Phyre

Phyre and Phyre2 (Protein Homology/AnalogY Recognition Engine; pronounced as fire) are free web-based services for protein structure prediction. Phyre is among the most popular methods for protein structure prediction having been cited over 1,500 times. Like other remote homology recognition techniques (see protein threading), it is able to regularly generate reliable protein models when other widely used methods such as PSI-BLAST cannot. Phyre2 has been designed to ensure a user-friendly interface for users inexpert in protein structure prediction methods. Its development is funded by the Biotechnology and Biological Sciences Research Council.

Phyre and Phyre2 (Protein Homology/AnalogY Recognition Engine; pronounced as fire) are free web-based services for protein structure prediction. Phyre is among the most popular methods for protein structure prediction having been cited over 1,500 times. Like other remote homology recognition techniques (see protein threading), it is able to regularly generate reliable protein models when other widely used methods such as PSI-BLAST cannot. Phyre2 has been designed to ensure a user-friendly interface for users inexpert in protein structure prediction methods. Its development is funded by the Biotechnology and Biological Sciences Research Council. ==Description== The Phyre and Phyre2 servers predict the three-dimensional structure of a protein sequence using the principles and techniques of homology modeling. Because the structure of a protein is more conserved in evolution than its amino acid sequence, a protein sequence of interest (the target) can be modeled with reasonable accuracy on a very distantly related sequence of known structure (the template), provided that the relationship between target and template can be discerned through sequence alignment. Currently the most powerful and accurate methods for detecting and aligning remotely related sequences rely on profiles or hidden Markov models (HMMs). These profiles/HMMs capture the mutational propensity of each position in an amino acid sequence based on observed mutations in related sequences and can be thought of as an 'evolutionary fingerprint' of a particular protein. Typically, the amino acid sequences of a representative set of all known three-dimensional protein structures is compiled, and these sequences are processed by scanning against a large protein sequence database. The result is a database of profiles or HMMs, one for each known 3D structure. A user sequence of interest is similarly processed to form a profile/HMM. This user profile is then scanned against the database of profiles using profile-profile or HMM-HMM alignment techniques. These alignments can also take into account patterns of predicted or known secondary structure elements and can be scored using various statistical models. See protein structure prediction for more information. The first Phyre server was released in June 2005¹ and uses a profile-profile alignment algorithm based on each protein's position-specific scoring matrix. The Phyre2 server was publicly released February 2011¹ as a replacement for the original Phyre server and provides extra functions over Phyre, a more advanced interface, fully updated fold library and uses the HH-suite (HHpred, HHsearch) package for homology detection among other improvements. ==Standard use== After pasting a protein amino acid sequence into the Phyre or Phyre2 submission form, a user will typically wait between 30 minutes and several hours (depending on factors such as sequence length, number of homologous sequences and frequency and length of insertions and deletions) for a prediction to complete. An email containing summary information and the predicted structure in PDB format are sent to the user together with a link to a web page of results. The Phyre2 results screen is divided into three main sections, described below. ==Applications== Applications of Phyre and Phyre2 include protein structure prediction, function prediction, domain prediction, domain boundary prediction, evolutionary classification of proteins, guiding site-directed mutagenesis and solving protein crystal structures by molecular replacement. There are two linked resources that use Phyre predictions for the structure-based analysis of missense variants typically resulting from single-nucleotide polymorphisms. PhyreRisk is a database which maps genetic variants to experimental and Phyre-predicted protein structures. The protein page displays the experimental and predicted structures. Users can map variants from either genetic or protein coordinates. Missense3D is a tool which provides a stereochemical report on the effect of a missense variant on protein structure. Users can upload their own variants and coordinates, including both PDB structures and Phyre-predicted models. ==History== Phyre and Phyre2 are the successors to the 3D-PSSM protein structure prediction system which has over 1,400 citations to date. 3D-PSSM was designed and developed by Lawrence Kelley and Bob MacCallum in the Biomolecular modelling Lab at the Cancer Research UK. Phyre and Phyre2 were Lawrence Kelley in the structural bioinformatics group, Imperial College London. Components of the Phyre and Phyre2 systems were developed by Benjamin Jefferys, Alex Herbert, and Riccardo Bennett-Lovsey. Research and development of both servers was supervised by Michael Sternberg. ==References==

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