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Protein-Protein Interactions Prediction
Sergey Knyazev
November 21, 2012

Outline
1) Introduction
2) Protein-Protein interaction
3) Protein-Protein interaction databases
4) Protein-Protein interaction prediction

Introduction
1) Introduction

There is Huge Ammount of
Interactions in a Cell
Example: Possible molecular interactions
in a spreading cell.

There is Many Ways Biomolecules
Interacts in a Cell.

Protein-Protein Interaction
1) Introduction

●
Physical contacts with molecular docking between
proteins that occur in a cell or in a living organism.
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Not just a ‘‘functional contact’’: The existence of
many other types of functional links between
biomolecular entities (genes, proteins, metabolites,
etc.) in living organisms should not be confused
with protein physical interactions.
●
‘‘Specific contact’’, not just all proteins that bump
into each other by chance.
●
Should be excluded interactions that a protein
experiences when it is being made, folded, quality
checked, or degraded.

Protein-Protein Interaction (PPI)
detection

Databases
1) Introduction
databases

Databases
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BIND - Biomolecular Interaction Network Database;
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BioGRID - Biological General Repository for
Interaction Datasets;
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DIP - Database of Interacting Proteins;
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IntAct - IntAct Molecular Interaction Database;
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HPRD - Human Protein Reference Database
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MINT - Molecular INTeraction database;
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PIPs - Human PPI Prediction database;
●
STRING - Known and Predicted Protein-Protein
Interactions.

PPI Network Derived from
Databases

PIPs human PPIs database
●
Contains predictions of 37 000 high probability
interactions of which 34 000 are not reported in the
interaction databases HPRD, BIND, DIP or OPHID.
●
Interactions predicted by a naive Bayesian model.
The method combines information from gene co-
expression, orthology, co-occurrence of domains,
post-translational modifications, co-localization of
the proteins within the cell and analysis of the local
topology of the predicted PPI network.
●
Based on a prediction algorithm described bellow...

Protein-Protein interaction
prediction
1) Introduction
prediction

Prediction
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The prediction of human protein-protein
interactions was investigated in a Bayesian
framework by considering combinations of
individual protein features known to be indicative
of interaction.
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The seven individual features are used.
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The features are grouped into five distinct
modules: Expression (E), Ortology(O),
Combined(C), Disorder(D), Transitive(T).

Expression Module
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Data Source:
–
GDS596 from the Gene Expression Omnibus
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Description:
–
Gene co-expression profiles from 79 physiologically normal
tissues obtained from various sources
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Scoring function:
–
Pearson correlation of coexpression over all conditions
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Bins:
–
20 of equal size covering the correlation value
range (-1 to +1)

Orthology Module
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Data Source:
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InParanoid, BIND, DIP and GRID databases
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Description:
–
Interactions of homologous protein pairs from yeast, fly, worm and human
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Scoring function:
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Organism-based using InParanoid score
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13 Bins:
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High, medium and low confidence bins were defined for human protein pairs that have
interacting orthologs in either yeast, fly or worm (for a total of 9 bins)
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two bin for human pairs that have interacting paralogs in human (a medium and a low
confidence)
–
one bin for human pairs that have interacting homologs in more than one organism
–
one bin for human pairs that have only noninteracting orthologs

Combined Module
●
This module incorporates three distinct features in a nonnaïve
Bayesian framework: subcellular localization, domain co-
occurrence and post-translational modification co-occurrence.
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Localization:
–
Data source:
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PSLT predictions
–
Description:
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PSLT is a human subcellular localization predictor that considers nine different
compartments (ER, Golgi, cytosol, nucleus, peroxisome, plasma membrane,
lysosome, mitochondria and extracellular)
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Scoring function:
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Qualitative score: proximity of compartments
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4 bins:
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same, neighboring, different compartments, or not localized

Combined module
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Domain co-occurrence
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Data source:
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InterPro and Pfam
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Description:
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Protein domains and motifs
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Scoring function:
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The chi-square test was used as a measure of the likelihood of co-
occurrence of specific InterPro domains and motifs in protein pairs
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Chi-square scores were calculated for all pairs of domains/motifs
that occurred in the training data
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Bins:
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5 covering range of Chi-square scores

Combined module
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PTM co-occurrence
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Data source:
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HPRD and UniProt
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Description:
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Post-translational modifications
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Scoring function:
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Bins:
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4 covering range of PTM scores

Disorder Module
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Data source:
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VLS2 predictions
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Description:
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Prediction of protein intrinsic disorder
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Scoring function:
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Sum of the percent disorder for each protein in a pair
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Bins:
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6 covering range of scoring function (0 to 200%)

Transitive Module
●
Description:
–
Module that considers local
topology of underlying network
predicted using combinations of
above features
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Scoring function:
●
Bins:
–
5 covering range of scoring
function

Independence of the Modules
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The final likelihood ratio output by the predictor is only
representative of the true likelihood of interaction of a protein pair if
the modules considered are independent. If the modules were not
independent, some likelihood ratios would likely be overestimated.
●
Previous studies have demonstrated that some of the features
considered here are indeed independent.
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Independence of all modules used in our predictor was verified by
calculating Pearson correlation coefficients for all pairs of modules.

Architecture of the Predictor and
Likelihoods of the Modules

Posterior Odds Ratio Estimation
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f1, … , fn — features
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I — interaction
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~I — non-interaction

Accuracy of the Predictors
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In order to analyze the predictions, five-fold cross validation
experiments were performed and the area under partial ROC
(receiver operator characteristic) curves (partial AUCs) measured.
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T is the total number of positives in the test set
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Ti is the number of positives that score higher than the ith highest
scoring negative

Prediction Accuracy of Different Combinations of Modules

PPI Prediction by Single Module

PPI Prediction by Combination of
Modules

Receiver Operator Characteristic
(ROC)

Comparison with Other Interaction
Datasets
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Estimated datasets:
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Rhodes probabilistic dataset
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LR400 (derived from our predictors)
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Lehner orthology-derived dataset
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The false positive rates:
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Reference datasets:
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Literature-mined Ramani dataset
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Human Protein Reference Database
(HPRD)

Comparison with Other Interaction
Datasets

Conclusion
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Predicted over 37000 human protein
interactions
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Explored a subspace of the human
interactome that has not been
investigated by previous large
interaction datasets.

References
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Protein–Protein Interactions Essentials: Key Concepts to
Building and Analyzing Interactome Networks 2010
Javier De Las Rivas, Celia Fontanillo
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PIPs: human protein–protein interaction prediction
database 2008
Mark D. McDowall, Michelle S. Scott and Geoffrey J. Barton
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Probabilistic prediction and ranking of human protein-
protein interactions 2007
Michelle S Scott and Geoffrey J Barton

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