Biomolecular Interaction Network Database

Current Abstractions

Sequence

GDKNADGWIEFEEL

Database of Sequences

AnalysisString Theory

BLAST

Pathways and Interaction Databases

Sequence databases teach us about biological “similarity”, how things are related.

The 1st wave of Bioinformatics...

An interaction database should likewise teach us about “specificity”, how things work.

The 2nd wave of Bioinformatics...

Interaction pair“A binds B”

Database of Interactions

AnalysisGraph Theory“PATHFIND”

New Abstractions

Goodsell

http://bioinfo.mshri.on.ca

A Quick tour of BIND

A simple BIND INTERACTION record

A B

1. Short label2. Type of molecule3. Database identifier4. Origin

5. Short label6. Type of molecule7. Database identifier8. Origin

9. Publication reference

Understanding the BIND data model

All cellular processescan be represented bya set of connected recordswhere each record describes a biomolecular interactionand its associated consequences.

A::B

?

C::D

?

E::F

?

Understanding the BIND data model

S PE

E + S E-S

INTERACTION record

S

CHEMICAL STATE data CHEMICAL ACTION data

S P

What BIND can encode...

Simple binding interactions Enzymes, substrates and complete metabolic

pathways including mechanisms Restriction enzymes, Transcription factors Limited proteolysis (insulin, clotting cascade,

complement) Reversible phosphorylation Glycosylation Intron splicing, tRNA base modifications Ubiquitin mediated protein degradation Viral life cycles in host cells

What BIND cannot encode

bulk phenomena membrane potentialsgradientscalcium waveswater

“perfect” cellular localization (4-D time-development/organism axis).

BIND Data Submission

BIND data

specification

API

BIND data

specification

API

data flow

TextData Entry

CGI

JavaChemistry

Tool

BIND SubmitterData Entry

Text Query

CGI

FlashVisualCGI

SeqHound

BIND VisitorQuery Internet clients

BIND servers

Backfillingand

Import

A c c D B

NCBI FTP Site

N C B IE M B LD D B JT I G R

S w is s - P r o tP D B

3D linksNUC-PROT

MEDLINE

" S e q H o u n d " S y s t e m A t S L R I

ASNDBGenBank binary data

Bioseqs

GenBank binary data Seq-Entries

SE l inks

S p e c ie s

T a x I D

ChromID

Redund

M M D B

BIND Software

A Visual Future...

How do we draw fast, high-quality, interactivepictures of pathways and mechanisms from BIND and support thousands or more of simultaneous web clients?

•keep “canned drawings” •long history (Metabolic Maps, 1968)•curators keep re-drawing… •large numbers of interactions•model may not scale well

•generate drawings “on the fly”•BIND data > symbolic interactions•graph theory (edge and vertex)•need consistent symbolic language for pathways•never been done for biological processes

BIND Visualization, Consider...

“On The Fly” Visualization Strategy

Algorithmic generation of pathway drawingsUser asks, “draw me a picture of ...”Server queries database for binding partners,

assembles an image, and sends it to the user

Define the symbolism in a creative and novel way continuous line-symbols for domains “mate-able” we have already a library of about 500 - 1000 symbols

Hand-drawn depiction ofputativecomputer generatedpathway graphic...

Algorithmic Visualization

length mapped to sequence mapping of sequence feature tables

legends automatically generated

can scale to the expected number of interactions/pathways

implementation is already underway...

bothStructure andFunction

Electronics CADsoftware showsschematicsalongsidephysicalrepresentations...

Electronics CAD systems are also database driven...

BIND Proposal

We propose a GenBank-style public interaction database public submissions of interactions active software development close ties to active proteomics and bioinformatics

research

We propose a distributed collaboration for managing indexing and database distribution.

BIND - Data Quality Assurances

Two-tiered expert indexing and validation professional indexers

public data submissionbackfilling of literature data

validation by active “interaction” scientists

BIND - Decentralized by Design

Indexing can be run at several sites enabling technology is a unique key

server

Indexing “nodes” should coincide with pockets of expertise

BIND - Hybrid Data Ownership Model

Like Entrez Some data is owned by databases (SWISSPROT) Other data is owned by submitters Ownership implies right to “edit”

Curated/Backfilled - BIND owns the record Submitted - Submitter owns the record

Redundant records are allowed (different citations) Dispute records may be entered

Data From Existing Literature

The “Backfilling” problem How do we go through the literature and put in the

relevant interactions into a new database?

Joel Martin (NRC-IIT, Ottawa) PubMed abstracts can be classified by SVM

intoprotein-protein interactions (95% accuracy)protein-DNA interactions (99% accuracy)2 seconds analysis time per abstract

Semi-Automated Backfilling

Automated text classification identifies paper describing interaction

Entrez-spiders find and cluster sequences of related papers

Backfilling indexers are presented with a “probable BIND record”

BIND Database Features

Provides for precise descriptions of biochemical mechanisms and function.

Provides a mapping of interaction space to graph theory.

Tightly linked to the Entrez system.

A Dynamic Data Specification

Ready for change, suggestions and evolution to a mature data model...

BIND interaction

Date

Updates

Accession

Molecule A

Molecule B

Descriptionplace, binding conditions, binding sites,

chemical mechanism, kinetics

Source (literature)

Molecule A Molecule B

Short Label

ID and DB reference

Origin/Cell Stage

Sequence (NCBI Seq)

Structure (NCBI Biostruc)

Text Description

Short Label

ID and DB reference

Origin/Cell Stage

Sequence (NCBI Seq)

Structure (NCBI Biostruc)

Text Description

Rapid Application Development

NCBI’s ASN.1 to C compiler, which generates bug-free code for each specified object: memory allocation freeing read from file (stream) write to file (stream)

This has saved us 2-4 person yearsAllows us to rapidly test changes to BIND

spec.We leveraging work already paid for!

The data is the database...

BIND has “exchange” types lists of BIND ASN.1 records Self-contained, extracted by an ASN.1 parser Automated rules derived from the specification. ASN.1 to XML via XER.

BIND data can be fed into any DBMS, on any platform.

We use a royalty-free DBMS allowing us to maintain distributed BIND indexing sites.

BIND the fine print...

Required Interaction Database Submissions… (when one is funded and ready to go)

At the discretion of the participating granting bodies, mandate that an interaction “accession” be required for publication, as for: sequences (GenBank) structures (PDB)

This ensures the growth and use of an interaction database and protects the investment in its development.

BIND Personnel

Software Developers System Administrators Help/Training Database Specialists BIND Indexers On-callers (validation)

Rotation, check entries for consistency, content

Resource for indexers to consult with

http://bioinfo.mshri.on.ca BIND@mshri.on.ca

Hogue LabGary Bader Ian DonaldsonKaterina MichalickovaAdrian HeilbutKiran Deol Submitters and Volunteers...Tony PawsonBerivan Baskin

BIND Colaborators: Francis Ouellette CMMT UBC VancouverJoel Martin IIT-NRC OttawaChristoph Sensen, IMB-NRC Halifax