4. Compute vulnerabilities

Given a genome-scale model in SBML format, contrabass computes chokepoints, dead-end metabolites, essential reactions, and essential genes, and saves the results in a spreadsheet report and a html report.

4.1. Pseudocode

This section presents the pseudocode with procedures on how each vulnerability is computed:

• Find chokepoints on a model

  function find_chokepoints(model)
      chokepoint_list = empty list
      for reaction in model
          if reaction upper flux bound not equal 0 and lower flux bound not equal 0
              for reactant in reaction
                  if reaction is the only consumer of reactant
                      chokepoint_list = chokepoint_list + (reaction, reactant)
              for product in reaction
                  if reaction is the only producer of product
                      chokepoint_list = chokepoint_list + (reaction, product)
      return chokepoint_list
  

• Find essential reactions

  function find_essential_reactions(model)
      essential_reactions = empty list
      for reaction in model
          knock out reaction
          if flux_balance_analysis on model is 0
              essential_reactions = essential_reactions + reaction
          undo knock out
      return essential_reactions
  

• Find and remove dead-end metabolites

  See 6. Remove Dead-End Metabolites

• Refine model with FVA

  Besides for computing the previous vulnerabilities, CONTRABASS constraints model fluxes to a certain growth (optimal growth by default) and computes again vulnerabilities for comparison. See 7. Refine model with FVA

4.2. Command

Vulnerabilities can be computed on the model with the following command, where MODEL.xml is the file with the SBML model.:

$ contrabass report critical-reactions MODEL.xml

.The prevoius command computes vulnerabilities using an optimal growth constraint. To use suboptimal growth constraints use the fraction to provide the fraction of optimal growht to use when constraining the model to a certain growth. See using a fraction of 95% growth:

$ contrabass report critical-reactions MODEL.xml --fraction 0.95

. The following figure shows the pipeline of the vulnerabilities computation process. For a given SBML file, computations are performed on 4 models with the following acronyms:

1. Model in the SBML file (M0).

2. Model without DEM (MNODEM).

3. Model refined with FVA, i.e. with flux bounds updated according to FVA (MFVA);

4. Model refined with FVA and without DEM (MFVANODEM).

4.2.1. Spreadsheet data

The previous command produces a spreadsheet file containing the following sheets:

• model_info: General model information.

• reactions: List of reactions of the model

• metabolites: List of metabolites of the model

• genes: List of genes of the model

• reactions_FVA: Upper and lower flux bound of each reaction obtained with Flux Variability Analysis.

• metabolites_FVA: Upper and lower flux bound of each reaction obtained with Flux Variability Analysis grouped by metabolite.

• reversible_reactions: List of reversible reactions of the model before and after FVA refinement.

• chokepoints: Chokepoint reactions and the metabolite/s they produce/consume. Chokepoints are computed in 4 different models:

  1. Input model in the SBML file.

  2. Model without DEM.

  3. Model refined with FVA.

  4. Model refined with FVA and without DEM.

• dead-end: Dead-end metabolites before and after FVA refinement.

• essential genes: List of essential genes of the model. Essential genes are computed in the 4 previously listed models.

• essential reactions: List of essential reactions of the model. Essential reactions are computed in the 4 previously listed models.

• comparison: Comparison of chokepoint, essential reactions and essential gene reactions in the 4 previously listed models.

• summary: Comparison the size of the previous sets and their intersections.