RAPTOR is protein threading software used for

protein structure prediction Protein structure prediction is the inference of the three-dimensional structure of a protein from its amino acid sequence—that is, the prediction of its secondary and tertiary structure from primary structure. Structure prediction is differen ...

. It has been replaced by RaptorX, which is much more accurate than RAPTOR.

Comparison of techniques

Protein threading vs. homology modeling

Researchers attempting to solve a protein's structure start their study with little more than a protein sequence. Initial steps may include performing a

PSI-BLAST In bioinformatics, BLAST (basic local alignment search tool) is an algorithm and program for comparing primary biological sequence information, such as the amino-acid sequences of proteins or the nucleotides of DNA and/or RNA sequences. A BLA ...

or PatternHunter search to locate a similar sequences with a known structure in the

Protein Data Bank The Protein Data Bank (PDB) is a database for the three-dimensional structural data of large biological molecules, such as proteins and nucleic acids. The data, typically obtained by X-ray crystallography, NMR spectroscopy, or, increasingly, c ...

(PDB). If there are highly similar sequences with known structures, there is a high probability that this protein's structure will be very similar to those known structures as well as functions. If there is no homology found, the researcher must perform either

X-ray crystallography X-ray crystallography is the experimental science determining the atomic and molecular structure of a crystal, in which the crystalline structure causes a beam of incident X-rays to diffract into many specific directions. By measuring the angle ...

or nuclear magnetic resonance (NMR) spectroscopy, both of which require considerable time and resources to yield a structure. Where these techniques are too expensive, time-consuming or limited in scope, researchers can use protein threading software, such as RAPTOR to create a highly reliable model of the protein. Protein threading is more effective than homology modeling, especially for proteins which have few homologs detectable by

sequence alignment In bioinformatics, a sequence alignment is a way of arranging the sequences of DNA, RNA, or protein to identify regions of similarity that may be a consequence of functional, structural, or evolutionary relationships between the sequences. Ali ...

. The two methods both predict protein structure from a template. Given a protein sequence, protein threading first aligns (threads) the sequence to each template in a structure library by optimizing a scoring function that measures the fitness of a sequence-structure alignment. The selected best template is used to build the structure model. Unlike homology modeling, which selects template purely based on homology information (sequence alignments), the scoring function used in protein threading utilizes both homology and structure information (sequence structure alignments). If a sequence has no significant homology found, homology modeling may not give reliable prediction in this case. Without homology information, protein threading can still use structure information to produce good prediction. Failed attempts to obtain a good template with BLAST often result in users processing results through RAPTOR.

Integer programming vs. dynamic programming

The

integer programming An integer programming problem is a mathematical optimization or feasibility program in which some or all of the variables are restricted to be integers. In many settings the term refers to integer linear programming (ILP), in which the objective ...

approach to RAPTOR produces higher quality models than other protein threading methods. Most threading software use

dynamic programming Dynamic programming is both a mathematical optimization method and a computer programming method. The method was developed by Richard Bellman in the 1950s and has found applications in numerous fields, from aerospace engineering to economics. I ...

to optimize their scoring functions when aligning a sequence with a template. Dynamic programming is much easier to implement than integer programming; however if a scoring function has pairwise contact potential included, dynamic programming cannot globally optimize such a scoring function and instead just generates a local optimal alignment. Pairwise contacts are very conserved in protein structure and crucial for prediction accuracy. Integer programming can globally optimize a scoring function with pairwise contact potential and produce a global optimal alignment.

Components

Threading engines

NoCore, NPCore and IP are the three different threading engines implemented in RAPTOR. NoCore and NPCore are based on dynamic programming and faster than IP. The difference between them is that in NPCore, a template is parsed into many "core" regions. A core is a structurally conserved region. IP is RAPTOR's unique integer programming-based threading engine. It produces better alignments and models than the other two threading engines. People can always start with NoCore and NPCore. If their predictions are not good enough, IP may be a better choice. After all three methods are run, a simple consensus may help to find the best prediction.

3D structure modeling module

The default 3D structure modeling tool used in RAPTOR is OWL. Three-dimensional structure modeling involves two steps. The first step is loop modeling which models regions in the target sequence that map to nothing in the template. After all the loops are modeled and the backbone is ready, side chains are attached to the backbone and packed up. For loop modeling, a cyclic coordinate descent algorithm is used to fill the loops and avoid clashes. For side chain packing, a tree decomposition algorithm is used to pack up all the side chains and avoid any clashes. OWL is automatically called in RAPTOR to generate the 3D output. If a researcher has MODELLER, they can also set up RAPTOR to call MODELLER automatically. RAPTOR can also generate ICM-Pro input files, with which people run ICM-Pro by themselves.

PSI-BLAST module

To make it a comprehensive tool set,

is also included in RAPTOR to let people do homology modeling. People can set up all the necessary parameters by themselves. There are two steps involved in running PSI-BLAST. The first step is to generate the sequence profile. For this step, NR non-redundant database is used. The next step is to let PSI-BLAST search the target sequence against the sequences from the Protein Data Bank. Users can also specify their own database for each step.

Protein structure viewer

There are many different structure viewers. In RAPTOR,

Jmol Jmol is computer software for molecular modelling chemical structures in 3-dimensions. Jmol returns a 3D representation of a molecule that may be used as a teaching tool, or for research e.g., in chemistry and biochemistry. It is written in th ...

is used as the structure viewer for examining the generated prediction.

Output

After a threading/PSI-BLAST job, one can see a ranking list of all the templates. For each template, people can view the alignment,

E-value In null-hypothesis significance testing, the ''p''-value is the probability of obtaining test results at least as extreme as the result actually observed, under the assumption that the null hypothesis is correct. A very small ''p''-value means ...

and numerous other specific scores. Also, the functional information of the template and its

SCOP A ( or ) was a poet as represented in Old English literature#Poetry, Old English poetry. The scop is the Old English counterpart of the Old Norse ', with the important difference that "skald" was applied to historical persons, and scop is used ...

classification are provided. One can also view the sequence's PSM matrix and secondary structure prediction. If a template has been reported by more than one method, it will be marked with the number of times it has been reported. This helps to identify the best template.

Performance in CASP

CASP Critical Assessment of Structure Prediction (CASP), sometimes called Critical Assessment of Protein Structure Prediction, is a community-wide, worldwide experiment for protein structure prediction taking place every two years since 1994. CASP prov ...

, Critical Assessment of Techniques for Protein Structure Prediction, is a biennial experiment sponsored by

NIH The National Institutes of Health, commonly referred to as NIH (with each letter pronounced individually), is the primary agency of the United States government responsible for biomedical and public health research. It was founded in the late 1 ...

. CASP represents the Olympic Games of the protein structure prediction community and was established in 1994. RAPTOR first appeared in

CAFASP CAFASP, or the Critical Assessment of Fully Automated Structure Prediction, is a large-scale blind experiment in protein structure prediction that studies the performance of automated structure prediction webservers in homology modeling, fold recog ...

3 (CASP5) in 2002 and was ranked number one in the individual server group for that year. Since then, RAPTOR has actively participated in every CASP for evaluation purpose and been consistently ranked in the top tier. The most recent CASP8 ran from May 2008 until August 2008. More than 80 prediction servers and more than 100 human expert groups worldwide registered for the event, where participants attempt to predict the 3D structure from a protein sequence. According to the ranking from Zhang's group, RAPTOR ranked 2nd among all the servers (meta server and individual servers). Baker lab's ROBETTA is placed 5th in the same ranking list.

Top five prediction servers in CASP8

References

* * *{{cite journal , vauthors=Xu J, Li M, Lin G, Kim D, Xu Y , title=Protein threading by linear programming , journal=Pac Symp Biocomput , year=2003 , pages=264–275 , pmid=12603034 *Xu J (2005). "Protein Fold Recognition by Predicted Alignment Accuracy". IEEE/ACM Trans. on ''Computational Biology and Bioinformatics''. *Xu J (2005). "Rapid Protein Side-Chain Packing via Tree Decomposition". ''RECOMB''.

External links

RaptorX WebsiteCASP experiments home pageAutomated assessment of protein structure prediction in CASP8
Molecular modelling software