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.

1. Increasingly Accurate Representation of Biochemistry (v2) 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 SemWeb Group::Vancouver 21/05/2009

2. Representational Issues Biochemical Identity Accurate Descriptions Precise Identifiers Modeling Situations

3. Which of these are different? # A, B Difference? 1 α -D-Glucose, alpha-D-Glucose None, multiple names 2 α -D-Glucose, β -D-Glucose 3 α -D-Glucose, β -D-Glucose, D-Glucose 4 α -D-Glucose, α -D-Glucose-6-phosphate 5 Hk, Hk(L529S) 6 Hk(human), Hk(mouse) 7 Hk(open), Hk(closed) 8 Hk (L529), Hk (L540) 9 Hk (L529), Hk (A530)

5. α -D-Glucose and β -D-Glucose are more specific types* of D-Glucose * They resolve an ambiguity in stereochemistry

8. Hexokinase (mutation) 50 0 51 0 52 0 53 0 54 0 RRFHKTLRRL VPDSDVRFLL SESGSGKGAA MVTAVAYR S A EQHRQIEETL 50 0 51 0 52 0 53 0 54 0 RRFHKTLRRL VPDSDVRFLL SESGSGKGAA MVTAVAYRLA EQHRQIEETL Leads to hemolytic anemia different sequence = different entity related by some mutation process

9. Hexokinase (human vs mouse) >sp|P19367|HXK1_HUMAN Hexokinase-1 OS=Homo sapiens GN=HK1 PE=1 SV=3 MIAAQLLAYYFTELKDDQVKKIDKYLYAMRLSDETLIDIMTRFRKEMKNGLSRDFNPTAT VKMLPTFVRSIPDGSEKGDFIALDLGGSSFRILRVQVNHEKNQNVHMESEVYDTPENIVH GSGSQLFDHVAECLGDFMEKRKIKDKKLPVGFTFSFPCQQSKIDEAILITWTKRFKASGV EGADVVKLLNKAIKKRGDYDANIVAVVNDTVGTMMTCGYDDQHCEVGLIIGTGTNACYME ELRHIDLVEGDEGRMCINTEWGAFGDDGSLEDIRTEFDREIDRGSLNPGKQLFEKMVSGM YLGELVRLILVKMAKEGLLFEGRITPELLTRGKFNTSDVSAIEKNKEGLHNAKEILTRLG VEPSDDDCVSVQHVCTIVSFRSANLVAATLGAILNRLRDNKGTPRLRTTVGVDGSLYKTH PQYSRRFHKTLRRLVPDSDVRFLLSESGSGKGAAMVTAVAYRLAEQHRQIEETLAHFHLT KDMLLEVKKRMRAEMELGLRKQTHNNAVVKMLPSFVRRTPDGTENGDFLALDLGGTNFRV LLVKIRSGKKRTVEMHNKIYAIPIEIMQGTGEELFDHIVSCISDFLDYMGIKGPRMPLGF TFSFPCQQTSLDAGILITWTKGFKATDCVGHDVVTLLRDAIKRREEFDLDVVAVVNDTVG TMMTCAYEEPTCEVGLIVGTGSNACYMEEMKNVEMVEGDQGQMCINMEWGAFGDNGCLDD IRTHYDRLVDEYSLNAGKQRYEKMISGMYLGEIVRNILIDFTKKGFLFRGQISETLKTRG IFETKFLSQIESDRLALLQVRAILQQLGLNSTCDDSILVKTVCGVVSRRAAQLCGAGMAA VVDKIRENRGLDRLNVTVGVDGTLYKLHPHFSRIMHQTVKELSPKCNVSFLLSEDGSGKG AALITAVGVRLRTEASS >sp|P17710|HXK1_MOUSE Hexokinase-1 OS=Mus musculus GN=Hk1 PE=1 SV=2 MGWGAPLLSRMLHGPGQAGETSPVPERQSGSENPASEDRRPLEKQCSHHLYTMGQNCQRG QAVDVEPKIRPPLTEEKIDKYLYAMRLSDEILIDILTRFKKEMKNGLSRDYNPTASVKML PTFVRSIPDGSEKGDFIALDLGGSSFRILRVQVNHEKSQNVSMESEVYDTPENIVHGSGS QLFDHVAECLGDFMEKRKIKDKKLPVGFTFSFPCRQSKIDEAVLITWTKRFKASGVEGAD VVKLLNKAIKKRGDYDANIVAVVNDTVGTMMTCGYDDQQCEVGLIIGTGTNACYMEELRH IDLVEGDEGRMCINTEWGAFGDDGSLEDIRTEFDRELDRGSLNPGKQLFEKMVSGMYMGE LVRLILVKMAKESLLFEGRITPELLTRGKFTTSDVAAIETDKEGVQNAKEILTRLGVEPS HDDCVSVQHVCTIVSFRSANLVAATLGAILNRLRDNKGTPRLRTTVGVDGSLYKMHPQYS RRFHKTLRRLVPDSDVRFLLSESGSGKGAAMVTAVAYRLAEQHRQIEETLSHFRLSKQAL MEVKKKLRSEMEMGLRKETNSRATVKMLPSYVRSIPDGTEHGDFLALDLGGTNFRVLLVK IRSGKKRTVEMHNKIYSIPLEIMQGTGDELFDHIVSCISDFLDYMGIKGPRMPLGFTFSF PCKQTSLDCGILITWTKGFKATDCVGHDVATLLRDAVKRREEFDLDVVAVVNDTVGTMMT CAYEEPSCEIGLIVGTGSNACYMEEMKNVEMVEGNQGQMCINMEWGAFGDNGCLDDIRTD FDKVVDEYSLNSGKQRFEKMISGMYLGEIVRNILIDFTKKGFLFRGQISEPLKTRGIFET KFLSQIESDRLALLQVRAILQQLGLNSTCDDSILVKTVCGVVSKRAAQLCGAGMAAVVQK IRENRGLDHLNVTVGVDGTLYKLHPHFSRIMHQTVKELSPKCTVSFLLSEDGSGKGAALI TAVGVRLRGDPTNA

11. Parts need to be identifiable and describable # A, B Difference? 1 α -D-Glucose, alpha-D-Glucose None, multiple names 2 α -D-Glucose, β -D-Glucose Structural (rearrangement) 3 α -D-Glucose, β -D-Glucose, D-Glucose More specific type 4 α -D-Glucose, α -D-Glucose-6-phosphate Structural (modification) 5 Hk, Hk(L529S) Structural (mutation) 6 Hk(human), Hk(mouse) Structural (sequence) 7 Hk(open), Hk(closed) Conformational 8 Hk (L529), Hk (L540) Positional 9 Hk (L529), Hk (A530) Structural, positional

12. Biochemical identity is necessarily based on a description of structure

13. To determine identity, we have compare their descriptions

14. Given A and B How would you know that they are different?

16. Biochemical identity is necessarily based on having accurate descriptions

17. Yet, current approaches add *annotations* rather than create new records with their respective descriptions

20. Biochemical relationship is necessarily based on a comparison of accurate descriptions

21. For each description, we must assign a unique name or identifier

22. If the description changes we need a new identifier!

25. (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

26. 2. Accurate Descriptions 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

28. 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.

29. RDF/OWL descriptions of molecules http://code.google.com/p/semanticwebopenbabel/

30. 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

32. Fully Classified Ontology 35 FG

34. Organic Compound Ontology 28 OC

41. Biological Identifier Service

42. Description to Identifier

47. Situational Modeling

49. We will add new knowledge about biochemicals and their parts into the linked data web through Bio2RDF!

52. dumontierlab.com [email_address] Special thanks to PhD Student Leonid Chepelev for insightful discussions  semanticscience.org