the nucleic acid  protein interaction database ( npidb ) provides an access to information about all available structures of dna  protein and rna  protein complexes .
almost 4000 structures of such complexes are now available in the protein data bank [ pdb , ( 1 ) ] .
the npidb automatically extracts data from the pdb , then the data are presented through a user - friendly interface .
a number of tools for the analysis of interactions between protein and nucleic acid molecules are offered . among the tools
are the original program clud for analysis of hydrophobic clusters on interfaces ( 2,3 ) , the program hb - angles for detecting potential hydrogen bonds and water bridges and visualization of structures with jmol ( 4 ) .
the database includes a classification of nucleoprotein complexes based on protein domain families according to pfam ( 5 ) and structural classification of proteins [ scop ( 6 ) ] .
there are a number of online databases providing information on dna  protein or rna  protein complexes . the 3d - footprint ( 7 ) , http://floresta.eead.csic.es/3dfootprint , contains information on dna  protein complexes .
its functionality partially overlaps the functionality of the npidb . among the differences , we would like to mention the following .
inter - molecular interactions in the 3d - footprint are visualized as a number of schematic pictures , while the npidb provides visualization of interactions with jmol .
parts of biological units that are not presented explicitly in a pdb entry and should therefore be reconstructed by symmetry are not taken into account in the 3d - footprint . on the other hand ,
the 3d - footprint contains comparative information on dna  protein interfaces , providing , for example , a dendrogram of similar interfaces , position weight matrices illustrating the binding specificities and other tools .
it also allows searching the dna sequence motifs recognized by dna - binding proteins . the protein - dna interface database [ pdidb ( 8) ] , http://melolab.org/pdidb/web/content/home , contains descriptions of dna  protein interfaces for 922 x - ray dna  protein complexes with resolution better than 2.5  ( the npidb contains 1193 such complexes ) .
these complexes are partitioned into several classes according to function of proteins , the classes are further divided into types . for each complex ,
information on different types of contacts can be visualized or downloaded as a text table .
the protein - rna interface database [ pridb ( 9 ) ] , http://bindr.gdcb.iastate.edu/pridb , contains structural information on rna  protein complexes . biological interaction database for protein - nucleic acid [ bipa ( 10 ) ] , http://mordred.bioc.cam.ac.uk/bipa/ , contains both dna  protein and rna  protein complexes .
at the moment , the total number of complexes in the bipa is 2570 ( the npidb contains 3846 complexes ) .
information on inter - molecular contacts is presented in graphical mode only , not in a parsable format .
web server of protein - dna complex structure analyzer [ webpda ( 11 ) ] , http://bioinfozen.uncc.edu/webpda/ , contains data on contacts between dna and protein molecules in dna  protein complexes .
contacts are presented both via an online jmol applet and in a parsable text format .
the protein - dna recognition database ( http://gibk26.bio.kyutech.ac.jp/jouhou/3dinsight/recognition.html ) consists of three main parts : the protein - nucleic acid complex database ( pronuc ) , the database of base - amino acid interactions ( baint ) and the thermodynamic database for protein - nucleic acid interactions [ pronit , ( 12 ) ] .
the pronuc allows searching over protein  dna complexes by pdb code , name of protein , type of dna - recognizing motif and some other features .
the baint allows finding information on interaction of amino acids of a certain type ( e.g. lysine ) with dna nucleotides of a certain type .
the nucleic acid database [ ndb ( 13 ) ] , http://ndbserver.rutgers.edu/ , is focused on structure of nucleic acid molecules , not on their interaction with proteins .
a number of new features were added , among them : ( i ) a new search engine ; ( ii ) improved storage and visualization of different kinds of nucleic acid  protein interactions ; ( iii ) detection of pfam domains in new entries with hmm profiles ; ( iv ) classification of dna  protein interaction modes ; and ( v ) information on conserved water molecules at protein  nucleic acid interfaces .
structures of protein  nucleic acid complexes are extracted from the pdb as files in pdb format representing both pdb entries ( asymmetric units ) and biological units . for each biological unit of x - ray files and for first models of nuclear magnetic resonance files ,
the interactions of three kinds are considered , namely , hydrogen bonds , hydrophobic interactions and water bridges ( water molecules that form hydrogen bonds both with protein and dna ) . for each protein chain ,
its secondary structure is detected by stride ( 18 ) and stored in the database .
each protein chain of each structure is analysed to identify pfam and scop domains ( 5,6 ) .
pfam domains are determined by means of hidden markov model ( hmm ) profiles of the pfam database .
the profiles are downloaded from the pfam ftp site ( ftp://ftp.sanger.ac.uk/pub/databases/pfam/current_release ) . to search pfam domains in the sequences , hmmer ( 19 ) software downloaded from the web site ( http://hmmer.janelia.org/ ) and the pfamscan script ( ftp://ftp.sanger.ac.uk/pub/databases/pfam/tools/pfamscan.tar.gz )
information on scop domains is extracted by perl scripts from scop parsable files ( http://scop.mrc-lmb.cam.ac.uk/scop/parse/index.html ) , release 1.75 .
for each ( pfam or scop ) domain , a structure file in pdb format is created .
this file contains description of the domain itself and of segments of nucleic acid chains that are in contact with the domain .
sets of representatives of pfam and scop families ( one complex for each family containing at least one domain with a known x - ray structure ) are created and stored .
these representatives are chosen from the complexes with best resolution among all complexes representing each particular family .
namely , there are 1847 scop domains in contact with double - stranded dna with at least 10 complementary base pairs .
for each of these 110 families , all their representatives were extracted from the pdb , including those that were solved in the absence of dna .
the service pdbefold [ protein structure comparison service fold at european bioinformatics institute , http://www.ebi.ac.uk/msd-srv/ssm , ( 20 ) ] was used . in a number of cases ,
some families were divided into subfamilies ; this was done if it was impossible to superimpose the entire family with an appropriate quality . for each superimposed set of protein chains , the sequence alignment generated by pdbefold
the superimposed families are partitioned into interaction classes according to the modes of their dna 
the definition of each interaction class takes into account , first , the part of dna involved into the interaction and specificity of contacts , namely , specific contacts through major groove , specific contacts through minor groove or non - specific contacts , and , second , the contacting elements of protein secondary structure , namely , alpha helices , beta strands and other chain segments called  loops. to determine the interaction class of a family , we determine , first , the main dna groove ( major or minor ) involved in specific interaction , and , second , the secondary structure elements involved in specific interaction with the main groove . at this step , a human judgement is essential in a number of cases because family representatives may vary in minor additional interactions .
thus , we have the following groups of families : ( i ) the main groove is the major one , and the elements are helices only ; ( ii ) the main groove is the major one , and the elements are helices and loops and so on .
there are two grooves and seven possible combinations of three secondary structure elements ; hence , there are 14 possible groups . at the moment , each of these 14 groups is divided into two classes , depending on presence or absence of small specific interaction via the other , not the main one , dna groove
. additionally , there are two more interaction classes : one , with almost equal role of both grooves in specific interaction , and , second , with non - specific contacts only .
altogether , there are 30 possible classes , but only 20 classes are really represented by dna - recognizing protein domains . among these 20 classes ,
a total of 13 families belong to the class  main specific contacts via the dna major groove , some specific contacts via the dna minor groove , contacting protein elements : helices and loops , 12 families belong to the class  main specific contacts via the dna major groove , some specific contacts via the dna minor groove , contacting protein elements : helices , 11 families belong to the class  specific contacts via the dna major groove only , contacting protein elements : helices. some classes contain only one family each , for example , the class  specific contacts via the dna major groove and the dna minor groove in almost equal level contains only the family 
ten classes are not presented at all , among them are eight classes where beta strands , but not loops , are involved , and also the classes where specific contacts are with the dna minor groove only and among the contacting elements are helices and loops together .
the list of interaction classes is available on the npidb web site . for each interaction class ,
a set of representatives of families of the type ( the subset of best resolution representatives of all scop families ) is available .
for the 73 superimposed families of dna - binding protein domains , information on conserved positions of water molecules at dna  protein interface is computed with the wlake program ( 21 ) and stored in the npidb .
information about water molecules in pdb files is usually less precise and less confident than analogous information about atoms of protein or dna .
however , if a water molecule is presented in several structures of a same complex or a number of closely related complexes in approximately same place , then this molecule can be considered as confident and important .
that is why we revealed so - called  conserved water bridges that are water molecules at dna  protein interfaces in similar complexes that approximately coincide after superposition of macromolecules .
a detailed description of the procedure that reveals conserved water bridges is given in ( 21 ) . in brief , the procedure is as follows . as an input ,
the procedure uses a set of superimposed structures of protein domains from the given family .
thus , a set of similar structures placed in a common coordinate space is analysed .
a conserved water bridge is a set of water molecules from different structures such that : ( i ) the distance between any two water oxygen atoms in the common space is < 1.5  ; ( ii )
each water molecule is closer than 5  to a dna atom from the same or other structure ; and ( iii ) each water molecule is closer than 5  to a protein atom from the same or other structure . lists of conserved water bridges and their visualization are available at pages of correspondent scop families . for a number of pfam families (  hom_end , 
ets and some other ) , a manually created description of their interaction with dna is available .
all structural files of the npidb are downloadable , as well as tables of structures , domain families and interactions .
a perl script identifies chains of dna , rna and protein directly in the coordinate (  atom and  hetatm ) section of a pdb file .
if a pdb file contains at least one protein chain and at least one nucleic acid chain , then it is selected for incorporating into the npidb .
the search engine allows searching entries according to the following criteria : pdb i d , year of deposition in pdb , keywords (  header ,  title and  organism fields of the pdb ) , experimental method , resolution and type of the nucleic acid ( dna , rna or hybrid ) . for storing derived data , a relational database under mysql
the data include headers , titles and creation dates of pdb entries , types of chains , secondary structure of protein chains , data on protein  nucleic interaction and coordinates ( start  end ) of scop and pfam domains in protein chains . the main part of information
also , the database contains sequence files in fasta format and output files of stride and the programs computing interactions .
perl and python scripts are used for regular update of the content of the relational database and collection of data files .
other scripts generate dynamic web pages using data both from the relational database and from the data files .
hydrogen bonds and water bridges calculations are based on a statistical potential derived from analysis of all available 3d structures of macromolecules .
the potential for a hydrogen bond is the product of three factors : the first factor depends on the distance between the centres of the donor and acceptor atoms ; the second factor depends on the angle formed by the donor , the acceptor and the covalently bound neighbour of the donor ; the third factor analogously depends on the angle formed by the donor , the acceptor and the covalently bound neighbour of the acceptor .
a hydrogen bond is detected if the potential is > 0.1 , and the distance between the centres of the donor and acceptor atoms is < 3.7  .
a water bridge is detected if there exists a water molecule that forms hydrogen bonds both with the protein molecule and the nucleic acid molecule .
the program hb - angles performing the computations is written in c. for interactive visualization of individual hydrogen bonds and water bridges , javascript is used .
the program clud ( 2,3 ) for detecting hydrophobic clusters in macromolecular structures is integrated into the npidb .
the main principle of the program is obtaining clusters of hydrophobic atomic groups ( such as methyl groups of thymine or threonine ) that fill some volume and thus displace the solvent .
thus , clud outputs hydrophobic clusters rather than pairwise residue - to - residue hydrophobic interactions
. the clusters may include atoms not only from entirely hydrophobic residues ( e.g. leucine ) but also from hydrophobic parts of side chains of lysine , glutamine and so on .
the main optional parameter of clud is the threshold for the distance between centres of hydrophobic groups ( that are carbon and sulphur atoms ) ; at the moment , the threshold is set to 5.4  , which is the theoretically maximal distance allowing two non - polar groups to displace a water molecule ( it is the sum of two van der waals radii of methyl groups and the diameter of a water molecule ) .
there are four entry points to the content , namely , the list of all complexes , the list of pfam families , the list of scop families and the list of interaction classes of dna - recognizing scop domains .
pdb id ,  date ( the date of deposition to the pdb ) ,  pdb header , 
experimental method ,  resolution and  kind ( type of the nucleic acid : dna , rna or hybrid ) .
the table can be sorted according to any column with a click on the column header .
the page of each entry contains the following sections ( figure 1 ) : 
 general information ( pdb i d , title , pdb header , date , experimental method , resolution , type of nucleic acid and organism);quick links to other databases;composition of the pdb entry and biounits : chains of the protein and the nucleic acid and models;lists of pfam and scop domains presented in the entry;sequences of the chains with additional information : secondary structure and contacts with the nucleic acid for the protein chains and contacts with the protein for the nucleic acid chains . 
 for each biological unit ,
there are pages with information on interaction between molecules of the nucleic acid and the protein .
three types of interaction are presented , namely , hydrogen bonds ( figure 2 ) , water bridges and hydrophobic interactions .
general information ( pdb i d , title , pdb header , date , experimental method , resolution , type of nucleic acid and organism ) ; quick links to other databases ; composition of the pdb entry and biounits : chains of the protein and the nucleic acid and models ; lists of pfam and scop domains presented in the entry ; sequences of the chains with additional information : secondary structure and contacts with the nucleic acid for the protein chains and contacts with the protein for the nucleic acid chains . a screenshot of the page of the complex 3exj . a screenshot of the page that shows hydrogen bonds in the complex 1a1k .
pfam id ,  domain ( short description of the family from pfam ) ,  number of entries ( number of complexes with representatives of the family ) ,  number of domains ( number of domains from the family in all complexes ) ,  number of bound domains ( number of domains bound to dna or rna ) .
the page of each family contains the list of entries ( with hyperlinks to entries pages ) . for a number of families ( for example , for 
the list of scop families is designed as a tree of scop classes , folds , superfamilies and families .
a hyperlink from each family name leads to a page containing a table analogous to a table of a pfam family , and , for a number of families of dna - recognizing domains contacting with a long ( > 10 bp ) double - stranded dna , a description of the family .
the description includes a structural superposition of all representatives of the family in the pdb , the corresponding multiple amino acid sequence alignment and an information on conserved water bridges on the protein  dna interface .
the list of interaction classes of dna - recognizing scop domains contains hyperlinks to lists of scop families whose representatives demonstrate the certain mode of dna  protein interaction .
russian foundation of basic research [ grant 10 - 07 - 00685-a and joint grant with german research foundation 
 11 - 04 - 91340 ] ; ministry of education and science of the russian federation [ state contract no . 07.514.11.4006 ] .
 the nucleic acid  protein interaction database ( http://npidb.belozersky.msu.ru/ ) contains information derived from structures of dna  protein and rna  protein complexes extracted from the protein data bank ( 3846 complexes in october 2012 ) . 
 it provides a web interface and a set of tools for extracting biologically meaningful characteristics of nucleoprotein complexes . 
 the content of the database is updated weekly . the current version of the nucleic acid  
 protein interaction database is an upgrade of the version published in 2007 . 
 the improvements include a new web interface , new tools for calculation of intermolecular interactions , a classification of scop families that contains dna  binding protein domains and data on conserved water molecules on the dna  protein interface . 