Synthetic Biology Software Suite (SynBioSS)

Category Cross-Omics>Agent-Based Modeling/Simulation/Tools and Cross-Omics>Pathway Analysis/Gene Regulatory Networks/Tools

Abstract SynBioSS is a suite of software for the modeling and simulation of synthetic genetic constructs.

SynBioSS utilizes the registry of standard biological parts, a database of kinetic parameters, and both graphical and command-line interfaces to multiscale simulation algorithms.

SynBioSS is a complete software suite for each step in the construction of a synthetic ‘network model’: creating a kinetic model, locating kinetic information and simulating that model accurately and efficiently.

The resulting probability distributions of dynamic biological phenotypes can provide insight useful for engineering synthetic biological networks.

SynBioSS facilitates computational synthetic biology and consists of three (3) independent components: the Designer, the Wiki, and the Desktop Simulator (DS).

1) SynBioSS Designer --

SynBioSS Designer is an application for the automatic generation of sets of biomolecular reactions. This software allows a user to input the molecular parts involved in gene expression and regulation (e.g. promoters, transcription factors, ribosomes, etc.).

The software then generates complete networks of reactions that represent transcription, translation, regulation, induction, and degradation of those parts.

The BioBricks foundation provides a database of genetic parts, standardized DNA sequences that may be composed into arbitrarily complex synthetic networks through standardized ligation and cloning procedures.

The expanding use of these BioBricks provides a particularly interesting avenue for the application of de novo gene network modeling.

To facilitate the creation of detailed kinetic models of synthetic gene networks composed of BioBricks, the manufacturer has adapted ‘SynBioSS Designer’ to automatically generate a kinetic model from a construct composed entirely of BioBricks. A Systems Biology Markup Language (SBML) or NetCDF file is generated for simulation(s).

SynBioSS Designer implements simple rules of how biological molecules interact in gene regulatory networks (GRNs), from transcription (e.g. RNAp holoenzyme binding a promoter), to translation (e.g. translational elongation), regulation, induction, etc.

2) SynBioSS Wiki --

SynBioSS Wiki is a web accessible database curated by users in a ‘Wiki’. It is a significant extension of the open-source Mediawiki software. Database structures and special pages have been added to Mediawiki to support the storage, retrieval, viewing and editing of species and reaction data.

The Wiki stores reaction kinetic data in a formatted and searchable scheme with references to the relevant literature. This framework allows for the input of reactions whose rates are described either by elementary first- and second-order rate equations or any arbitrarily complex rate equation defined using MathML (e.g. Hill-type reactions).

Reactions can be searched via participating molecules which may be proteins, DNA sequences, small molecules, etc. Once located, reactions of interest (along with their associated kinetic data) can be collected. The completed model can be exported in SBML format for additional editing or simulation in SynBioSS simulation packages.

It is also through the SynBioSS Wiki databases that ‘SynBioSS Designer’ can access and proliferate kinetic information related to the simulation of BioBricks, thus extending the utility of the database for the synthetic biology community.

To jump-start the process, the manufacturer has entered the known biomolecular interactions in the expression and regulation of well-studied operons, such as the lactose and the tetracycline operons.

3) SynBioSS Simulator --

As synthetic biology operates in femtoliter volumes, even modest concentrations equate to fewer than one million molecules per cell. Importantly, genomic DNA exists with precisely one copy per cell and the number of plasmids is often countable.

Such systems are far from the thermodynamic limit and consequently cannot be accurately modeled using deterministic integrators.

While, the exact stochastic simulation algorithm can be easily overwhelmed by the multiple time scales present in protein-DNA interactions, many accelerated methods exist.

Both the graphical desktop and command-line supercomputer simulators in SynBioSS are based on ‘Hy3S’, a hybrid jump-continuous Markov process integrator.

This algorithm maintains accuracy while significantly accelerating time- consuming high-concentration interactions, such as protein-protein and protein-inducer interactions. Hy3S is written in FORTRAN 90 utilizing NetCDF for data storage and (Message Passing Interface) MPI for message passing on supercomputing clusters.

a) Desktop Simulator (DS) -

The desktop version of the SynBioSS simulator is implemented in Python using GTK+ to provide a graphical interface. These choices enable cross- platform deployment of the same code.

First, users can load a model. SynBioSS DS uses libSBML to read models specified in SBML and can also read models created directly for Hy3S as NetCDF files. Models can then be edited or, alternatively, created within the model interface and saved. The user can subsequently specify simulation parameters.

Typically, this is merely the amount of simulation time and the number of stochastic trajectories to be sampled (stochastic simulation requires multiple samples to construct population distributions).

The simulator includes default simulation parameters for stable simulation of Escherichia coli. Simulations can either be run locally or exported to a NetCDF file appropriate for the supercomputer simulator.

If conducted locally, the results can be exported as either an ASCII comma separated value (CSV) file for import into any spreadsheet program, or as a NetCDF file appropriate for MATLAB.

b) Supercomputer Simulator --

The supercomputer simulator uses MPI to coordinate parallel execution of multiple trajectories on multiple processors. Such parallel execution is an example of a trivially parallelizable problem, where perfect scaling is achieved and the number of processors utilized is limited only by the number of trajectories simulated.

Parallel execution may be necessary for algorithms to determine the optimum set of parts for a synthetic networ’ to match a targeted biological phenotype.

Once completed, the simulation results are stored in a NetCDF file and can be loaded into MATLAB or converted to an ASCII CSV file.

System Requirements

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Manufacturer Web Site SynBioSS

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G6G Abstract Number 20591

G6G Manufacturer Number 104194