Kinetic Modeling using BioPAX ontology

Abstract

Thousands of biochemical interactions are available for download from curated databases such as Reactome, Pathway Interaction Database and other sources in the Biological Pathways Exchange (BioPAX) format. However, the BioPAX ontology does not encode the necessary information for kinetic modeling and simulation. The current standard for kinetic modeling is the System Biology Markup Language (SBML), but only a small number of models are available in SBML format in public repositories. Additionally, reusing and merging SBML models presents a significant challenge, because often each element has a value only in the context of the given model, and information encoding biological meaning is absent. We describe a software system that enables a variety of operations facilitating the use of BioPAX data to create kinetic models that can be visualized, edited, and simulated using the Virtual Cell (VCell), including improved conversion to SBML (for use with other simulation tools that support this format).

Fig. 1

BioPAX modeling framework. Data from multiple sources in BioPAX format are imported into the BioPAX modeling framework, and can be converted into BioPAX-annotated reusable SBML, and further exported into the VCell modeling framework. The BioPAX modeling framework can be used to merge several BioPAX files. BioPAX-annotated SBML files can be stored locally or in the VCell database. Solid lines denote the implemented conversions. Dashed lines denote features to be implemented.

Fig. 2

Flowchart of algorithm for identification of unique p-entities. The first “else” stands for the case when either one or both p-entities have no unifXREF. Individual types tests include comparing sequence property for protein and rna, chemical-formula for smallMolecule, etc. The user sets negative and positive thresholds for the score function. If the score is above a positive threshold, p-entities are declared to be identical, if below negative threshold – distinct, otherwise the user has to make the decision.

Fig. 3

Screenshots of BioPAX modeling user interface prototype. (a) Phosphorylation of Cyclin A:Cdk2 complexes by Wee1 as displayed by Reactome. (b) A compact representation: only species and reactions are shown in the form compliant with the VCell GUI. (c) An extended view, where a user gains an understanding that both complexes contain the same components Cyclin_A and Cdk2; Cdk2 is a protein, which participates in one of these complexes in phosphorylated form. (d) The model exported into VCell, kinetic parameters and rate constants added within VCell framework.