Protein Structure and Function: Applications of Bioinformatics Methods - John Rigden 2014



Introduction

ab initio Protein Structure Prediction

Ab initio protein structure prediction

Energy Functions

Energy functions

Rational energy functions

ab initio Protein Structure Prediction

Energy Functions

Combination of Empirical Energy Functions and Fragment Assembly

Ab Initio Protein Structure Prediction

Conformational Search Methods

Monte Carlo Modeling

Ab initio Protein Structure Prediction

Molecular Dynamics

Ab Initio Protein Structure Prediction

Genetic Algorithms

Ab initio Protein Structure Prediction

Mathematical Optimization

Ab initio protein structure prediction

Model selection

Rational energy function

Empirical energy function

Ab Initio Protein Structure Prediction

Model Selection

Structure-Sequence Compatibility Function

Clustering of Structural Models

ab initio Protein Structure Prediction

Comments and Discussion

References

Fold Recognition

Introduction

Fold recognition

The importance of "blind" tests: The CASP competition

Fold Recognition

Ab Initio Structure Prediction and Homology Modeling

Limits of the Fold Type Space

On terminology: “threading” and “fold recognition”

Fold recognition

“Threading”

Empirical potentials

Alignment search

Heuristic alignment rules

Fold Recognition

Remote Homology Detection Without Gaps

Heuristic Alignment Rules

Remote Homology Detection Without Alignment

Utilization of Predicted Structural Properties

Fold recognition

Detection of remote homology without alignment

Sequence profiles and Hidden Markov Models

Fold Recognition

Remote Homology Detection Without Alignment

Classification of Fold Types and the Support Vector Machine Method

Consensus Approaches

Detection of Remote Homology without Alignment

Homology Network Traversal

Alignment Accuracy, Model Quality, and Statistical Significance

Alignment Generation Algorithms and Scoring

Evaluation of Statistical Significance

Web Tools for Fold Recognition

Prospects

References

Comparative Protein Structure Modeling

Introduction

Structure Determines Function

Sequences, Structures, and Structural Genomics

Protein Structure Prediction Methods

Steps in Comparative Protein Structure Modeling

Searching for Structures Potentially Related to the Target

Stages of Comparative Protein Structure Modeling

Template Selection

Steps in Comparative Protein Structure Modeling

Sequence-to-Structure Alignment

Model Building

Model Evaluation

Efficiency of Comparative Modeling Methods

Accuracy of Methods

Errors in Comparative Models

Applications of Comparative Modeling

Single Protein Modeling

Comparative Modeling and the Protein Structure Research Project

Conclusion

References

Prediction of membrane protein structure

Introduction

Structural classes

Alpha-helical bundles

Prediction of Membrane Protein Structure

Structural Classes

Beta-barrels

Prediction of membrane protein structure

Characteristics of membrane protein crystallization

Prediction of Membrane Protein Structure

Databases

Multiple Sequence Alignments

Prediction of Transmembrane Protein Topology

Alpha-Helical Proteins

Beta-Barrel Proteins

Membrane Protein Structure Prediction

Genome-Wide Association Studies

Prediction of Membrane Protein Structure

Datasets, Homology, Accuracy, and Cross-Validation

Prediction of Spatial Structure

Future Prospects for Membrane Protein Structure Prediction Methods

References

Bioinformatics methods for studying the structure and function of intrinsically disordered proteins

The concept of protein disorder

Bioinformatics methods for studying the structure and functions of disordered proteins

Properties of IDP sequences

Unusual amino acid composition of IDPs

Bioinformatics Methods for Studying the Structure and Function of Intrinsically Disordered Proteins

Properties of IDP Sequences

IDP Sequence Patterns

Bioinformatics Methods for Studying the Structure and Function of Unordered Proteins

Low Sequence Complexity and Disorder

Prediction of Disorder

Bioinformatics methods for studying the structure and function of disordered proteins

Disorder prediction

Prediction of low-complexity regions

Charge-hydropathy plots

Bioinformatics Methods for Studying the Structure and Function of Disordered Proteins

Disorder Prediction

Propensity-Based Prediction Methods

Bioinformatics Methods for Studying the Structure and Functions of Disordered Proteins

Prediction Methods Based on the Absence of Well-Defined Secondary Structure

Bioinformatics methods for studying the structure and function of disordered proteins

Disorder prediction

Machine learning algorithms

Bioinformatics Methods for Studying the Structure and Function of Unordered Proteins

Prediction of Disorder

Prediction Based on Contact Potentials

Bioinformatics Methods for Studying the Structure and Function of Disordered Proteins

Disorder Prediction

A reduced alphabet is sufficient for disorder prediction

Bioinformatics methods for studying the structure and function of disordered proteins

Prediction of disorder

Comparison of disorder prediction methods

Bioinformatics Methods for Studying the Structure and Function of Disordered Proteins

Functional Classification of IDPs

Functional Classification of IDPs Based on Gene Ontology

Bioinformatics Methods for Studying the Structure and Functions of Disordered Proteins

Classification of IDPs Based on Mechanism of Action

Bioinformatics methods for studying the structure and function of disordered proteins

Functional classification of IDPs

Structural elements of IDPs associated with functioning

Bioinformatics methods for studying the structure and functions of disordered proteins

Prediction of IDP functions

Correlation of disorder model and function

Bioinformatics methods for studying the structure and function of disordered proteins

Prediction of short recognition motifs in IDPs

SMOR prediction

Bioinformatics Methods for Studying the Structure and Function of Disordered Proteins

Prediction of IDP Functions

Combining Sequence and Disorder Information: Phosphorylation Sites and CaM-Binding Motifs

Maintenance of Disorder

Limitations of IDP Function Prediction Methods

Rapid Evolution of IDPs

Sequence-Function Independence and Ambiguity

Conservation and Disorder

Bioinformatics methods for studying the structure and function of disordered proteins

Conclusion

Bioinformatics Methods for Studying the Structure and Functions of Disordered Proteins

References

Functional diversity in packing elements and superfamilies

Function determination

Functional Diversity in Packing Elements and Superfamilies

From Fold to Function

Fold Determination

Functional Diversity in Packing Motifs and Superfamilies

From Folding to Function

Relationship Between Folding Patterns and Function Prediction

Functional diversity in packing elements and superfamilies

Functional diversity of homologous proteins

Definitions

Diversity of functions in homologous proteins

Evolution of protein superfamilies

Functional Diversity in Packing Elements and Superfamilies

Functional Diversity of Homologous Proteins

Functional Divergence during Protein Evolution

Functional diversity in packing motifs and superfamilies

Conclusion

Functional Diversity in Packaging Motifs and Superfamilies

References

Predicting Protein Function from Surface Properties

Methods of Surface Representation

Van der Waals Surface

Surface Representation Methods

Molecular Surface (Solvent-Excluded Surface)

Prediction of protein function based on its surface properties

Methods of surface representation

Solvent-accessible surface

Predicting Protein Function from Surface Properties

Surface Properties

Hydrophobicity

Protein Function Prediction via Surface Properties

Electrostatic Properties

Protein Function Prediction Based on Surface Properties

Surface Conservation

Prediction of protein function based on its surface properties

Prediction of functions by surface properties

Hydrophobic surface

Protein Function Prediction Based on Surface Properties

Function Prediction from Surface Properties

Electrostatic Surface

Prediction of Protein Function from Surface Properties

Functional Prediction Based on Surface Properties

Surface Conservation

Predicting protein function from surface properties

Function prediction from surface properties

Combining surface properties for function prediction

Prediction of protein function based on its surface properties

Ligand-protein interaction

Properties of ligand-protein interactions

Prediction of Protein Function from Surface Properties

Ligand-Protein Interaction

Prediction of Active Site Location

Prediction of protein function from its surface properties

Ligand-protein interaction

Prediction of drug sensitivity

Annotation of ligand-binding sites

Prediction of Protein Function from Surface Properties

Protein-Protein Interface

Properties of the Protein-Protein Interface

Hot Spots in Protein Interfaces

Prediction of protein function based on surface properties

Protein-protein interface

Prediction of interface location

Predicting Protein Function from Surface Properties

Conclusion

Prediction of Protein Function from Its Surface Properties

References

Spatial Motifs

Background and Significance

Structural Motifs

What is a Function?

Spatial Motifs

Structural Motifs: Definition and Scope

Structural Motifs

Overview of Methods

Motif Search

Spatial Motifs

Identification and Selection of Motifs

Interpretation of Results

Spatial motifs

Specific methods

User-defined motifs

Structural motifs

Motif detection

Spatial Motifs

Similar Methods

Point-Surface Hybrid Descriptions

Spatial motifs

Similar methods

Single-point descriptions

Structural Motifs

Application of Molecular Docking in Function Annotation

Discussion

Spatial Motifs

Conclusion

Structural Motifs

References

Protein Dynamics: From Structure to Function

Molecular Dynamics Calculations

Principles and Approximations

Appendices

Limitations and Enhanced Sampling Algorithms

Principal Component Analysis

Collective Variable Sampling Algorithms

Collective Variable Sampling Algorithms

TEE-REX

Methods for Predicting Functional Modes

Normal Mode Analysis

Elastic Network Models

CONCOORD

Conclusions and Perspectives

References

Integrated Servers for Structure-Based Function Prediction

Introduction

Integrated Servers for Function Prediction from Structure

The Problem of Function Prediction from Structure

Integrated Servers for Structure-Based Function Prediction

Structure-Function Prediction Methods

ProKnow

Integrated servers for structure-based function prediction

Prediction of fold type

Structural motifs

Integrative servers for structure-based function prediction

Sequence homology

Integrative Servers for Structure-Based Function Prediction

Sequence Motifs

Integrated Servers for Structure-Based Function Prediction

Protein Interactions

Combining Predictions

Integrated servers for structure-based function prediction

Prediction success rate

Integrative Servers for Function Prediction from Structure

ProFunc

Integrative servers for structure-based function prediction

Structure-based methods employed by ProFunc

Integrated servers for function prediction from structure

Evaluation of structural methods

Integrated Servers for Structure-Based Function Prediction

Conclusion

References

Examples: prediction of the function of structures obtained in structural genomics projects

Introduction

Examples of large-scale protein function prediction

Examples: predicting the function of structures obtained from structural genomics projects

Several Special Examples

Examples: prediction of the function of structures obtained in structural genomics projects

Collaborative Annotation

Examples: prediction of the function of structures obtained through structural genomics projects

Conclusion

Examples: prediction of function for structures obtained in structural genomics projects

References

Prediction of Protein Function Based on Theoretical Models

Introduction

Protein Models as a Publicly Available Resource

Prediction of protein function based on their theoretical models

Protein models as a publicly available resource

Model quality

Protein models as a publicly accessible resource

Model databases

Accuracy and added value of model-based predictions

Predicting Protein Function from Theoretical Models

Accuracy and Added Value of Model-Based Predictions

Implementation

Prediction of Protein Function Based on Theoretical Models

Practical Application

Plasticity of Catalytic Site Residues

Practical Applications

Mutation Mapping

Protein Complexes

Protein Function Prediction Based on Theoretical Models

Ab Initio Function Prediction

Prediction of Protein Function Based on Theoretical Models

Practical Application

Prediction of Ligand Specificity

Structure Modeling of Alternatively Spliced Isoforms

From General Function to Molecular Details

What's Next?

References

Full-color illustrations