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Computational Compound Protonation and Reaction Balancing in MetaCyc and EcoCyc

Computational Compound Protonation and Reaction Balancing in MetaCyc and EcoCyc. Tomer Altman Bioinformatics Research Group SRI International taltman@ai.sri.com. What is ‘Protonation’?.

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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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