Computational analysis of protein-protein interactions for bench biologists 2-8 September, Berlin

Protein Interaction Databases

Francesca Diella

Computational analysis of protein-protein interactions for bench biologists 2-8 September, Berlin

• Protein interactions determine the outcome of most cellular processes therefore, identifying and characterizing protein–protein interactions and their networks is essential for understanding the molecular mechanisms of biological processes

Computational analysis of protein-protein interactions for bench biologists 2-8 September, Berlin

Types of protein interactions:

A)Direct (physical) interaction via the formation of an interaction complex, more or less stable depending of the affinity of the interaction

B)Indirect (just functional) interaction via a variety of genetic dependencies, transcriptional regulation mechanisms

Computational analysis of protein-protein interactions for bench biologists 2-8 September, Berlin

Common Methods for Identifying Protein Interactions

Methods Type of interaction

Yeast two-hybrid (Y2H)

Tandem affinity purification (TAP)

Physical interactions (binary)

Physical interactions

Co-Immunoprecipitation Physical interactions

Affinity purification–MS Physical interactions (complex)

Phage display Physical interactions (complex)

X-ray crystallography, NMR spectroscopy Physical interactions

Synthetic lethality Genetic Interaction (Functional association)

DNA microarray/ Gene expression Functional association

Computational analysis of protein-protein interactions for bench biologists 2-8 September, Berlin

Schematic Representations of some interaction detection MethodsShoemaker, 2007

Computational analysis of protein-protein interactions for bench biologists 2-8 September, Berlin

Experimental data(LTP, HTP)

Literature

Databases

Computational analysis of protein-protein interactions for bench biologists 2-8 September, Berlin

Protein Interaction Databases

• IntAct http://www.ebi.ac.uk/intact/

• BioGRID http://thebiogrid.org/

• MINT http://mint.bio.uniroma2.it/mint/• DIP http://dip.doe-mbi.ucla.edu/dip/Main.cgi

• HPRD http://www.hprd.org/

• STRING http://string-db.org/

• MIPS http://mips.helmholtz-muenchen.de/proj/ppi/

Additional links to Interaction Databases can be found at: http://ppi.fli-leibniz.de/jcb_ppi_databases.html

Computational analysis of protein-protein interactions for bench biologists 2-8 September, Berlin

Databases specific for certain diseases or organisms only

• NCBI’s HIV-1, Human Protein Interaction DB http://www.ncbi.nlm.nih.gov/projects/RefSeq/HIVInteractions)

• Tair (Arabidopsis) http://www.arabidopsis.org/portals/proteome/proteinInteract.jsp

• DroID (Drosophila) http://www.droidb.org/• SPIDEr (Saccharomyces) http://cmb.bnu.edu.cn/SPIDer/index.html

Computational analysis of protein-protein interactions for bench biologists 2-8 September, Berlin

Intact

Computational analysis of protein-protein interactions for bench biologists 2-8 September, Berlin

BioGrid

Computational analysis of protein-protein interactions for bench biologists 2-8 September, Berlin

MINT

Computational analysis of protein-protein interactions for bench biologists 2-8 September, Berlin

MINT (2)

Computational analysis of protein-protein interactions for bench biologists 2-8 September, Berlin

Classification of PPI databases, based on the methods used to collect or generate the data

• DBs of experimental data, collected either through manual curation, computational extraction, or direct deposit by the authors, such as DIP, MINT, BioGRID and IntAct.

• DBs which store predicted PPI, such as PIPs and HomoMINT.

• Portals that provides unified access to a variety of protein interaction databases, such as STRING.

Computational analysis of protein-protein interactions for bench biologists 2-8 September, Berlin

Annotation policy

Curated data are generally of higher quality, but more expensive to produce

Automated/electronic(text mining)

Manual Curation

Computational analysis of protein-protein interactions for bench biologists 2-8 September, Berlin

• Standardization is a necessary requirement to allow exchange of data among various sources

• The Molecular Interactions workgroup is concentrating on:– improving the annotation and representation of molecular interaction data wherever it is published,

be this in journal articles, authors web-sites or public domain databases– improving the accessibility of molecular interaction data to the user community. By using a common

standard, data can be downloaded from multiple sources and easily combined using a single parser

PMID: 17687370

Computational analysis of protein-protein interactions for bench biologists 2-8 September, Berlin

Confidence scoring of interactions

• It is important to assess the quality of individual interactions reported in the DBs

• LTP versus HTP• Interaction scores have been introduced• User have to be critical, e.g. proteins that have

different localization patterns are unlikely to interact

Computational analysis of protein-protein interactions for bench biologists 2-8 September, Berlin

Score

0

0.2

0.4

0.6

0.8

1

0 0.5 1 1.5 2 2.5

cumulative evidence (x)

Score (S)

CoIP, Pull-downLow-throughput

TAPHigh-throughput

2-hybrid, peptide chipHigh-throughput

2-hybrid, X-ray crystallographyLow-throughput

Contribution of different experimental setups to cumulative evidence and score for direct interaction.

X-ray crystallography + 2-hybrid+Co-IP+GST-pull down

Andrew Chatr-aryamontri

Computational analysis of protein-protein interactions for bench biologists 2-8 September, Berlin

Score (2)• The MINT score takes into account all the experimental evidence associated with

the interaction detection method. The score is calculated as a function of the cumulative evidence (x) according to the formula:

• The IntAct MI score is based on the manual annotation of every instance of a binary interaction (A-B). First all instances of the A-B interacting pair are clustered by accession number. The score takes in account also the interaction detection method and the interaction type. Additionally the number of publications the interaction has appeared in are counted. 1 represents an interaction which have the highest confidence.

S=1−a− x

a determines the initial slope of the curve and is chosen (a=1.6) so that the function has a suitable dynamic range and only well supported interactions obtain a value close to 1. (PMID: 17135203)