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Introduction to bioinformatics Sylvia B. Nagl

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What is bioinformatics?

an emerging interdisciplinary research area

deals with the computational managementand analysis of biological information: genes,genomes, proteins, cells, ecological systems,medical information, robots, artificialintelligence...

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Relationships between

sequence 3D structure protein functions

Properties and evolution of genes, genomes,proteins, metabolic pathways in cells

Use of this knowledge for prediction, modelling, and

design

The Core of Bioinformatics to date

TDQAAFDTNIVTLTRFVM

EQGRKARGTGEMTQLLNS

LCTAVKAISTAVRKAGIA

HLYGIAGSTNVTGDQVKK

LDVLSNDLVINVLKSSFA

TCVLVTEEDKNAIIVEPE

KRGKYVVCFDPLDGSSNI

DCLVSIGTIFGIYRKNSTDEPSEKDALQPGRNLVAA

GYALYGSATML V

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The holy grail of bioinformatics

GCTCCTCACTGTCTGTGTTTATTCTTTTAGCTTCTTCAGATCTTTTAGTCTGAGGAAGCCTGGCATGTGCAAATGAAGTTAACCTAA...

> 500, 000 genessequenced to date

Expected number ofunique protein

structures:

~ 700-1, 000

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Basic concepts

conceptual foundations of bioinformatics: evolution

protein foldingprotein function

bioinformatics builds mathematical modelsof these processes -to infer relationships between componentsof complex biological systems

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Information processing in cells

coding regions

regulatory

sites

nucleic acids

transcripts

proteins

One-to-many mappings!

Context-dependence!

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Global cell state

Genome activationpatterns : transcriptomics

Protein population :

proteomics

Organisation:

tissue imaging EM X-ray, NMR

cells

molecular complexes

Global approaches: Toward a new Systems Biology

How does the spatial andtemporal organisation of

living matter give rise tobiological processes?

Genome

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Living cell

Virtual cell

Perturbation Dynamic response

Biological knowledge(computerised)

Sequence information

Structural information

Basic principles

Practicalapplications

Global approaches: Toward a new Systems Biology

Bioinformatics

Mathematicalmodelling

Simulation

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Bioinformatics in context

Genomics

Molecularevolution

Biophysics Molecularbiology

Ethical, legal,and social

implications

Bioinformatics

Mathematics/computerscience

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Current challenges to users

Potential hurdles:Methods are in flux and not fully developed-scattered and heterogeneous resources

Remedies: Web resourcesnavigation guidesintegration of tools and databanks

http://www.biochem.ucl.ac.uk/~nagl/bioinformatics.html

http://www.biochem.ucl.ac.uk/~nagl/bioinformatics.htmlhttp://www.biochem.ucl.ac.uk/~nagl/bioinformatics.html

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Sequence homology search of the

genome of Pla smo d iu m

falc iparum

Target identification for antimalerialdrugs

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The search for new antimalarialdrugs

Malaria is one of the leading causes of morbidityand mortality in the tropics.

300 to 500 million estimated clinical cases and 1.5million to 2.7 million deaths per year.

Nearly all fatal cases are caused by Plasmod iumfalciparum.

The parasite's resistance to conventionalantimalarial drugs such as chloroquine is growingat an alarming rate.

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P. falc ip aru m has a plastidlike organelle, called theapicoplast, acquired by endosymbiosis of an alga.

Self-replicating, maternally inherited (35kb, circular DNA). Comparative genome analysis : Search for orthologs.

Apicoplast contains enzymes found in plant and bacterial,but not animal metabolic pathways. Potential target for antimalerial drugs:

DOXP reductoisomerase

Jomaa et al. (1999)

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Jomaa et al . (1999) Science 285: 1573-1576:

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Biological databases

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In 1995, the number of genes in the database started to exceedthe number of papers on molecular biology and genetics in the

literature!

(Boguski, 1999 )

The challenge

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Data types primary data

secondary data

tertiary data

sequence

DNA

amino acid

AATGCGTATAGGC

DMPVERILEALAVE

primary database

secondaryprotein structure motifs: regular

expressions, blocks,

profiles, fingerprintse. g., alpha-helices, beta-strands

secondary db

domains, folding units

tertiary proteinstructure

tertiary db

atomic co-ordinates

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Primary biological databases

Nucleic aci d

EMBLGenBankDDBJ (DNA

Data Bank of Japan)

Protein

PIR

MIPS

SWISS-PROTTrEMBL

NRL-3D

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International nucleotide data banks

EMBL

Europe

EMBL

EBI

GenBank

USA NLM

NCBI

DDBJ

Japan NIG

CIB

International

Advisory Meeting

Collaborative Meeting

TrEMBL NRDB

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GenBank file format

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GenBank file format

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Swiss-Prot

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SWISS-PROT file format

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SWISS-PROT file format

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SWISS-PROT file format

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SWISS-PROT file format

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Other primary protein databases

TrEMBL (translated EMBL) in SWISS-PROT formatrapid access to sequence data from genome projectscomputer-annotated supplement to SWISS-PROT

translations of all coding sequences (CDS) in EMBL

SP-TrEMBL

REM-TrEMBL: immunoglobulins, T-cell receptors, shortfragments, synthetic and patented sequences

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Other primary protein databases

The Protein Information Resource (PIR)

integrated system of protein sequence databasesand derived related databases, e. g., alignmentdatabases

rapid searching, comparison, and pattern matching ofprotein sequences

retrieval of descriptive, bibliographic, feature, andconcurrent cross-reference information

aims to be comprehensive and consistentlyannotated

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PIR: related databases

NRL-3D Sequence-Structure Database

produced by PIR from sequence and annotationinformation extracted from three-dimensionalstructures in the Protein Databank (PDB)

allows keyword and similarity searches

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PIR: related databases

PATCHX integrated with PIR

a non-redundant database of protein sequencesproduced by MIPS, the European branch of PIR-International

The PIR Protein Sequence Database and PATCHX

together provide the most complete collection ofprotein sequence data currently available in thepublic domain.

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Composite protein sequence dbs

NRDB OWL MIPSX(PIR+PATCHX) SP+TrEMBL PIR PIR PIR TrEMBL

SP SP SP SP

PDB GenBank MIPSOwn

GenPept NRL-3D NRL-3D

MIPSH

PIRMOD

MIPSTrn

EMTrans

GBTrans

Kabat

PseqIP

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OWL composite database

OWL only released every 6-8weeks

By accession number

By database code

By text

By sequence

By title

By author

By query language

By regular expressionDirect OWL access:

OWL Blast server

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Two other useful sites

INFOBIOGEN-The Public Catalog of Databases

http://www.infobiogen.fr/services/dbcat/

KEGG-Kyoto Encyclopedia of Genes and Genomes

http://www.genome.ad.jp/kegg/Kyoto Encyclopedia of Genes and Genomes (KEGG) is an effort tocomputerize current knowledge of molecular and cellular biology in

terms of the information pathways that consist of interacting moleculesor genes and to provide links from the gene catalogs produced bygenome sequencing projects.

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Sequence Retrieval System (SRS)

Database browser that allowsusers to

retrieve

link

access

entries from all interconnectedresources.

Users can formulate queriesacross a range of differentdatabase types.

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Guide to Protein Databases:http://www.biochem.ucl.ac.uk/~robert/bioinf/lecture1/index.html http://www.biochem.ucl.ac.uk/~robert/bioinf/lecture2/index.html

With thanks to Dr Roman Laskowski.

http://www.biochem.ucl.ac.uk/~robert/bioinf/lecture1/index.htmlhttp://www.biochem.ucl.ac.uk/~robert/bioinf/lecture1/index.htmlhttp://www.biochem.ucl.ac.uk/~robert/bioinf/lecture1/index.htmlhttp://www.biochem.ucl.ac.uk/~robert/bioinf/lecture1/index.html