Computational prediction of protein-protein interactions

Rong Liu2014-04-22

Quaternary structure

Types of protein-protein interactions

• Homo-oligomers vs. hetero-oligomers• Permanent vs. transient interactions

• Strong transient• Weak transient

• Covalent vs. non-covalent interactions• Classification based on function

• enzyme-inhibitor • antibody-antigen• Others (e.g. hormone-receptor, signaling-effector)

Experimental methods to detect PPI

• Yeast two hybrid (Y2H)• Tandem affinity purification coupled to mass

spectrometry (TAP-MS)• Co-inmunoprecipitation (CoIP)• Protein microarrays• Phage display• Surface plasmon resonance• ……

Reliability of high-throughput methods

PPI database

A sample of DIP protein table

List of interacting partners

Graphic representation of interactions

• Nodes are proteins

• Edges are PPIs

• The center node is DIP:1143N

• Edge width encodes the number of independent experiments identifying the interactions.

• Green (red) is used to draw core (unverified) interactions.

• Click on each node (edge) to know more about the protein (interaction).

Techniques to study the protein complex structures

• X-ray crystallography• Nuclear magnetic resonance spectroscopy• Electron Microscopy

Header of PDB file

Format of PDB file

Preparation of PPI and non-PPI datasets

PPI dataset (Gold standard dataset)• Data from multiple database• At least two separate publications• Each of these publications needs to have a binary

evidence code

Non-PPI dataset• Random selection from all possible protein pairs• Proteins come from different sub-localization

The first non-PPI database

PPI prediction based on homology

InParanoid8

Genome context-based methods

Domain association-based method

Domain combination

Machine learning-based method

Feature representation of amino acid sequences

Feature representation of amino acid sequences

Protein feature server

Validation of the predicted PPIs

Protein-protein binding interface

Hotspots in binding interface (ΔΔG >2kcal/mol)

Definition of binding interface • Define surface residue (DSSP, NACCESS)

• Define interface residue• Distance-based method• Solvent accessible surface area-based method

Format of DSSP file

Characteristics analysis of binding interface

Features of transient and obligate interactions

Features used to predict PPI binding interface

• Sequence conservation• Propensity of residue types in binding regions• Secondary structure• Solvent accessibility• Protrusion index• Side-chain conformational entropy

Position specific scoring matrix and neighborhood

Training and testing

• Cross-validation and independent test• Balanced positive and negative samples• Evaluation measures

State-of-the-arts of feature-based prediction

Similarity between binding interfaces

Protein interface conservation across structure space

Performance comparison between different algorithms

Hybrid method

Residue interaction network

Network-based features

• Degree centrality

• Closeness centrality

• Betweenness centrality

• Clustering coefficient

Protein complexes and small-world networks

Network-based features of other binding sites

Graph-based interface alignment

InterPreTS: protein Interaction Prediction throughTertiary Structure

Structure-based prediction of protein–proteininteractions on a genome-wide scale

Protein Docking

Procedure of protein docking

Search of conformations

Scoring function

Docking programs and benchmark

Evaluation measures

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Structure visualization toolsFeature RasMol Cn3D PyMol SWISS-

PDBViewerChimera

Architecture Stand-Alone Plug-in Stand-Alone Web-enabled Web-enabled

Manipulation Power

Low High High High High

Hardware Requirements

Low/Moderate High High Moderate High

Ease of Use High; command line

Moderate Moderate High Moderate;GUI +command line

Special Features Small Size; easy install

Powerful GUI

GUI; ray tracing

Powerful GUI GUI; collaboration

Output Quality Moderate Very high High High Very high

Documentation Good Good Limited Good Very good

Support Online; Users groups

Online; Users groups

Online; Users groups

Online; Users groups

Online; Users groups

Speed High Moderate Moderate Moderate Moderate/Slow

OpenGL Support Yes Yes Yes Yes Yes

Pymol

• http://www.jhu.edu/pfleming/bioinform/files/PyMOL_Tutorial.pdf• http://wenku.baidu.com/view/483b70fa0242a8956bece41f.html

Application of PPI network