20090511 Manchester Biochemistry


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Biochemical ontologies aim to capture and represent biochemical entities and the relations that exist between them in an accurate manner. A fundamental starting point is biochemical identity, but our current approach for generating identifiers is haphazard and consequently integrating data is error-prone. I will discuss plausible structure-based strategies for biochemical identity whether it be at molecular level or some part thereof (e.g. residues, collection of residues, atoms, collection of atoms, functional groups) such that identifiers may be generated in an automatic and curator/database independent manner. With structure-based identifiers in hand, we will be in a position to more accurately capture context-specific biochemical knowledge, such as how a set of residues in a binding site are involved in a chemical reaction including the fact that a key nitrogen atom must first be de-protonated. Thus, our current representation of biochemical knowledge may improve such that manual and automatic methods of bio-curation are substantially more accurate.

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  • 20090511 Manchester Biochemistry

    1. 1. Increasingly Accurate Representation of Biochemistry Michel Dumontier , Ph.D. Assistant Professor of Bioinformatics Department of Biology, School of Computer Science Institute of Biochemistry, Ottawa Institute of Systems Biology Carleton University IMG Seminar:Manchester:Michel Dumontier 11/05/2009
    2. 2. Biochemistry <ul><li>Biochemistry aims to understand the structure and function of all living things at the molecular level </li></ul>http://multimedia.mcb.harvard.edu/media.html
    3. 3. Representational Issues <ul><li>Identity </li></ul><ul><li>Descriptions </li></ul><ul><li>Situations </li></ul>
    4. 4. Case Study: HIF1 α <ul><li>Hypoxia-Inducible Factor 1, alpha chain (uniprot:Q16665) </li></ul><ul><li>Master transcriptional regulator of the adaptive response to hypoxia </li></ul><ul><li>Under normoxic conditions , HIF1 α is hydroxylated on Pro-402 </li></ul><ul><li>and Pro-564 in the oxygen-dependent degradation domain (ODD) by EGLN1/PHD1 and EGLN2/PHD2. EGLN3/PHD3 has also been shown to hydroxylate Pro-564. The hydroxylated prolines promote interaction with VHL, initiating rapid ubiquitination and subsequent proteasomal degradation. </li></ul><ul><li>Situation </li></ul><ul><li>Normoxic </li></ul><ul><li>Hypoxic </li></ul><ul><li>Other/Unspecified </li></ul>Multiple structural forms Part, named/ unnamed regions The part is the agent in the process Selective interaction with parts
    5. 5. Structure-based biochemical identity: Differences between apples and oranges <ul><li>HIF1 α – au naturel </li></ul><ul><li>HIF1 α </li></ul><ul><ul><li>hydroxylated @P402 </li></ul></ul><ul><li>HIF1 α </li></ul><ul><ul><li>hydroxylated @P564 </li></ul></ul><ul><li>HIF1 α </li></ul><ul><ul><li>hydroxylated @P402 & @P564 </li></ul></ul><ul><li>HIF1 α </li></ul><ul><ul><li>hydroxylated @P402 & (@P564) </li></ul></ul><ul><ul><li>ubiquitinated @K532 </li></ul></ul><ul><li>HIF1 α </li></ul><ul><ul><li>L400A & L397A </li></ul></ul>
    6. 6. Current approach to biochemical identity is erroneous, misleading or underspecified <ul><li>Information gathered from multiple structural variants are attributed to the unmodified form. </li></ul><ul><ul><ul><li>Uniprot / Genbank </li></ul></ul></ul><ul><ul><li>This conflates functionality arising from similar, but different structural forms </li></ul></ul><ul><ul><ul><li>Inaccurate specification of knowledge </li></ul></ul></ul><ul><li>Incomplete descriptions are just as bad </li></ul><ul><ul><li>Reactome has an internal identifier for referring to different forms, but links to Uniprot entries </li></ul></ul><ul><ul><li>Obfuscates identity between databases </li></ul></ul>
    7. 7. 11/05/2009 IMG Seminar::Michel Dumontier
    8. 8. Bio2RDF: 2.3B triples of SPARQL-accessible linked biological data! Chemical Parts!
    9. 9. 1. Precise Biochemical Identifiers <ul><li>Identifiers and their exact descriptions are required for these kinds of entities: </li></ul><ul><ul><li>atom : atomic interactions, catalytic mechanism </li></ul></ul><ul><ul><li>collection of atoms : binding/catalytic site, interaction </li></ul></ul><ul><ul><li>residue : post translational modification </li></ul></ul><ul><ul><li>collection of residues : motif/domain/interaction site </li></ul></ul><ul><ul><li>molecule : metabolism, signalling </li></ul></ul><ul><ul><li>complex : metabolism , signalling, scaffolds, containers </li></ul></ul><ul><li>We need a reproducible methodology </li></ul>
    10. 10. Different molecules must have different identifiers <ul><li>IUPAC International Chemical Identifier (InChI) </li></ul><ul><li>A data string that provides </li></ul><ul><ul><li>the structure of a chemical compound </li></ul></ul><ul><ul><li>the convention for drawing the structure </li></ul></ul><ul><li>It can be made by anyone, anywhere at any time – a deterministic algorithm ensures that is always written in the same way (syntactic identity), and fully specifies the molecular description (semantic identity). </li></ul><ul><ul><li>It is a data identifier </li></ul></ul>
    11. 11. (S)-Glutamic Acid InChI= {version}1 /{formula}C5H9NO4 /c{connections}6-3(5(9)10)1-2-4(7)8 /h{H_atoms}3H,1-2,6H2,(H,7,8)(H,9,10) /p{protons}+1 /t{stereo:sp3}3- /m{stereo:sp3:inverted}0 /s{stereo:type (1=abs, 2=rel, 3=rac)}1 /i{isotopic:atoms}4+1
    12. 12. 2. Structure Accurate and Extensible Descriptions Required CML SDF O1[C@@H]([C@@H](O)([C@H](O)([C@@H](O)([C@@H]1(O)))))(CO) 79025 IUPAC InChI=1/C6H12O6/c7-1-2-3(8)4(9)5(10)6(11)12-2/h2-11H,1H2/t2-,3-,4+,5-,6+/m1/s1 InCHI α -D-Glucose 6-(hydroxymethyl)oxane-2,3,4,5-tetrol OR (2R,3R,4S,5R,6R)-6 -(hydroxymethyl)tetrahydro -2H-pyran-2,3,4,5-tetraol SMILES
    13. 13. OWL Has Explicit Semantics <ul><li>Can therefore be used to capture knowledge in a machine understandable way </li></ul>
    14. 14. http://code.google.com/p/semanticwebopenbabel/
    15. 15. Chemical Ontology Chemical Knowledge for the Semantic Web. Mykola Konyk ,  Alexander De Leon , and  Michel Dumontier . LNBI . 2008. 5109:169-176.  Data Integration in the Life Sciences (DILS2008) . Evry. France. 
    16. 16. Describing chemical functional groups in OWL-DL for the classification of chemical compounds hydroxyl group methyl group Knowledge of functional groups is important in chemical synthesis, pharmaceutical design and lead optimization. Functional groups describe chemical reactivity in terms of atoms and their connectivity, and exhibits characteristic chemical behavior when present in a compound. N Villanueva-Rosales, MDumontier. 2007. OWLED, Innsbruck, Austria. Ethanol
    17. 17. Describing Functional Groups in DL <ul><li>HydroxylGroup: </li></ul><ul><li>CarbonGroup that (hasSingleBondWith some (OxygenAtom that hasSingleBondWith some HydrogenAtom) </li></ul>O H R R group
    18. 18. Fully Classified Ontology 35 FG
    19. 19. And, we define certain compounds <ul><li>Alcohol: </li></ul><ul><li>OrganicCompound that (hasPart some HydroxylGroup) </li></ul>
    20. 20. Organic Compound Ontology 28 OC
    21. 21. Question Answering <ul><li>Query all attributes </li></ul><ul><li>Query PubChem, DrugBank and dbPedia* </li></ul>* Requires import of relevant URIs
    22. 22. But... <ul><li>Molecules represented as individuals because OWL-DL only allows tree-like class expressions </li></ul><ul><ul><li>No variable binding (e.g. ?x) ... no cyclic molecule/functional group descriptions at the class level  </li></ul></ul><ul><li>Boris Motik et al proposed Description Graphs </li></ul><ul><ul><li>Robert Stevens, Duncan Hull, Uli Sattler (and I) exploring their use for chemical representation and sub-structure reasoning.... </li></ul></ul>
    23. 23. turns out that… <ul><li>Using InChI’s precise numbering system, we can specify molecular graphs at the class level </li></ul><ul><li>Simple 3-carbon ring system </li></ul><ul><li>CarbonAtom that hasPosition value 1 </li></ul><ul><li>and hasSingleBondTo exactly 1 (CarbonAtom that hasPosition value 2 </li></ul><ul><li>and hasSingleBondTo exactly 1(CarbonAtom that hasPosition value 3 </li></ul><ul><li>and hasSingleBondTo exactly 1 ( CarbonAtom that hasPosition value 1 ))) </li></ul><ul><li>(ignoring hydrogens) </li></ul>InChI=1/C3H6/c1-2-3-1/h1-3H2
    24. 24. <ul><li>Possible... but a 1000 residue protein would contain ~15,000 atoms on average.... </li></ul><ul><ul><li>Size of the string will be enormous </li></ul></ul><ul><ul><ul><li>We can use InChiKeys (SHA1 hash), but then we need to provide a you-submit-InChI , we-store-both and they-look-it-up service. </li></ul></ul></ul><ul><ul><li>OpenBabel seemed to struggle with anything over 100 residues </li></ul></ul><ul><ul><ul><li>Needs some performance tweaking / commercial solutions </li></ul></ul></ul><ul><ul><li>Modularize InChI construction for (linear) polymers? </li></ul></ul><ul><ul><ul><li>Make InChi strings for each residue, and concatenate – rename the atoms according to the residue position </li></ul></ul></ul>InCHI for Proteins???
    25. 25. Identifiers for Atoms <ul><li>Atom identifiers can be consistently retrieved from the InChI model. </li></ul><ul><ul><li>Canonical numbering means we can reliably refer to a specific region rather than a (possibly degenerate) sub-graph match. </li></ul></ul><ul><ul><li>In our plugin, component naming was based on the assigned molecule identifier </li></ul></ul><ul><ul><ul><li>e.g. pubchemid#aN, </li></ul></ul></ul><ul><ul><ul><li>where a is the “atom” label and N is the position </li></ul></ul></ul><ul><ul><li>Use hash of InChI as base? </li></ul></ul><ul><ul><ul><li>e.g. id#aN </li></ul></ul></ul>
    26. 26. What about identifiers for collection of atoms? <ul><li>Potentially useful in describing residues, PTMs, binding sites, etc. </li></ul><ul><ul><li>Is the lack of connectivity sufficient? </li></ul></ul><ul><li>Contiguous: </li></ul><ul><ul><li>ranges (id#aN-aN) </li></ul></ul><ul><ul><li>enumerations (id#aN,aN,aN) </li></ul></ul><ul><li>Non-contiguous: </li></ul><ul><ul><li>Combination of ranges, enumerations? </li></ul></ul>
    27. 27. Can we reuse our positional nomenclature for residues? <ul><li>Residues are generally referred to by their absolute position in the biopolymer sequence. </li></ul><ul><ul><li>e.g. Pro @ X on Protein Y </li></ul></ul><ul><ul><li>id#a50-a65 owl:sameAs id#r5 </li></ul></ul><ul><ul><li>id#r5_a1-r5_a15 owl:sameAs id#r5 </li></ul></ul><ul><li>Collection of residues might follow the same rules as a collection of atoms. </li></ul><ul><ul><li>Useful for defining domains, motifs, etc </li></ul></ul>
    28. 28. <ul><li>We already have a simplified representation for biopolymers... </li></ul><ul><ul><li>Canonical sequence is represented by a string of single letter characters </li></ul></ul><ul><ul><ul><li>DNA: ACGT </li></ul></ul></ul><ul><ul><ul><li>RNA: ACGU </li></ul></ul></ul><ul><ul><ul><li>Proteins: 20 amino acids (not B,J,O,U,X,Z) </li></ul></ul></ul><ul><ul><li>Modifications can be referred to with ChEBI/PSI-MOD ontology (e.g. Prolyl hydroxylated residue @ 402) </li></ul></ul><ul><ul><ul><li>Each (modified) residue must have its InChi description so as to capture explicit structural deviations (de-protonation, etc) </li></ul></ul></ul>An Alternative Scheme
    29. 29. PSI-MOD contains modified residues with links to structural descriptions
    30. 30. But what if we have a modification that isn’t contained in the ontology! <ul><li>No problem... define your own term, with the corresponding structural description (InChI, SMILES), and add to an ontology document... </li></ul><ul><ul><li>If you’re using OWL, you can add the import statement and publish it. </li></ul></ul><ul><li>And, of course, you should submit it to the appropriate ontology development teams. (and later make it equivalent to) </li></ul>
    31. 31. While we’re at it, we could extend our expressive capability to create broader descriptions: <ul><li>Specification </li></ul><ul><ul><li>Exactly mod1@pos X </li></ul></ul><ul><ul><li>Only mod1@posX </li></ul></ul><ul><li>Minimum : </li></ul><ul><ul><li>At least [email_address] </li></ul></ul><ul><li>Combination: </li></ul><ul><ul><li>mod1@posX AND mod2@posY, X != Y </li></ul></ul><ul><li>Possibilities/Uncertainty: </li></ul><ul><ul><li>(mod1 OR mod2) @posX </li></ul></ul><ul><li>Exclusion : </li></ul><ul><ul><li>not mod1 @ posX </li></ul></ul>
    32. 32. So what if... <ul><li>we describe the structural features of the molecule with OWL (sequence + PTMs), and generate an identifier from one of its serializations (RDF/XML?) </li></ul><ul><li>that way we get a unique identifier with a description that is extensible and compatible with the semantic web. </li></ul>
    33. 33. Biological Identifier Service
    34. 35. Extensible to create other class descriptions <ul><li>Chemical </li></ul><ul><ul><li>Conformation (e.g. Open vs closed form) </li></ul></ul><ul><li>Biological </li></ul><ul><ul><li>Species </li></ul></ul><ul><ul><li>mRNA/Gene from which it was transcribed/encoded </li></ul></ul>
    35. 36. What does this mean to providers and consumers? <ul><li>Automatic identifier and description generation </li></ul><ul><li>Data providers can get the identifier that exactly matches their entity. </li></ul><ul><li>Consumers can get the exact description of a reported identifier. </li></ul><ul><li>Registry can keep track of provider to entity </li></ul><ul><ul><li>Discover where additional information can be found </li></ul></ul>
    36. 37. Semantic Science will create a Bio2RDF endpoint to link semantically equivalent biochemical identifiers
    37. 38. Situational Modeling
    38. 39. Uniprot example revisited <ul><li>Under normoxic conditions , HIF1 α is hydroxylated on Pro-402 </li></ul><ul><li>and Pro-564 in the oxygen-dependent degradation domain (ODD) by EGLN1/PHD1 and EGLN2/PHD2. The hydroxylated prolines promote interaction with VHL, initiating rapid ubiquitination and subsequent proteasomal degradation </li></ul><ul><li>. </li></ul>:A rdfs:subClassOf :Hydroxylation :A hasParticipant (:0#r402 and :Substrate) :A hasParticipant (:1#r402 and :Product) :A hasParticipant (:5 and :Enzyme) :B rdfs:subClassOf :Interaction :B :hasParticipant (:2#r402 or :3#r564 or :4#r402,r564) :B :hasParticipant (:6) :1 (HIF1 α ) :2 (HIF1 α + P402hyd) :3 (HIF1 α + P564hyd) :4 (HIF1 α + P402hyd + P564hyd) :5 (EGLN1) :6 (VHL) Please ignore the made up short-hand syntax!
    39. 40. Infering Protein Participation <ul><li>OWL Role Chain </li></ul><ul><li>hasParticipant o isPartOf -> hasParticipant </li></ul><ul><li>if process has the part as a participant, then the whole is also a participant </li></ul>:0#r402 :isPartOf :0 :1#r402 :isPartOf :1 :A rdfs:subClassOf :Hydroxylation :A hasParticipant (:0#r402 and :Substrate) :A hasParticipant (:1#r402 and :Product) :A hasParticipant :0 :A hasParticipant :1
    40. 41. Summary <ul><li>Biochemical identity is tightly linked to accurate descriptions. </li></ul><ul><li>Automatic and consistent identifier generation will allow anybody to specify findings according to the biopolymers for which it was observed </li></ul><ul><ul><li>No curation required!!!! </li></ul></ul><ul><ul><li>Will be discovered automatically </li></ul></ul><ul><ul><li>link biochemical knowledge at various levels of granularity </li></ul></ul><ul><li>Situational modeling enables the careful separation of what is known under a particular circumstance. </li></ul>
    41. 42. dumontierlab.com [email_address] Special thanks to PhD Student Leonid Chepelev for insightful discussions  semanticscience.org