC 2010, arXiv:1011.005

Compositionality, stochasticity and cooperativity in dynamic models of gene regulation

We present an approach for constructing dynamic models for the simulation of gene regulatory networks from simple computational elements. Each element is called a ``gene gate'' and defines an input/output-relationship corresponding to the binding and production of transcription factors. The proposed reaction kinetics of the gene gates can be mapped onto stochastic processes and the standard ode-description. While the ode-approach requires fixing the system's topology before its correct implementation, expressing them in stochastic pi-calculus leads to a fully compositional scheme: network elements become autonomous and only the input/output relationships fix their wiring. The modularity of our approach allows to pass easily from a basic first-level description to refined models which capture more details of the biological system. As an illustrative application we present the stochastic repressilator, an artificial cellular clock, which oscillates readily without any cooperative effects.Comment: 15 pages, 8 figures. Accepted by the HFSP journal (13/09/07

Model checking probabilistic and stochastic extensions of the pi-calculus

We present an implementation of model checking for probabilistic and stochastic extensions of the pi-calculus, a process algebra which supports modelling of concurrency and mobility. Formal verification techniques for such extensions have clear applications in several domains, including mobile ad-hoc network protocols, probabilistic security protocols and biological pathways. Despite this, no implementation of automated verification exists. Building upon the pi-calculus model checker MMC, we first show an automated procedure for constructing the underlying semantic model of a probabilistic or stochastic pi-calculus process. This can then be verified using existing probabilistic model checkers such as PRISM. Secondly, we demonstrate how for processes of a specific structure a more efficient, compositional approach is applicable, which uses our extension of MMC on each parallel component of the system and then translates the results into a high-level modular description for the PRISM tool. The feasibility of our techniques is demonstrated through a number of case studies from the pi-calculus literature

Parallel BioScape: A Stochastic and Parallel Language for Mobile and Spatial Interactions

BioScape is a concurrent language motivated by the biological landscapes found at the interface of biology and biomaterials. It has been motivated by the need to model antibacterial surfaces, biofilm formation, and the effect of DNAse in treating and preventing biofilm infections. As its predecessor, SPiM, BioScape has a sequential semantics based on Gillespie's algorithm, and its implementation does not scale beyond 1000 agents. However, in order to model larger and more realistic systems, a semantics that may take advantage of the new multi-core and GPU architectures is needed. This motivates the introduction of parallel semantics, which is the contribution of this paper: Parallel BioScape, an extension with fully parallel semantics.Comment: In Proceedings MeCBIC 2012, arXiv:1211.347

Abstract Interpretation for Probabilistic Termination of Biological Systems

In a previous paper the authors applied the Abstract Interpretation approach for approximating the probabilistic semantics of biological systems, modeled specifically using the Chemical Ground Form calculus. The methodology is based on the idea of representing a set of experiments, which differ only for the initial concentrations, by abstracting the multiplicity of reagents present in a solution, using intervals. In this paper, we refine the approach in order to address probabilistic termination properties. More in details, we introduce a refinement of the abstract LTS semantics and we abstract the probabilistic semantics using a variant of Interval Markov Chains. The abstract probabilistic model safely approximates a set of concrete experiments and reports conservative lower and upper bounds for probabilistic termination

Computational Modeling for the Activation Cycle of G-proteins by G-protein-coupled Receptors

In this paper, we survey five different computational modeling methods. For comparison, we use the activation cycle of G-proteins that regulate cellular signaling events downstream of G-protein-coupled receptors (GPCRs) as a driving example. Starting from an existing Ordinary Differential Equations (ODEs) model, we implement the G-protein cycle in the stochastic Pi-calculus using SPiM, as Petri-nets using Cell Illustrator, in the Kappa Language using Cellucidate, and in Bio-PEPA using the Bio-PEPA eclipse plug in. We also provide a high-level notation to abstract away from communication primitives that may be unfamiliar to the average biologist, and we show how to translate high-level programs into stochastic Pi-calculus processes and chemical reactions.Comment: In Proceedings MeCBIC 2010, arXiv:1011.005

Stochastic Calculus of Wrapped Compartments

The Calculus of Wrapped Compartments (CWC) is a variant of the Calculus of Looping Sequences (CLS). While keeping the same expressiveness, CWC strongly simplifies the development of automatic tools for the analysis of biological systems. The main simplification consists in the removal of the sequencing operator, thus lightening the formal treatment of the patterns to be matched in a term (whose complexity in CLS is strongly affected by the variables matching in the sequences). We define a stochastic semantics for this new calculus. As an application we model the interaction between macrophages and apoptotic neutrophils and a mechanism of gene regulation in E.Coli

Flux Analysis in Process Models via Causality

We present an approach for flux analysis in process algebra models of biological systems. We perceive flux as the flow of resources in stochastic simulations. We resort to an established correspondence between event structures, a broadly recognised model of concurrency, and state transitions of process models, seen as Petri nets. We show that we can this way extract the causal resource dependencies in simulations between individual state transitions as partial orders of events. We propose transformations on the partial orders that provide means for further analysis, and introduce a software tool, which implements these ideas. By means of an example of a published model of the Rho GTP-binding proteins, we argue that this approach can provide the substitute for flux analysis techniques on ordinary differential equation models within the stochastic setting of process algebras

On Designing Multicore-aware Simulators for Biological Systems

The stochastic simulation of biological systems is an increasingly popular technique in bioinformatics. It often is an enlightening technique, which may however result in being computational expensive. We discuss the main opportunities to speed it up on multi-core platforms, which pose new challenges for parallelisation techniques. These opportunities are developed in two general families of solutions involving both the single simulation and a bulk of independent simulations (either replicas of derived from parameter sweep). Proposed solutions are tested on the parallelisation of the CWC simulator (Calculus of Wrapped Compartments) that is carried out according to proposed solutions by way of the FastFlow programming framework making possible fast development and efficient execution on multi-cores.Comment: 19 pages + cover pag