20090511 Manchester Biochemistry

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

Biochemistry

Biochemistry aims to understand the structure and function of all living things at the molecular level

http://multimedia.mcb.harvard.edu/media.html

Representational Issues

Identity

Descriptions

Situations

Case Study: HIF1 α

Hypoxia-Inducible Factor 1, alpha chain (uniprot:Q16665)

Master transcriptional regulator of the adaptive response to hypoxia

Under normoxic conditions , HIF1 α is hydroxylated on Pro-402

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.

Situation

Normoxic

Hypoxic

Other/Unspecified

Multiple structural forms Part, named/ unnamed regions The part is the agent in the process Selective interaction with parts

Structure-based biochemical identity: Differences between apples and oranges

HIF1 α – au naturel

HIF1 α

hydroxylated @P402

HIF1 α

hydroxylated @P564

HIF1 α

hydroxylated @P402 & @P564

HIF1 α

hydroxylated @P402 & (@P564)

ubiquitinated @K532

HIF1 α

L400A & L397A

Current approach to biochemical identity is erroneous, misleading or underspecified

Information gathered from multiple structural variants are attributed to the unmodified form.

Uniprot / Genbank

This conflates functionality arising from similar, but different structural forms

Inaccurate specification of knowledge

Incomplete descriptions are just as bad

Reactome has an internal identifier for referring to different forms, but links to Uniprot entries

Obfuscates identity between databases

11/05/2009 IMG Seminar::Michel Dumontier

Bio2RDF: 2.3B triples of SPARQL-accessible linked biological data! Chemical Parts!

1. Precise Biochemical Identifiers

Identifiers and their exact descriptions are required for these kinds of entities:

atom : atomic interactions, catalytic mechanism

collection of atoms : binding/catalytic site, interaction

residue : post translational modification

collection of residues : motif/domain/interaction site

molecule : metabolism, signalling

complex : metabolism , signalling, scaffolds, containers

We need a reproducible methodology

Different molecules must have different identifiers

IUPAC International Chemical Identifier (InChI)

A data string that provides

the structure of a chemical compound

the convention for drawing the structure

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).

It is a data identifier

(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

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

OWL Has Explicit Semantics

Can therefore be used to capture knowledge in a machine understandable way

http://code.google.com/p/semanticwebopenbabel/

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.

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

Describing Functional Groups in DL

HydroxylGroup:

CarbonGroup that (hasSingleBondWith some (OxygenAtom that hasSingleBondWith some HydrogenAtom)

O H R R group

Fully Classified Ontology 35 FG

And, we define certain compounds

Alcohol:

OrganicCompound that (hasPart some HydroxylGroup)

Organic Compound Ontology 28 OC

Question Answering

Query all attributes

Query PubChem, DrugBank and dbPedia*

* Requires import of relevant URIs

But...

Molecules represented as individuals because OWL-DL only allows tree-like class expressions

No variable binding (e.g. ?x) ... no cyclic molecule/functional group descriptions at the class level 

Boris Motik et al proposed Description Graphs

Robert Stevens, Duncan Hull, Uli Sattler (and I) exploring their use for chemical representation and sub-structure reasoning....

turns out that…

Using InChI’s precise numbering system, we can specify molecular graphs at the class level

Simple 3-carbon ring system

CarbonAtom that hasPosition value 1

and hasSingleBondTo exactly 1 (CarbonAtom that hasPosition value 2

and hasSingleBondTo exactly 1(CarbonAtom that hasPosition value 3

and hasSingleBondTo exactly 1 ( CarbonAtom that hasPosition value 1 )))

(ignoring hydrogens)

InChI=1/C3H6/c1-2-3-1/h1-3H2

Possible... but a 1000 residue protein would contain ~15,000 atoms on average....

Size of the string will be enormous

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.

OpenBabel seemed to struggle with anything over 100 residues

Needs some performance tweaking / commercial solutions

Modularize InChI construction for (linear) polymers?

Make InChi strings for each residue, and concatenate – rename the atoms according to the residue position

InCHI for Proteins???

Identifiers for Atoms

Atom identifiers can be consistently retrieved from the InChI model.

Canonical numbering means we can reliably refer to a specific region rather than a (possibly degenerate) sub-graph match.

In our plugin, component naming was based on the assigned molecule identifier

e.g. pubchemid#aN,

where a is the “atom” label and N is the position

Use hash of InChI as base?

e.g. id#aN

What about identifiers for collection of atoms?

Potentially useful in describing residues, PTMs, binding sites, etc.

Is the lack of connectivity sufficient?

Contiguous:

ranges (id#aN-aN)

enumerations (id#aN,aN,aN)

Non-contiguous:

Combination of ranges, enumerations?

Can we reuse our positional nomenclature for residues?

Residues are generally referred to by their absolute position in the biopolymer sequence.

e.g. Pro @ X on Protein Y

id#a50-a65 owl:sameAs id#r5

id#r5_a1-r5_a15 owl:sameAs id#r5

Collection of residues might follow the same rules as a collection of atoms.

Useful for defining domains, motifs, etc

We already have a simplified representation for biopolymers...

Canonical sequence is represented by a string of single letter characters

DNA: ACGT

RNA: ACGU

Proteins: 20 amino acids (not B,J,O,U,X,Z)

Modifications can be referred to with ChEBI/PSI-MOD ontology (e.g. Prolyl hydroxylated residue @ 402)

Each (modified) residue must have its InChi description so as to capture explicit structural deviations (de-protonation, etc)

An Alternative Scheme

PSI-MOD contains modified residues with links to structural descriptions

But what if we have a modification that isn’t contained in the ontology!

No problem... define your own term, with the corresponding structural description (InChI, SMILES), and add to an ontology document...

If you’re using OWL, you can add the import statement and publish it.

And, of course, you should submit it to the appropriate ontology development teams. (and later make it equivalent to)

While we’re at it, we could extend our expressive capability to create broader descriptions:

Specification

Exactly mod1@pos X

Only mod1@posX

Minimum :

At least [email_address]

Combination:

mod1@posX AND mod2@posY, X != Y

Possibilities/Uncertainty:

(mod1 OR mod2) @posX

Exclusion :

not mod1 @ posX

So what if...

we describe the structural features of the molecule with OWL (sequence + PTMs), and generate an identifier from one of its serializations (RDF/XML?)

that way we get a unique identifier with a description that is extensible and compatible with the semantic web.

Biological Identifier Service

Extensible to create other class descriptions

Chemical

Conformation (e.g. Open vs closed form)

Biological

Species

mRNA/Gene from which it was transcribed/encoded

What does this mean to providers and consumers?

Automatic identifier and description generation

Data providers can get the identifier that exactly matches their entity.

Consumers can get the exact description of a reported identifier.

Registry can keep track of provider to entity

Discover where additional information can be found

Semantic Science will create a Bio2RDF endpoint to link semantically equivalent biochemical identifiers

Situational Modeling

Uniprot example revisited

Under normoxic conditions , HIF1 α is hydroxylated on Pro-402

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

.

: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!

Infering Protein Participation

OWL Role Chain

hasParticipant o isPartOf -> hasParticipant

if process has the part as a participant, then the whole is also a participant

: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

Summary