- Open Access
Defining and searching for structural motifs using DeepView/Swiss-PdbViewer
© Johansson et al.; licensee BioMed Central Ltd. 2012
- Received: 15 September 2011
- Accepted: 6 July 2012
- Published: 23 July 2012
Today, recognition and classification of sequence motifs and protein folds is a mature field, thanks to the availability of numerous comprehensive and easy to use software packages and web-based services. Recognition of structural motifs, by comparison, is less well developed and much less frequently used, possibly due to a lack of easily accessible and easy to use software.
In this paper, we describe an extension of DeepView/Swiss-PdbViewer through which structural motifs may be defined and searched for in large protein structure databases, and we show that common structural motifs involved in stabilizing protein folds are present in evolutionarily and structurally unrelated proteins, also in deeply buried locations which are not obviously related to protein function.
The possibility to define custom motifs and search for their occurrence in other proteins permits the identification of recurrent arrangements of residues that could have structural implications. The possibility to do so without having to maintain a complex software/hardware installation on site brings this technology to experts and non-experts alike.
- Structural Motif
- Distance Constraint
- Common Structural Motif
- Anthrax Protective Antigen
- Lower Distance Bound
The three-dimensional structure of proteins has been an extensively studied topic for several decades. More than fifty years ago, Pauling and Corey described the two dominant forms of secondary structure, the α-helix and the β-sheet . Subsequently, a variety of further patterns and regularities (e.g., [2–4]) in protein structures have been found, that have proven useful in the context of protein structure determination and quality assessment of determined structures. During the last twenty years, increasingly sophisticated methods for secondary structure prediction [5, 6], fold recognition and comparison (e.g., FSSP , THREADER , FOLDFIT , and others [10–12] have been developed, followed by methods for fold classification, such as SCOP  and CATH . More or less simultaneously, methods were developed for identifying and searching for structural similarities involving limited numbers of amino acid residues (e.g., [15–19]), and more recently for the prediction of protein function, or functional groups, through recognition of geometrical patterns that involve small numbers of residues (e.g., [18, 20–25]).
Quite a few of the previously mentioned patterns and regularities in protein structures, and the associated methods for detecting them, in particular, have constraints and limitations that make them ill-suited to searching for general structural motifs, such as only dealing with sequentially compact fragments , only considering amino-acids that are conserved among homologous proteins , or restricted to small subsets of atom types (i.e., N, Cα and C’ , Cα and Cβ , and Cα and pseudo atom at side-chain centre of gravity ). What is much more important from a practical usability perspective, however, is the fact that none of the mentioned methods have been well integrated into any comprehensive and widely available molecular graphics software package. Our purpose in this paper is to present the mechanisms and facilities whereby structural motifs can be defined and searched for using the freely available and well established modelling tool Swiss-PdbViewer , and to present illustrative examples of the types of information that can be obtained by doing so. In particular, the facilities for defining and searching for structural motifs now available in Swiss-PdbViewer include an interactive visual interface for defining structural motifs, and a machinery that is able to quickly search very large collections of structures for such motifs. Finally, to our knowledge, the presented structure-search machinery is the only one to permit arbitrary combinations of amino-acid-type constraints, secondary structure constraints, distance constraints, and sequence separation constraints.
The main reason for our interest in general (i.e., sequentially non-contiguous) structural motifs, is the crucial role played by side-chains in the correct packing of proteins. In the context of structural protein modelling, slight differences in backbone conformations may accommodate entirely different combinations of side-chain conformations , and inadequate sampling of conformational space typically leads to suboptimal conformations being found, which in turn leads to a degradation of model quality as artificially loose protein cores are formed in order to leave more space for side-chains . Side-chain conformations are not currently given sufficient consideration, and new approaches need to be pursued in order to make it possible to do so.
and thus increases at least exponentially with respect to k (for k < ⌊m/2⌋) and as a kth-order polynomial with respect to m. Although the number of operations needed to compute one single rmsd-value grows linearly with motif size and would thus not be a limiting factor, the overall number of computations necessary to evaluate the superposition of a k-residue motif loosely defined with respect to sequence constraints onto all possible combinations of k-residues drawn from a structure can nonetheless become noticeable in practice.
Furthermore, the rmsd measure is also in itself problematic in the present context, because values implying a meaningful degree of molecular similarity vary with the number and type of amino acid residues or atoms being used, and is also quite sensitive to outliers. This problem has been addressed by several authors [31–33], but the solutions proposed tend to involve empirically determined parameters and/or probability distributions that depend on the number of atoms involved and the presence or absence of chemical bonds between said atoms. In contexts where the number and types of amino acid residues in motifs as well as the sequential distance between residues in motifs will be highly variable, and the collection of protein structures participating in the analysis is allowed to vary (the pdb database is itself a constantly changing entity) it appears that making effective use of the mentioned methods for judging rmsd-values would be difficult. These well known issues with the rmsd measure have also prompted the assessors of the CASP community to develop more robust metrics to judge the quality of models . The reasons mentioned above prompted us to choose a different approach than rmsd to identify atom configurations that satisfy a motif specification.
The structural similarity measure so obtained has more or less the same shortcomings as rmsd-values when it comes to interpreting its meaning. In addition thereto, the computations implied by Eqs. (3) and (4) require at least n2 operations, and it is thereby computationally more expensive than calculating rmsd values, for large values of n.
for all (i,j) ∈ S. Defining motifs through upper and lower distance bounds as just described is intuitively straightforward and flexible with respect to which distances to constrain and what constrains to impose on each such distance. For collections of amino acids that are sufficiently small to reappear in multiple unrelated protein structures (i.e., ⪅ 10 aa), it is feasible in practice to search for motifs defined through sets of distance constraints despite the large number of potential combinations implied by Eqn. (2), in part because the set S of constrained distances is typically rather small, and in part because candidate configurations may be rejected upon detection of the first constraint violation. For the reasons mentioned, sets of distance constraints are used to specify the geometric aspects of motifs in Swiss-PdbViewer.
The program Swiss-PdbViewer (a.k.a. DeepView)  was designed to integrate functions for protein structure visualization, analysis and manipulation into a sequence-to-structure workbench with a user-friendly interface. It allows the user to manage complex modelling projects, and Swiss-PdbViewer has been augmented with facilities whereby general structural motifs may be defined and subsequently searched for in a collection of structures (through a web server at the Vital-IT Center for High-Performance Computing of the Swiss Institute of Bioinformatics).
As one example of how to use Swiss-PdbViewer for motif searches, we use the His/Asp/Ser catalytic triad of trypsin from Atlantic salmon (pdb: 1a0j, 1.7 Å resolution). To search for a structural motif such as that represented by His57/Asp102/Ser195, an appropriate set of constraints must be specified. This can be done interactively from within Swiss-PdbViewer by measuring a freely chosen collection of distances (after having opened a pdb structure file, distance measurement mode is activated by clicking on the icon labelled “1.5 Å”. Individual distances are measured by picking pairs of atoms in the structure display window, which is displayed when opening a pdb-file. Distance measurement mode is exited by pressing the keyboard's escape key), as illustrated in Figure 1A, and subsequently selecting the item “Generate 3D Motif from Current Selection …” in the “Tools” menu. Alternatively, programs external to Swiss-PdbViewer can be used to generate motif specifications that can subsequently be opened into Swiss-PdbViewer and used in 3D motif searches as described below. One such program external to Swiss-PdbViewer (the perl-script make-spdbv-motif) is provided in Additional file 1. Since both methods described create motif specifications from existing structures, it is guaranteed that at least one structure satisfying the specification exists. Finally, regardless of which of the two different methods for defining motifs that is used, motif specifications may at present comprise a maximum of 32 groups/residues and up to 150 distance constraints, with a maximum of 31 distance constraints between each pair of residues. The mentioned limits on groups/residues and distance constraints in motif specifications do not represent inherent limitations of the method or its implementation. The limits may be increased in future releases of Swiss-PdbViewer.
A sample motif specification, corresponding to the His/Asp/Ser structural motif, is shown in Figure 1B. As can be seen, motif specifications consist of three parts, each dealing with particular and distinct aspects of the motif, and given by lines of text starting with one of three characteristic keywords (GROUP, DIST or DELTA). In the first part of a motif specification (lines 5–7 in Figure 1B) each residue in the motif is uniquely associated with a numeric group label, followed by residue type and secondary structure restrictions (one of h, s, c, *, hs, hc, or sc, with * meaning no restriction) that need to be satisfied by corresponding residues in actual structures. The alphabetic characters used to specify secondary structure restrictions have the following meanings: h = helix, s = strand, c = coil, and sequences of such characters as well as sequences of single character residue-type abbreviations are seen as being implicitly separated by logical disjunctions. In the second part of a motif specification (lines 10–19 in Figure 1B) distance constraints in Ångström are given that need to hold between specific atoms of the motif residues. The atoms involved in distance constraints are identified by a group label (as given in the first section) and pdb-format atom names, and this is followed by three numeric values, corresponding to the least, measured and greatest distance, respectively. When motif specifications are defined interactively, as described in the previous paragraph, users are prompted to enter a tolerance value (x), and the greatest and least value of each distance constraint is set to the distance measured ±x Å, (or ± x%) respectively. However, all aspects of a motif specification may be further altered using a conventional text editor. In the third part of a motif specification (lines 22–23 in Figure 1B) sequence separation constraints can be given for the residue labels given in the first part of the motif specification. In each sequence-separation constraint, column two and three specify the group labels of the groups between which the constraint shall hold, and columns four and five contain the minimum and maximum sequence separation between the groups in question. Sequence separation constraints are present in motif specifications because it is often desirable to impose restrictions of this kind, but doing so is not a requirement. To avoid imposing sequence separation constraints, corresponding upper limits can be set arbitrarily high (and lower limits set to zero), or the line of text specifying the constraint in question can be left out of the motif specification altogether.
Given a motif specification, individual pdb files as well as a collection of pdb files can be searched for constellations of atoms and amino acid residues that satisfy the constraints in the motif specification. Both of these alternatives are available from within Swiss-PdbViewer, by selecting the item “Search 3D Motif in Current Layer…” or the item “Submit 3D Motif Search Against Subset of PDB…”, both of which are located in the “Tools” menu. The collection of PDB structures currently searched when selecting the second item is the set of 13180 90% non-redundant X-ray structures first mentioned in the section “Common structural motifs in related proteins” above, and in forthcoming releases of Swiss-PdbViewer further PDB-subsets to search will be provided. Submitting a search against a subset of the PDB typically yields a list of hits, for which the constraints of the motif specification used were satisfied.
Upon completion of a search, one line of text is displayed for each combination of residues found to satisfy the constraints of the motif specification used. By clicking on a result line corresponding to a search hit, the appropriate pdb file is loaded into Swiss-PdbViewer and by performing a “Search in Current Layer”, the corresponding residues are selected. It is then easy to superpose the loaded structures and display only the selected residues. The selected residues of each structure are superposed by selecting the item “Fit molecules (from selection)”, located in the “Fit” menu. Through a dialog box, the user is then given the choice of superposing “Carbon Alpha Only”, “Backbone Atoms Only”, “Sidechain Atoms Only” or “All Atoms”, and to select the reference structure onto which the others will be superposed as well as which other structures that are to be superposed onto the reference structure. If not already displayed, an alignment of the amino-acid sequences of loaded structures, with selected residues highlighted, is displayed by selecting the item “Alignment” located in the “Wind” menu. For the purpose of defining and searching for structural motifs, Swiss-PdbViewer is thus a flexible tool, with which the inspection and evaluation of search-results is made easier since sets of residues satisfying structural motifs are kept track of and highlighted in various contexts. In addition, it is of course also possible to analyze or manipulate selected structures and/or substructures using the battery of other tools available for this purpose in Swiss-PdbViewer.
Searching for 3–6-residue motifs in a database of 13180 structures (vide infra) takes 80–100 seconds of wall-clock time on a single 2.8 GHz Intel Xeon type processor. The by far most costly part of searches is the reading of files containing molecular structures, and the variations in measured execution times appear not to be correlated with motif size, but instead most likely caused by variations in I/O throughput.
Common structural motifs in related proteins
As a first example of a structural motif, we consider the well-known His/Asp/Ser catalytic triad of trypsin (Figure 1A). Using the coordinates of 1a0j, a motif specification such as that shown in Figure 1B, was created interactively using Swiss-PdbViewer. A search for the generated motif specification was performed across a collection of pdb structures (13180 90% non-redundant X-ray structures having a resolution of 3.0 Å or better obtained by using the PISCES sequence culling server [38, 39]). A total of 33 sets of atom coordinates satisfying the motif-specification were found, located in 25 uniquely named structures. This corresponds to all structures (and all catalytic triads) present in our database that are related to 1a0j, in the sense of having a blast  expectation value (pre-calculated E-value tables were downloaded from rcsb.org) less than 10.0 (the maximum blast E-value observed among these was 1.08·10-25). When the search is repeated with all distance constraint error tolerances increased from 1.0 Å to 2.0 Å, the same 33 sets of atom coordinates from 25 uniquely named pdb structures were obtained, indicating that the identified geometric configuration is indeed present as a distinct motif in the corresponding structures.
Common structural motifs in unrelated proteins
Our third example of structural motifs, concerns pig insulin. Functional residues are evolutionarily conserved in proteins, and we assumed that residues that contribute to the folding and/or stability of a protein region are also good candidates for conservation. As a part of investigations with a different purpose, residues of importance for the stability of the pig insulin fold have been identified using CMEPS  and FOLDEF . According to these results, LeuB11 and LeuB15 (pdb id: 4ins, chain B) are among the most important for fold stability, with the structural neighbors TyrB26 and ValB12 being identified as potential contributor and non-contributor to fold stability, respectively. The importance of ValB12 is on the other hand suggested by experimental results .
A motif specification was designed based on LeuB11, ValB12, LeuB15 and TyrB26 in pig insulin (pdb: 4ins, 1.5 Å resolution), with the strict 11-residue sequence separation constraint between the 3rd and 4th residue of the motif loosed by permitting deviations of ±25 (Additional file 3, line 22). As the result of this search, the very same spatial constellation of Leu, Val, Leu and Tyr was found to be present in the His6 enzyme from Saccharomyces cerevisiae (, pdb: 2agk).
When the CMEPS- and FOLDEF-calculations mentioned above are repeated for pdb id 2agk, the residues Leu193, Leu197 and Tyr211 (corresponding to LeuB11, LeuB15 and TyrB26, respectively, in 4ins) were identified as the most important for fold stability and Val194 was identified as a potential contributor to fold stability (Additional file 5).
The purpose of the examples given above is to illustrate some of the possibilities available when searching for structural motifs using Swiss-PdbViewer. Neither example is intended to be a comprehensive treatment of the corresponding topic (e.g., searching for calcium-binding motifs). Furthermore, searching for structural motifs should not in itself be expected to be competitive with methods developed for and dedicated to identifying specific properties of proteins, such as being calcium-binding [48, 49], zinc-binding [50, 51], exhibiting catalytic activity , etc. In particular, methods dedicated to identifying specific properties of proteins are often based on machine-learning techniques and make extensive use of sets of parameters chosen and parameter-values tuned for the specific problem being addressed (e.g., [50, 51]).
The examples given above also show that searches for structural motifs can be set up in different ways. Choices of atom-type pairs between which to impose distance constraints, distance constraint tolerance limits, etc., can obviously depend both on what is being searched for and the quality of the structures that are searched. Since motif specifications are text files, they can easily be edited (using conventional text editors) to fit particular user requirements prior to starting/submitting the search. For example, the strict requirement of having an aspartate for the third residue of the motif presented in Additional file 1 could be relaxed to also tolerating an asparagine simply by changing the D to DN. Likewise, individual distance constraints can be tightened or relaxed at will.
As is clearly demonstrated by the examples we have presented, common structural motifs are indeed present and possible to find in evolutionarily and structurally unrelated protein structures in the Protein Data Bank . For the observed motifs, backbone rmsd-values are less than 0.5 Å, which is less than that typically observed across the ensemble for atoms in protein structures determined by NMR spectroscopy [54, 55]. Thus, considering the similar geometric configurations of amino acid residues that we have observed in different structures to be instances of common motifs, is well justified.
Previous studies of sequentially non-contiguous structural motifs have been almost exclusively concerned with functional groups on the surfaces of proteins. By contrast, we have also observed structural motifs that exist deeply buried in the interiors of structures (third and fourth example above).
Considering the relative ease with which the given examples were found, we expect such motifs to be a frequently occurring phenomenon. A large number of unanswered questions remain, however. For example, how many such motifs are present on average in each protein structure? In how many distinct structures is a specific motif typically present?, etc. Due to the crucial role of side-chain packing in native protein structures, we suspect that structural motifs may become useful for protein structure prediction and refinement.
Investigations to address the questions posed above, as well as to evaluate the usefulness of structural motifs for structure prediction and refinement are currently underway. Irrespectively, however, it is already clear that the mechanisms to search for structural motifs integrated into DeepView/Swiss-PdbViewer is a useful and valuable tool. The processing time to search for structural motifs of potentially interesting kinds is sufficiently small that it can be used as a standard technique whenever the kinds of information illustrated by our examples would be useful. Furthermore, thanks to being integrated into DeepView/Swiss-PdbViewer, structural motifs can not only be defined by running external programs, but can also be interactively defined with direct visual feedback, from within DeepView/Swiss-PdbViewer. Finally, structure searches, irrespectively of how motifs have been defined, are submitted from within DeepView/Swiss-PdbViewer, so that anyone can benefit from this searching capability without having to maintain a complex hardware/software installation.
Project name: Swiss-PdbViewer
Operating system(s): Microsoft Windows and Mac OS X
Programming language: ANSI C
Other requirements: None
License: freely available in binary/executable form.
Any restrictions to use by non-academics: No
The computations were performed at the Vital-IT (http://www.vital-it.ch) Center for High-Performance Computing of the Swiss Institute of Bioinformatics. This work was supported by the Swiss National Science Foundation [grant number 31003A_125098]. We thank the two anonymous reviewers for their useful comments and suggestions.
- Pauling L, Corey RB: Stable configurations of polypeptide chains. Proc R Soc Lond. 1953, B141: 21-33.View ArticleGoogle Scholar
- Ramachandran GN, Ramakrishnan C, Sasisekharan V: Stereochemistry of polypeptide chain configurations. J Mol Biol. 1963, 7: 95-99. 10.1016/S0022-2836(63)80023-6.View ArticlePubMedGoogle Scholar
- Venkatachalam CM: Stereochemical criteria for polypeptides and proteins. V. Conformation of a system of three linked peptide units. Biopolymers. 1968, 6: 1425-1436. 10.1002/bip.1968.360061006.View ArticlePubMedGoogle Scholar
- Kabsch W, Sander C: Dictionary of protein secondary structure: pattern recognition of hydrogen bonded and geometrical features. Biopolymers. 1983, 22: 2577-2637. 10.1002/bip.360221211.View ArticlePubMedGoogle Scholar
- Jones DT: Protein secondary structure prediction based on position-specific scoring matrices. J Mol Biol. 1999, 292: 195-202. 10.1006/jmbi.1999.3091.View ArticlePubMedGoogle Scholar
- Rost B, Sander C, Schneider R: PHD – an automatic mail server for protein secondary structure prediction. Comput Appl Biosci. 1994, 10: 53-60.PubMedGoogle Scholar
- Holm L, Sander C: Touring protein fold space with Dali/FSSP. Nucleic Acids Res. 1998, 26: 316-319. 10.1093/nar/26.1.316.PubMed CentralView ArticlePubMedGoogle Scholar
- Jones DT, Taylor WR, Thornton JM: A new approach to protein fold recognition. Nature. 1992, 358: 86-89. 10.1038/358086a0.View ArticlePubMedGoogle Scholar
- Russel RB, Saqi MA, Bates PA, Sayle RA, Sternberg MJ: Recognition of analogous and homologous protein folds – assessment of prediction success and associated alignment accuracy using empirical substitution matrices. Protein Eng. 1998, 11: 1-9. 10.1093/protein/11.1.1.View ArticleGoogle Scholar
- Holm L, Sander C: Searching protein structure databases has come of age. Proteins. 1994, 19: 165-173. 10.1002/prot.340190302.View ArticlePubMedGoogle Scholar
- Mizuguchi K, Deane CM, Blundell TL, Overington JP: HOMSTRAD: a database of protein structure alignments for homologous families. Protein Sci. 1998, 7: 2469-2471. 10.1002/pro.5560071126.PubMed CentralView ArticlePubMedGoogle Scholar
- Shindyalov IN, Bourne PE: A database and tools for 3-D protein structure comparison and alignment using the Combinatorial Extension (CE) algorithm. Nucleic Acids Res. 2001, 29: 228-229. 10.1093/nar/29.1.228.PubMed CentralView ArticlePubMedGoogle Scholar
- Murzin AG, Brenner SE, Hubbard T, Chothia C: SCOP: a structural classification of proteins database for the investigation of sequences and structures. J Mol Biol. 1995, 247: 536-540.PubMedGoogle Scholar
- Orengo CA, Michie AD, Jones S, Jones DT, Swindells MB, Thornton JM: CATH – a hierarchic classification of protein domain structures. Structure. 1997, 5: 1093-1108. 10.1016/S0969-2126(97)00260-8.View ArticlePubMedGoogle Scholar
- Oldfield TJ: Creating structure features by data mining the PDB to use as molecular-replacement models. Acta Cryst. 2001, D57: 1421-1427.Google Scholar
- Russell RB: Detection of protein three-dimensional side-chain patterns: new examples of convergent evolution. J Mol Biol. 1998, 279: 1211-1227. 10.1006/jmbi.1998.1844.View ArticlePubMedGoogle Scholar
- Pennec X, Ayache N: A geometric algorithm to find small but highly similar 3D substructures in proteins. Bioinformatics. 1998, 14: 516-522. 10.1093/bioinformatics/14.6.516.View ArticlePubMedGoogle Scholar
- Debret G, Martel A, Cuniasse P: RASMOT-3D PRO: a3D motif search webserver. Nucleic Acids Res. 2009, 37 (Suppl. 2): W459-464.PubMed CentralView ArticlePubMedGoogle Scholar
- Kleywegt GJ: Recognition of spatial motifs in protein structures. J Mol Biol. 1999, 285: 1887-1897. 10.1006/jmbi.1998.2393.View ArticlePubMedGoogle Scholar
- Rigden DJ, Galperin MY: The DxDxDG motif for calcium binding: multiple structural contexts and implications for evolution. J Mol Biol. 2004, 343: 971-984. 10.1016/j.jmb.2004.08.077.View ArticlePubMedGoogle Scholar
- Pal D, Eisenberg D: Inference of protein function from protein structure. Structure. 2005, 13: 121-130. 10.1016/j.str.2004.10.015.View ArticlePubMedGoogle Scholar
- Torrance JW, Bartlett GJ, Porter CT, Thornton JM: Using a library of structural templates to recognise catalytic sites and explore their evolution in homologous families. J Mol Biol. 2005, 347: 565-581. 10.1016/j.jmb.2005.01.044.View ArticlePubMedGoogle Scholar
- Laskowski RA, Watson JD, Thornton JM: Protein function prediction using local 3D templates. J Mol Biol. 2005, 351: 614-626. 10.1016/j.jmb.2005.05.067.View ArticlePubMedGoogle Scholar
- Gold ND, Jackson RM: Fold independent structural comparisons of protein-ligand binding sites for exploring functional relationships. J Mol Biol. 2006, 355: 1112-1124. 10.1016/j.jmb.2005.11.044.View ArticlePubMedGoogle Scholar
- Fetrow JS, Siew N, Skolnick J: Structure-based functional motif identifies a potential disulfide oxidoreductase active site in the serine/threonine protein phosphatase-1 subfamily. FASEB J. 1999, 13: 1866-74.PubMedGoogle Scholar
- Guex N, Peitsch MC: SWISS-MODEL and the Swiss-PdbViewer: an environment for comparative protein modeling. Electrophoresis. 1997, 18: 2714-2723. 10.1002/elps.1150181505.View ArticlePubMedGoogle Scholar
- Misura KM, Chivian D, Rohl CA, Kim DE, Baker D: Physically realistic homology models built with ROSETTA can be more accurate than their templates. Proc Natl Acad Sci. 2006, 103: 5361-5366. 10.1073/pnas.0509355103.PubMed CentralView ArticlePubMedGoogle Scholar
- Das R, Qian B, Raman S, Vernon R, Thompson J, Bradley P, Khare S, Tyka MD, Bhat D, Chivian D, Kim DE, Sheffler WH, Malmström L, Wollacott AM, Wang C, André I, Baker D: Structure prediction for CASP7 targets using extensive all-atom refinement with Rosetta@home. Proteins. 2007, 69: 118-128. 10.1002/prot.21636.View ArticlePubMedGoogle Scholar
- Hanson RJ, Norris MJ: Analysis of measurements based on the singular value decomposition. SIAM J Sci and Stat Comput. 1981, 2: 363-373. 10.1137/0902029.View ArticleGoogle Scholar
- Arun K, Huang T, Blostein S: Least-squares fitting of two 3-d point sets. IEEE Trans Pattern Anal Mach Intell. 1987, 9: 698-700.View ArticlePubMedGoogle Scholar
- Barker JA, Thornton JM: An algorithm for constraint-based structural template matching: application to 3D templates with statistical analysis. Bioinformatics. 2003, 19: 1644-1649. 10.1093/bioinformatics/btg226.View ArticlePubMedGoogle Scholar
- Hamelryck T: Efficient identification of side-chain patterns using a multidimensional index tree. Proteins. 2003, 51: 96-108. 10.1002/prot.10338.View ArticlePubMedGoogle Scholar
- Stark A, Sunyaev S, Russel RB: A model for statistical significance of local similarities in structure. J Mol Biol. 2003, 326: 1307-1316. 10.1016/S0022-2836(03)00045-7.View ArticlePubMedGoogle Scholar
- Zemla A, Venclovas C, Moult J, Fidelis K: Processing and analysis of CASP3 protein structure predictions. Proteins. 1999, S3: 22-29.View ArticleGoogle Scholar
- Sippl MJ: On the problem of comparing protein structures. Development and applications of a new method for the assessment of structural similarities of polypeptide conformations. J Mol Biol. 1982, 156: 359-388. 10.1016/0022-2836(82)90334-5.View ArticlePubMedGoogle Scholar
- Holm L, Sander C: Protein structure comparison by alignment of distance matrices. J Mol Biol. 1993, 233: 123-138. 10.1006/jmbi.1993.1489.View ArticlePubMedGoogle Scholar
- Crippen GM, Havel TF: Distance Geometry and Molecular Conformation. 1988, Research Studies Press, Taunton, EnglandGoogle Scholar
- Wang G, Dunbrack RL: PISCES: a protein sequence culling server. Bioinformatics. 2003, 19: 1589-1591. 10.1093/bioinformatics/btg224.View ArticlePubMedGoogle Scholar
- Wang G, Dunbrack RL: PISCES: recent improvements to a PDB sequence culling server. Nucleic Acids Res. 2005, 33 (Suppl 2): W94-W98.PubMed CentralView ArticlePubMedGoogle Scholar
- Altschul SF, Madden TL, Schäffer AA, Zhang J, Zhang Z, Miller W, Lipman DJ: Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. Nucleic Acids Res. 1997, 25: 3389-3402. 10.1093/nar/25.17.3389.PubMed CentralView ArticlePubMedGoogle Scholar
- Houdusse A, Gaucher JF, Krementsova E, Mui S, Trybus KM, Cohen C: Crystal structure of apo-calmodulin bound to the first two IQ motifs of myosin V reveals essential recognition features. Proc Natl Acad Sci. 2006, 103: 19326-19331. 10.1073/pnas.0609436103.PubMed CentralView ArticlePubMedGoogle Scholar
- Zoete V, Meuwly M: Importance of individual side chains for the stability of a protein fold: computational alanine scanning of the insulin monomer. J Comput Chem. 2006, 27: 1843-1857. 10.1002/jcc.20512.View ArticlePubMedGoogle Scholar
- Guerois R, Nielsen JE, Serrano L: Predicting changes in the stability of proteins and protein complexes: a study of more than 1000 mutations. J Mol Biol. 2002, 320: 369-387. 10.1016/S0022-2836(02)00442-4.View ArticlePubMedGoogle Scholar
- Kristensen C, Kjeldsen T, Wiberg FC, Schäffer L, Hach M, Havelund S, Bass J, Steiner DF, Andersen AS: Alanine scanning mutagenesis of insulin. J Biol Chem. 1997, 272: 12978-12983. 10.1074/jbc.272.20.12978.View ArticlePubMedGoogle Scholar
- Quevillon-Cheruel S, Leulliot N, Graille M, Blondeau K, Janin J, van Tilbeurg H: Crystal structure of the yeast His6 enzyme suggests a reaction mechanism. Protein Sci. 2006, 15: 1516-1521. 10.1110/ps.062144406.PubMed CentralView ArticlePubMedGoogle Scholar
- Opazo JC, Soto-Gamboa M, Bozinovic F: Blood glucose concentration in caviomorph rodents. Comp Biochem Physiol Part A. 2004, 137: 57-64. 10.1016/j.cbpb.2003.09.007.View ArticleGoogle Scholar
- Schymkowitz J, Borg J, Stricher F, Nys R, Rousseau F, Serrano L: The FoldX web server: an online force field. Nucleic Acids Res. 2005, 33 (Suppl 2): W382-W388.PubMed CentralView ArticlePubMedGoogle Scholar
- Liang MP, Banatao DR, Klein TE, Brutlag DL, Altman RB: WebFEATURE: an interactive web tool for identifying and visualizing functional sites on macromolecular structures. Nucleic Acids Res. 2003, 31: 3324-3327. 10.1093/nar/gkg553.PubMed CentralView ArticlePubMedGoogle Scholar
- Wei L, Altman RB: Recognizing protein binding sites using statistical descriptions of their 3D environments. Pac Symp Biocomput. 1998, 3: 497-508.Google Scholar
- Ebert JC, Altman RB: Robust recognition of zinc binding sites in proteins. Protein Sci. 2008, 17: 54-65.PubMed CentralView ArticlePubMedGoogle Scholar
- Zhao W, Xu M, Liang Z, Ding B, Niu H, Teng M: Structure-based de novo prediction of zinc-binding sites in proteins of unknown function. Bioinformatics. 2011, 27: 1262-1268. 10.1093/bioinformatics/btr133.View ArticlePubMedGoogle Scholar
- Bagley SC, Altman RB: Conserved features in the active site of nonhomologous serine proteases. Fold Des. 1996, 1: 371-379. 10.1016/S1359-0278(96)00052-1.View ArticlePubMedGoogle Scholar
- Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE: The Protein Data Bank. Nucleic Acids Res. 2000, 28: 235-242. 10.1093/nar/28.1.235.PubMed CentralView ArticlePubMedGoogle Scholar
- Güntert P: Structure calculation of biological macromolecules from NMR data. Q Rev Biophys. 1998, 31: 145-237. 10.1017/S0033583598003436.View ArticlePubMedGoogle Scholar
- Andrec M, Snyder DA, Zhou Z, Young J, Montelione GT, Levy RM: A large data set comparison of protein structures determined by crystallography and NMR: statistical test for structural differences and the effect of crystal packing. Proteins. 2007, 69: 449-465. 10.1002/prot.21507.View ArticlePubMedGoogle Scholar
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