Protein Domains and their Classifications

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Table of contents

1 Introduction 
1.1 The Protein Interactome
1.2 Modelling 3D Structures of Protein-Protein Complexes
1.3 Structural PPI Resources
1.4 Knowledge Discovery in Databases and Data Mining
1.5 Thesis Aims and Objectives
1.6 Overview of Thesis
2 Biological Context – Modelling 3D Protein-Protein Interactions 
2.1 Protein Molecules and their 3D Structures
2.1.1 Why Study Proteins?
2.1.2 Building Blocks and Architecture of Proteins
2.1.3 Protein Domains and their Classifications
2.1.4 Coverage of Protein 3D Structures
2.1.5 Computational Methods to Predict 3D Structures of Proteins
2.2 Protein-Protein Interactions and their 3D Structures
2.2.1 Why Study Protein-Protein Interactions?
2.2.2 Databases of Experimentally-Detected and Predicted PPIs
2.2.3 Different Types of Protein-Protein Interactions
2.2.4 Coverage of 3D Protein-Protein Interactions
2.2.5 Previous Analyses of Protein-Protein Complexes
2.2.6 Current Protein-Protein Interface Prediction Algorithms
2.3 Modelling 3D Structures of Protein-Protein Complexes
2.3.1 Template-Based Modelling of Protein Complexes
2.3.2 Ab-Initio Docking
2.3.3 The CAPRI Blind Docking Experiment
2.4 Existing Structural PPI Resources
2.4.1 Classifications of 3D Structures of Protein-Protein Complexes
2.4.2 Characterisations of Protein Functional Sites
2.4.3 Classifications of Protein-Protein Interfaces
2.4.4 Structural Databases of Protein-Protein Complexes
2.4.5 Integrated Databases, APIs and Libraries
2.4.6 Docking Benchmark Datasets
2.5 Conclusion
3 Introducing KBDOCK – An Integrated Database of 3D Protein Domain Interactions 
3.1 Introduction
3.2 The Three Selected Data Sources
3.2.1 The Pfam Protein Domain Family Database
3.2.2 The 3DID Domain-Domain Interaction Database
3.2.3 The Protein Data Bank
3.3 Representing and Querying Pfam and 3DID Data Using Prolog
3.4 Collecting Representative Biological Hetero Structural PPIs
3.4.1 Classifying DDIs as Intra, Homo and Hetero
3.4.2 Distinguishing Between Crystallographic and Biological Contacts
3.4.3 Obtaining a Non-Redundant Set of DDIs
3.5 Annotating DDIs with Sequence and Structural Information
3.5.1 Identifying Conserved PDB Residues Using Pfam Consensus Sequences
3.5.2 Classifying Interface Residues as Core or Rim
3.5.3 Adding Secondary Structure Information Using DSSP
3.6 Superposing DDIs in 3D Space Using ProFit
3.7 Summary of the KBDOCK Data Processing Steps
3.8 The KBDOCK Data Model
3.9 Exploring DDIs in Protein Domain Families with KBDOCK
3.9.1 Querying KBDOCK
3.9.2 Exploring Pfam Domain Family Superpositions
3.10 Conclusion
4 Spatial Clustering of Protein Domain Family Binding Sites 
4.1 Previous Protein-Protein Interface Classifications
4.1.1 The PIBASE Domain-Domain Interface Classification
4.1.2 The SCOPPI Domain-Domain Interface Classification
4.1.3 The 3DID Database of Domain-Domain Interfaces
4.1.4 The I2I-SiteEngine Protein-Protein Interface Classification
4.1.5 Keskin’s Classification of Protein-Protein Interfaces
4.1.6 The PPiClust Approach for Clustering Protein-Protein Interfaces
4.2 Previous Studies of Protein-Protein Interaction Modes
4.2.1 Aloy’s Analysis of Interaction Modes Between Domain Families
4.2.2 Korkin’s Analysis of Binding Sites Within SCOP Families
4.2.3 Shoemaker’s Analysis of Interaction Modes Between Domain Family Pairs
4.3 How Large is the Space of Interface Types?
4.4 Reusing Protein Interface or Binding Site Information
4.5 Classifying Domain Binding Sites in KBDOCK
4.5.1 Defining a Domain Binding Site Vector
4.5.2 Spatial Clustering of Domain Binding Site Vectors
4.6 Defining Domain Family Binding Sites
4.7 Distribution of DFBS in Pfam Domain Families
4.8 Discussion
5 Classifying and Analysing Domain Family Binding Sites 
5.1 Related Work on Protein-Protein Interface Analysis
5.1.1 Various Ways of Dissecting Protein Binding Sites
5.1.2 Hot Spot Residues
5.1.3 Hydrogen Bonds and Salt Bridges Across Interfaces
5.1.4 Interface Residue Composition
5.1.5 Interface Residue-Residue Contacts
5.1.6 Conservation of Amino Acid Residues at Interfaces
5.1.7 Non-Homologous Interactions With Structurally-Similar Faces
5.1.8 Secondary Structure Preferences at Interfaces
5.1.9 Structural Analyses of Hub Proteins
5.2 Large-Scale Analysis of Protein Domain Family Binding Sites
5.3 KBDOCK Provides a Large Dataset for Statistical Analyses
5.4 Annotating DFBSs with Secondary Structure Information
5.5 Classifying and Analysing DFBSs
5.6 Secondary Structure-Based Classification of DFBSs
5.7 Do DFIs Have SSE Pairing Preferences?
5.8 Are Binding Site Surfaces Special?
5.9 Are Multi-Partner Binding Sites Special?
5.10 Discussion and Conclusion
6 Protein-Protein Docking Using Case-Based Reasoning 
6.1 Introduction
6.2 Overview of Case-Based Reasoning
6.3 A Formal CBR Approach to Docking By Homology
6.4 The KBDOCK Case Representation
6.5 The KBDOCK Case Retrieval
6.5.1 Pfam-based Case Retrieval
6.5.2 The Single-Domain Docking Test Set
6.5.3 Coverage of FH, SH-two and SH-one Cases
6.6 The KBDOCK Case Adaptation
6.6.1 Modelling FH Problems Using Substitution Adaptation
6.6.2 Modelling SH Problems Using Transformation Adaptation
6.6.3 Evaluating the FH and SH Cases
6.6.4 Summary of KBDOCK Case Retrieval Results
6.7 The KBDOCK Case Refinement
6.7.1 The Extended Docking Test Set
6.7.2 Docking Refinement Results for Single-Domain Targets
6.8 Modelling Multi-Domain Docking Problems
6.8.1 Aggregating Multiple DDIs
6.8.2 KBDOCK Modelling Results for Multi-Domain Targets
6.9 Discussion and Conclusion
7 Conclusions 
7.1 Summary of the Main Contributions
7.1.1 The KBDOCK Database of 3D Non-Redundant Hetero DDIs
7.1.2 The Domain Family Binding Site Concept
7.1.3 Structural Classification and Study of Domain Family Binding Sites
7.1.4 Case-Based Protein Docking
7.1.5 The KBDOCK Web Server
7.2 Timeliness and Novelty
7.3 Future Extensions to KBDOCK
7.4 Future Prospects