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Situational Modeling: Defining Molecular Roles in Biochemical Pathways and Reactions


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Central to a coherent understanding of cellular biology is a faithful representation of biochemical processes as it pertains to its molecular participants. Current representations underspecify our knowledge because they fail to indicate the roles of the molecular components during relevant processes. Here, we describe a knowledge representation using OWL2 that overcomes previous limitations in modeling biochemical events and has clear implications for the accurate functional/role based annotation of molecular components.


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Situational Modeling: Defining Molecular Roles in Biochemical Pathways and Reactions

  1. 1. Situational Modeling: Defining Molecular Roles in Biochemical Pathways and Reactions Michel Dumontier , PhD Assistant Professor of Bioinformatics Department of Biology, School of Computer Science, Institute of Biochemistry, Ottawa Institute of Systems Biology Carleton University
  2. 2. Statement of Problem <ul><li>Plenty going on at the molecular level. </li></ul><ul><li>Current knowledge captures statements about role, function, location, modification, etc, but without context </li></ul><ul><li>Translated to OWL classes – attributes are possibly erroneous when represented as necessary conditions </li></ul>
  3. 3. First, some Biochemistry <ul><li>Glucose is the ubiquitous fuel for life </li></ul><ul><li>Undergoes a series of transformations that stimulates the production of ATP, the cell’s currency </li></ul><ul><li>Glucokinase reaction (GR) (in the liver) is the first </li></ul>
  4. 4. Parts of speech <ul><li>Process: Biochemical Reaction, GKR </li></ul><ul><li>Objects : Glc, G6P, ATP, Mg 2+ , Glucokinase </li></ul><ul><li>Parts: phosphate, carbon, hydrogen, oxygen </li></ul><ul><li>Locations: γ position, C6 </li></ul><ul><li>Roles: enzyme, substrate, product, co-factor, transfer/transferred group </li></ul>
  5. 5. Hmmm... <ul><li>We normally say that </li></ul><ul><ul><li>Glucose is a Substrate in GKR </li></ul></ul><ul><ul><li>Mixing of types (natural vs role) makes ontology harder to maintain </li></ul></ul><ul><ul><li>OWL binary predicates disallow reification </li></ul></ul><ul><ul><li>Represented as a class restriction wouldn’t be universally true </li></ul></ul><ul><li>Approach </li></ul><ul><ul><li>Represent knowledge from the event perspective </li></ul></ul><ul><ul><li>GKR involves Glucose as a Substrate </li></ul></ul><ul><ul><li>Vague – could be substrate in any number of other reactions. Need a temporal pivot </li></ul></ul><ul><ul><li>GKR realizes the Substrate Role held by Glucose </li></ul></ul><ul><ul><li>We don’t want to talk about roles, but fully defined roleplayers </li></ul></ul><ul><ul><li>A Substrate is an Object that holds the Substrate Role </li></ul></ul>
  6. 6. Ontology
  7. 7. Role Modeling & Property Chains <ul><li>Class based representation </li></ul><ul><ul><li>Use of N&S conditions aims to classify instances </li></ul></ul><ul><ul><li>Roles are pivot that must be instantiated and realized </li></ul></ul><ul><ul><li>Role chains bypass pivots, and makes queries more natural </li></ul></ul><ul><li>Inspired by Basic Formal Ontology (BFO) </li></ul><ul><ul><li>Some disagreement on treatment of role/function </li></ul></ul>
  8. 8. Roles for all the important parts Mechanistic Event Decomposition
  9. 9. <ul><li>Representation contains cycles </li></ul><ul><ul><li>Tree-like class descriptions are inadequate </li></ul></ul><ul><ul><li>Description Graphs are more accurate </li></ul></ul>
  10. 10. Some? <ul><li>We can currently ask in what reaction is glucose a substrate, but we can`t ask which molecules are substrates (because not every member of the class is). </li></ul><ul><ul><li>P4 has this useful class usage feature... </li></ul></ul><ul><li>Wacky Idea: query </li></ul><ul><ul><li>some (Glucose and Substrate) </li></ul></ul><ul><ul><li>and get </li></ul></ul><ul><ul><li>Glucose that isBearerOf some SubstrateRole that isRealizedBy some GKR </li></ul></ul>
  11. 11. Summary <ul><li>Alternative framework to accurately represent roles in the context in which they occur </li></ul><ul><li>Can be applied to precisely describe reactions, their mechanisms, and pathways </li></ul><ul><ul><li>Do larger scale implementation </li></ul></ul><ul><li>Some queries that we routinely ask will have no answer (practicality?) </li></ul><ul><ul><li>How to pull the subclass that does </li></ul></ul><ul><li>DGs may also be useful here. </li></ul>