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Paper text:
as the genome sequencing and metagenomics projects are continuing to deliver huge numbers of new protein sequences , the percentage of sequences characterized as  unknown function is growing rapidly ( 1,2 ) .
in addition , as a result of structural genomics , there is also an increasing number of proteins with known structure but with no functional information ( 3 ) .
functional characterization of a new protein can be based on sequence similarity to a family of well - characterized proteins ( 4,5 ) . in most cases ,
when the sequence similarity between the query protein and a well - characterized protein sequence is high , an automatic transfer of function can be made .
however , when the similarity is lower , this automatic  annotation can be misleading and other methods are needed .
one method is based on template searching , where the query sequence is searched for sequence motifs , patterns or fingerprints as defined in databases such as prosite ( 6 ) and interpro ( 7 ) .
other methods attempt to transfer gene ontology terms ( 810 ) or ec terms ( 11 ) to a new sequence .
however , such a transfer is only reliable when there is a clear match to a homolog of known function .
although 3d - structural information is often very valuable in understanding protein function , there is an increasing number of proteins with known structures but with unknown functions .
recently , new methods for functional inference for such 3d - structures have been developed ( 12 ) .
fr methods lie in the midpoint between sequence - homology and 3d - structural similarity approaches . in the lack of significant sequence similarity and of an experimental 3d - structure , fr
methods are often able to identify compatible 3d - templates with relatively accurate sequence  structure alignments ( 13 ) .
because the compatible template is often characterized functionally , a fr result can be a rich source of functional information ( 14,15 ) .
functional transfer from a template to the query sequence can be attempted using the functionally significant residues in the template that are conserved in the fr sequence  structure alignment .
fralanyzer ( fold recognition alignment analyzer ) is a web tool , aimed at visualizing and annotating sequence  structure alignments .
functional residues in a query sequence of unknown function are identified based on the conservation of functionally significant residues in sequence  structure and structure  structure alignments .
thus , the input to fralanyzer is an alignment , obtained independently ( i.e. not a part of fralanyzer ) . to facilitate the human interface and to avoid the need of cutting and pasting of alignments
for fr sequence  structure alignments , a user can enter the job i d of the ( independently generated ) fr results from the bioinfo meta server ( 16 ) or the fr inub server ( 17 ) .
fralanyzer displays a copy of the fr server results with an additional column labeled as  fralanyzer which consists of the pdb codes of the templates identified by the fr server .
a sequence  structure alignment is defined by selecting one of the pdb codes . for structure 
structure alignments , fralanyzer accepts the results of the vast server , which are displayed so that the user selects one of the templates as before .
we submitted the conserved hypothetical protein ef3048 to bioinfo , which returned the bioinfo i d 
49416. we used this i d as input to fralanyzer ( see http://fralanyzer.cse.buffalo.edu/samples/ for the initial output window as well as our online documentation files ) , and selected the first template ( pdb 1w1a ) . figure 1 shows the main fralanyzer output . along with the alignment ,
the sequence identity % and the secondary structure identity of the aligned query and template are shown ( 14 and 70% , respectively ) .
identical residues and identical secondary structure states in the query and template sequences are highlighted .
the secondary structure of the query and template are obtained from the fr server and/or pdbsum ( 18 ) . 

figure 1.fralanyzer results of the alignment of the conserved hypothetical protein ef3048 with the 3d - structure of pdaa protein ( pdb code 1w1a ) . the alignment was obtained from the bioinfo fr meta - server , ( job i d 49416 ) . for clarity ,
only the first 120 residues are shown ( see our  samples url for the full alignment ) .
the predicted secondary structures ( h and e ) of ef3048 are shown above its sequence .
pdbsum features of the template such as active site residues , contacts to metal and ligands are shown in separate rows and are marked as asterisks or hyphens .
1w1a belongs to the carbohydrate esterase family 4 , and contains a conserved d and 3  h residues ( d , h , h and h ) , which interact with the substrate .
other active site residues ( e.g. g ) annotated by pdbsum line the active site groove .
the fralanyzer results highlight the conservation of the residues d , g , h and h. the alignment also shows that h is shifted 2 residues from h in the query , probably due to a misalignment in the fr result .
thus , by quickly visualizing the fr alignment , we are able to derive a verifiable hypothesis that identifies ef3048 s catalytic residues d , h , h and h , suggesting that ef3048 is also a member of the carbohydrate esterase family 4 .
fralanyzer results of the alignment of the conserved hypothetical protein ef3048 with the 3d - structure of pdaa protein ( pdb code 1w1a ) .
the alignment was obtained from the bioinfo fr meta - server , ( job i d 49416 ) . for clarity ,
only the first 120 residues are shown ( see our  samples url for the full alignment ) .
the predicted secondary structures ( h and e ) of ef3048 are shown above its sequence .
pdbsum features of the template such as active site residues , contacts to metal and ligands are shown in separate rows and are marked as asterisks or hyphens .
1w1a belongs to the carbohydrate esterase family 4 , and contains a conserved d and 3  h residues ( d , h , h and h ) , which interact with the substrate .
other active site residues ( e.g. g ) annotated by pdbsum line the active site groove .
the fralanyzer results highlight the conservation of the residues d , g , h and h. the alignment also shows that h is shifted 2 residues from h in the query , probably due to a misalignment in the fr result .
thus , by quickly visualizing the fr alignment , we are able to derive a verifiable hypothesis that identifies ef3048 s catalytic residues d , h , h and h , suggesting that ef3048 is also a member of the carbohydrate esterase family 4 .
further automatic annotation of the alignment can be obtained from functional features of the template from the pdbsum and the swissprot databases ( 19 ) .
pdbsum functional features include consurf residue conservation , active site residues , prosite motifs , contacts to dna , ligands , metals and h - bonds to ligands .
to bring ( access the pdbsum site ) and  local copy ( access local copies instead , if they exist ) . in the present example
, the pdbsum features , active site residues , contacts to ligand , metal and hbonds to ligand are retrieved and the respective checkboxes are checked ( figure 1 ) .
each feature is displayed in a separate row with 1-letter amino acid of the template ( if present in the template ) or 
in addition , the functionally important positions that are conserved in the alignment ( aligned to identical residues in the query ) are further highlighted with vertical bars .
for example , see the template active site residues ( d , g , h and h ) highlighted in figure 1 .
other possible annotations include : catalytic csa , prosite patterns , ligand type or residue conservation .
the residue conservation of the template is displayed as colored bars according to the consurf ( 20 ) coloring scheme , where the most variable positions are colored turquoise , intermediately conserved positions are colored white and the most conserved positions are colored maroon .
the user can access further functional information for the template or the query from swissprot .
if selected , a blast search is executed to identify the swissprot sequences that are most similar ( if any ) .
features are extracted from the swissprot ft lines from entries having sequence identity > 90% . currently , fralanyzer has links to cognitor ( 21 ) , to meta - dp for domain prediction ( 22 ) and to meta - go for functional inference ( unpublished ) .
our example shown in figure 1 corresponds to a prediction for the hypothetical upf0249 protein ef3048 , a protein of unknown 3d - structure . to identify a compatible template and to generate a sequence  structure alignment
, we submitted this sequence to bioinfo , which identified the structure of the hydrolase pdaa ( pdb code 1w1a ; a carbohydrate esterase ) as a compatible template ( with a very reliable score ; see our  samples url ) . to determine whether any functional inference can be obtained
the alignment shows ( figure 1 ) that a number of the active site residues of 1w1a annotated in pdbsum are aligned to identical residues in the query .
based on this conservation of functionally important residues , the following hypothesis may be worthwhile to analyze in further detail : the conserved residues of ef3048 correspond to active site residues , and ef3048 is functionally related to the carbohydrate esterase family ( see legend of figure 1 ) .
the second example corresponds to a functional prediction obtained for the recently determined structure of a hypothetical protein of unknown function ( pdb code 1ylo ) .
fralanyzer was used to visualize the structural alignment and to identify possibly functional important residues in the query ( see our  samples url ) . based on the conservation of functionally important residues , a plausible hypothesis locating the active site residues of 1ylo and its possible function as a peptidase can be postulated .
currently , fralanyzer has links to cognitor ( 21 ) , to meta - dp for domain prediction ( 22 ) and to meta - go for functional inference ( unpublished ) .
our example shown in figure 1 corresponds to a prediction for the hypothetical upf0249 protein ef3048 , a protein of unknown 3d - structure . to identify a compatible template and to generate a sequence  structure alignment
, we submitted this sequence to bioinfo , which identified the structure of the hydrolase pdaa ( pdb code 1w1a ; a carbohydrate esterase ) as a compatible template ( with a very reliable score ; see our  samples url ) . to determine whether any functional inference can be obtained
the alignment shows ( figure 1 ) that a number of the active site residues of 1w1a annotated in pdbsum are aligned to identical residues in the query .
based on this conservation of functionally important residues , the following hypothesis may be worthwhile to analyze in further detail : the conserved residues of ef3048 correspond to active site residues , and ef3048 is functionally related to the carbohydrate esterase family ( see legend of figure 1 ) .
the second example corresponds to a functional prediction obtained for the recently determined structure of a hypothetical protein of unknown function ( pdb code 1ylo ) .
fralanyzer was used to visualize the structural alignment and to identify possibly functional important residues in the query ( see our  samples url ) . based on the conservation of functionally important residues , a plausible hypothesis locating the active site residues of 1ylo and its possible function as a peptidase can be postulated .
predicting functionally important residues of a protein of unknown function is a useful step in characterizing it .
an effective way to is to identify conserved functional key residues in an alignment with a template of known 3d - structure .
if an experimental structure exists for the query protein , the alignment can be obtained from structural alignments .
relevant functional features of the query can be predicted based on the functional features of the template .
fralanyzer automatically extracts important functional residues from annotated databases and displays them along with the sequence  structure alignment , highlighting the conserved positions .
this helps the user to quickly locate functionally important residues in the query , which in turn can help in its functional characterization .
fralanyzer can also be useful in the visualization of structural alignments to known templates of newly determined proteins of unknown function .
future versions may include links and automatic accesses to other annotated databases and servers , as well as graphical enhancements , faster response times and distinction between different types of ligands .
we describe fralanyzer ( fold recognition alignment analyzer ) , a new web tool to visually inspect sequence  structure alignments in order to predict functionally important residues in a query sequence of unknown function . 
 this tool is aimed at helping to infer functional relationships between a query sequence and a template structure , and is particularly useful in analyzing fold recognition ( fr ) results . 
 because similar folds do not necessarily share the same function , it is not always straightforward to infer a function from an fr result alone . 
 manual inspection of the fr sequence - structure alignment is often required in order to search for conservation of functionally important residues . 
 fralanyzer automates parts of this time - consuming process . 
 fralanyzer takes as input a sequence  structure alignment , automatically searches annotated databases , displays functionally significant residues and highlights the functionally important positions that are identical in the alignment . 
 fralanyzer can also be used with sequence - structure alignments obtained by other methods , and with structure  structure alignments obtained from structural comparison of newly determined 3d - structures of unknown function . 
 fralanyzer is available at http://fralanyzer.cse.buffalo.edu/.