Has anyone encountered the following problem:
If an SBML model is defined using ancillary algebraic equations to specify a portion of a rate law, it appears that information on regulation is sometimes lost. I apologize that I don't have time to document this in detail, but here is a specific example.
The curated version of Kathy Chen's 2004 cell cycle model can be downloaded from biomodels.net. When I import this into our ProcessDB tool OR when I display it using the GIF tool on the biomodels.net site, there are two subsystems displayed with no connection to the main body of the model. This surprised me so I looked at the equations in the Chen/Tyson paper to see what might be the explanation.
The dephosphorylation of Net1-P, regulated by PPX, is clearly shown in the published equations. Similarly, the activation of Cdh1 by Cdc14 is explicitly shown in the published equations.
Nevertheless, these subsystems appear in the diagram of the curated SBML model as totally disconnected from the rest of the cell cycle machinery.
This could be just a curation problem, and if it is then there is no general SBML issue. My worry, however, is that because these modifiers appear in ancillary equations, rather than explicitly in the terms of the RHS of the ODEs, they are not recognized as modifiers by SBML. Computationally, this would present no difficulties, but it leads to incorrect or at least incomplete diagrams.
If you look at the ODE for Net1 in the Chen paper, you will see a term
+ Vpp,net [Net1P]
This is apparently interpreted as a mass action term, but Vpp,net is defined by a separate (ancillary) equation as:
Vpp,net = k'pp,net + k"pp,net [PPX]
In this way, the phosphatase reaction is correctly regulated by PPX.
The problem is that PPX is not recognized as a modifier of the Net1-P dephosphorylation reaction and so the PPX portion of the resulting diagram is misleadingly left dangling, unconnected to the appropriate reaction.
The same is true for the Cdc14 regulation of Cdh1 activation. I have not checked the other reactions defined in part by ancillary equations. I did check two of the modifiers that ARE coded in the SBML, and neither of them is defined by an ancillary equation.
So the question for the forum is: Is this really a problem and if so is it something we need to address at the level of the SBML specification or should it be handled at the time of curation?