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Jennie Varghese 09BIF089

Protein structure prediction

Protein structure prediction is another important application of bioinformatics. The amino acid sequence of a protein, the so-

called primary structure, can be easily determined from the sequence on the gene that codes for it. In the vast majority of cases, this primary structure uniquely determines a structure in its native environment.

For lack of better terms, structural information is usually classified as one of secondary, tertiary and

quaternary structure. A viable general solution to such predictions remains an open problem. As of now, most efforts have been directed towards heuristics that work most of the time.

One of the key ideas in bioinformatics is the notion of homology. In the genomic branch of bioinformatics, homology is used to predict the function of a gene: if the sequence of gene A, whose function is known, is homologous to the sequence of gene B, whose function is unknown, one could infer that B may share A's function. In the structural branch of bioinformatics, homology is used to determine which parts of a protein are important in structure formation and interaction with other proteins

. In a technique called homology modeling, this information is used to predict the structure of a protein once the structure of a

homologous protein is known. This currently remains the only way to predict protein structures reliably. techniques for predicting protein structure include protein threading and de novo (from scratch) physics-based modeling.

Protein structure prediction

A good protein structure

Minimizes disallowed torsion angles Maximizes number of

hydrogen bonds Minimizes interstitial cavities or spaces Minimizes number of bad contacts Minimizes number of buried charges

Protein structure prediction

Secondary structure
3D structure Modeling by homology (Comparative modeling) Fold recognition (Threading) Ab initio prediction
Rule-based approaches Lattice models Simulating the time dependence of folding

Refinement Exploring the effect of single amino acid substitutions Ligand effects on protein structure and dynamics (induced fit)

Modeling by Homology (Comparative Modeling)

Comparative modeling predicts the three-dimensional structure of a given

protein sequence (target) based primarily on its alignment to one or more proteins of known structure (templates). The prediction process consists of

fold assignment, target template alignment, model building, and model evaluation and refinement.

The number of protein sequences that can be modeled and the accuracy of the predictions are increasing steadily because of the growth in the number of known protein structures and because of the improvements in the modeling software.

Further advances are necessary in recognizing weak sequence structure

similarities, aligning sequences with structures, modeling of rigid body shifts, distortions, loops and side chains, as well as detecting errors in a model. Despite these problems, it is currently possible to model with useful accuracy significant parts of approximately one third of all known protein sequences.

Modeling by Homology (Comparative Modeling)

Modeling by Homology (Comparative Modeling)

Modeling by Homology (Comparative Modeling)

Modeling by Homology (Comparative Modeling)

Modeling by Homology (Comparative Modeling)

Fold Recognition (Threading)

Methods of protein fold recognition attempt to detect similarities between protein 3D structure that are not accompanied by any significant sequence similarity.

The unifying theme of these appraoches is to try and find folds that are compatible with a particular sequence. Unlike sequence-only comparison, these methods take advantage of the extra information made available by 3D structure information.

Rather than predicting how a sequence will fold, they predict how well a fold will fit a sequence.

Fold Recognition (Threading) 2 Kinds

2D Threading or Prediction Based Methods (PBM)
Predict secondary structure (SS) or ASA of query Evaluate on basis of SS and/or ASA matches

3D Threading or Distance Based Methods (DBM)

Create a 3D model of the structure Evaluate using a distance-based hydrophobicity or

pseudo-thermodynamic potential

Fold Recognition (Threading)

Fold Recognition
Database of 3D structures and sequences
Protein Data Bank (or non-redundant subset)

Query sequence
Sequence < 25% identity to known structures

Alignment protocol
Dynamic programming

Evaluation protocol
Distance-based potential or secondary structure

Ranking protocol

Fold Recognition

Ab Initio Prediction
Predicting the 3D structure without any prior knowledge
Used when homology modelling or threading have failed (no homologues are evident) Equivalent to solving the Protein Folding Problem Still a research problem

Ab Initio Prediction

Ab Initio Prediction

Ab Initio Prediction

Combining Prediction Procedures

Structure Validation
A structure can (and often does) have mistakes
A poor structure will lead to poor models of

mechanism or relationship Unusual parts of a structure may indicate something important (or an error)

Structure Validation
Assess experimental fit
look at Resolution, R-Factor or RMSD

Assess correctness of overall fold

look at disposition of hydrophobic residues

Assess structure quality

packing stereochemistry contacts

Structure Validation Servers

WHAT IF Verify3D


Structure Validation Programs





Protein structures are now sufficiently abundant and well defined that they can be classified using well-developed rules of

taxonomy Distant relationships and common rules of folding can be uncovered through fold classification & comparison

Structure prediction is still one of the key areas of active research in bioinformatics and computational biology Significant strides have been made over the past decade through the use of larger databases, machine learning methods and

faster computers