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Introduction
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.
Introduction
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.
Introduction
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
Introduction
. 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.
hydrogen bonds Minimizes interstitial cavities or spaces Minimizes number of bad contacts Minimizes number of buried charges
Refinement Exploring the effect of single amino acid substitutions Ligand effects on protein structure and dynamics (induced fit)
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.
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.
pseudo-thermodynamic potential
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
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
VADAR
http://redpoll.pharmacy.ualberta.ca
http://www.biochem.ucl.ac.uk/~roman/procheck/procheck.html
VADAR
http://www.pence.ca/software/vadar/latest/vadar.html
DSSP
http://www.cmbi.kun.nl/gv/dssp
Procheck
Conclusions
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
Conclusions
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