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Computational Compound Protonation and Reaction Balancing in MetaCyc and EcoCyc

This article discusses the protonation of compounds and the balancing of reactions in the MetaCyc and EcoCyc databases, using ChemAxon's Marvin software and stoichiometric vector calculations in Pathway Tools. Future work includes extending the analysis to include compounds with coordination bonds and providing code for users to protonate their own databases.

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Computational Compound Protonation and Reaction Balancing in MetaCyc and EcoCyc

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  1. Computational Compound Protonation and Reaction Balancing in MetaCyc and EcoCyc Tomer Altman Bioinformatics Research Group SRI International taltman@ai.sri.com

  2. What is ‘Protonation’? • A ‘protocenter’ is typically a C, N, or O in a molecule, that might have a variable number of bound H as a function of pH • Molecules that differ only by the state of their various protocenters are known as ‘protoisomers’

  3. Problem Motivation • MetaCyc and EcoCyc compounds were curated with no consistent pH in mind • Compound sources come from various sources, each of which might have its own favorite reference pH • Often, compound structures are not specified to this level • Makes the auto-generation of Flux Balance Analysis models more complicated

  4. Protonation of Compounds in MetaCyc • ChemAxon’s Marvin chemoinformatics software • Major microspecies plug-in • Uses a electronegativity partial charge PDE approach (approximation method) • Validated by exhaustive comparison with published pKa data from the liturature (IUPAC “Dissociation Constants of Organic Bases in Aqueous Solution”) • Statistically-significant differences were sent to ChemAxon, which tweaked their software to improve their algorithm (Marvin >=5.1.2)

  5. Protonation of Compounds in MetaCyc • Compounds that can be protonated by Marvin (no coordination bonds), and that are not specified at a particular pH state (H2SO4), are evaluated • If protonation would change the compound structure, the change is saved, otherwise discarded (avoid history changes) • Use of Condor cluster for protonating >7000 compounds • Done for each release based on compounds with modified structures

  6. Reaction Balancing • All small molecule reactions in a PGDB are evaluated • Reactions that cannot be balanced for various reasons (classes, R-groups, etc.) are skipped • Reactions that can be balanced are grouped by the types of elements that are out of balance • Reactions only unbalanced by hydrogen are balanced by the addition or subtraction of proton moieties • Implemented as a stoichiometric vector calculation in Pathway Tools • Done for every release

  7. Balanced Reaction

  8. Future Work • Protonation of compounds with coordination bonds • Provide code that will allow users to protonate their own PGDBs • Extend auto-balancing code to cover more complicated conditions • Recast stoichiometric vector calculations to other applications, such as FBA analysis and stoichiometric consistency checks

  9. Further Reference • Please see the BioCyc Guide: • http://biocyc.org/biocyc-guide.shtml#protonation

  10. Ron Caspi Ingrid Keseler Markus Krummenacker Anamika Kothari Jeremy Zucker Stanford University Organic Chemistry Library Acknowledgements MetaCyc.org EcoCyc.org

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