A procedure for detecting structural domains in proteins.

A procedure is described for detecting domains in proteins of known structure. The method is based on the intuitively simple idea that each domain should contain an identifiable hydrophobic core. By applying the algorithm described in the companion paper (Swindells MB, 1995, Protein Sci 4:93-102) to identify distinct cores in multi-domain proteins, one can use this information to determine both the number and the location of the constituent domains. Tests have shown the procedure to be effective on a number of examples, even when the domains are discontinuous along the sequence. However, deficiencies also occur when hydrophobic cores from different domains continue through the interface region and join one another.     

POLYVIEW: a flexible visualization tool for structural and functional annotations of proteins

The POLYVIEW visualization server can be used to generate protein sequence annotations, including secondary structures, relative solvent accessibilities, functional motifs and polymorphic sites. Two-dimensional graphical representations in a customizable format may be generated for both known protein structures and predictions obtained using protein structure prediction servers. POLYVIEW may be used for automated generation of pictures with structural and functional annotations for publications and proteomic on-line resources. AVAILABILITY: http://polyview.cchmc.org.     

Assessing local structural perturbations in proteins

Background  

Protein structure research often deals with the comparison of two or more structures of the same protein, for instance when handling alternative structure models for the same protein, point mutants, molecule movements, structure predictions, etc. Often the difference between structures is small, restricted to a local neighborhood, and buried in structural "noise" due to trivial differences resulting from experimental artifacts. In such cases, whole-structure comparisons by means of structure superposition may be unsatisfactory and researchers have to perform a tedious process of manually superposing different segments individually and/or use different frames of reference, chosen roughly by educated guessing.     

JCoDA: a tool for detecting evolutionary selection

Background  

The incorporation of annotated sequence information from multiple related species in commonly used databases (Ensembl, Flybase, Saccharomyces Genome Database, Wormbase, etc.) has increased dramatically over the last few years. This influx of information has provided a considerable amount of raw material for evaluation of evolutionary relationships. To aid in the process, we have developed JCoDA (Java Codon Delimited Alignment) as a simple-to-use visualization tool for the detection of site specific and regional positive/negative evolutionary selection amongst homologous coding sequences.     

Finding functional sites in structural genomics proteins

Assigning function to structures is an important aspect of structural genomics projects, since they frequently provide structures for uncharacterized proteins. Similarities uncovered by structure alignment can suggest a similar function, even in the absence of sequence similarity. For proteins adopting novel folds or those with many functions, this strategy can fail, but functional clues can still come from comparison of local functional sites involving a few key residues. Here we assess the general applicability of functional site comparison through the study of 157 proteins solved by structural genomics initiatives. For 17, the method bolsters confidence in predictions made based on overall fold similarity. For another 12 with new folds, it suggests functions, including a putative phosphotyrosine binding site in the Archaeal protein Mth1187 and an active site for a ribose isomerase. The approach is applied weekly to all new structures, providing a resource for those interested in using structure to infer function.     

Functional annotation by identification of local surface similarities: a novel tool for structural genomics

Background  

Protein function is often dependent on subsets of solvent-exposed residues that may exist in a similar three-dimensional configuration in non homologous proteins thus having different order and/or spacing in the sequence. Hence, functional annotation by means of sequence or fold similarity is not adequate for such cases.     

Proboscis profiler: a tool for detecting acanthocephalan morphotypes

Molecular studies conducted over the past 25 years have revealed previously unrecognised diversity in the phylum Acanthocephala. Several nominal species have been shown to represent complexes of morphologically cryptic biological species, a situation potentially confounding the analysis of ecological data. A software tool, ‘Proboscis profiler’, was developed to detect morphological heterogeneity in collections of superficially similar acanthocephalan worms based on the multivariate statistical analysis of proboscis hook dimensions. Proboscis profiler identifies objective, natural groups in a collection of acanthocephalans which may correspond to distinct biological species or populations. Initial trials demonstrate that Proboscis profiler can discriminate biological acanthocephalan species of the Echinorhynchus gadi Zoega in Müller, 1776 complex and differentiate between dorsal and ventral hook rows from the proboscis of E. salmonis Müller, 1784. Proboscis profiler is free software and can be downloaded from .     

SCOPExplorer: a tool for browsing and analyzing structural classification of proteins (SCOP) data

We have developed a tool, named "SCOPExplorer", for browsing and analyzing SCOP information. SCOPExplorer 1) contains a tree-style viewer to display an overview of protein structure data, 2) is able to employ a variety of options to analyze SCOP data statistically, and 3) provides a function to link protein domains to protein data bank (PDB) resources. SCOPExplorer uses an XML-based structural document format, named "SCOPML", derived from the SCOP data. To evaluate SCOPExplorer, proteins containing more than 20 domains were analyzed. The Skp1-Skp2 protein complex and the Fab fragment of IgG2 contain the largest numbers of domains in the current eukaryotic SCOP database. These proteins are known to either bind to various proteins or generate diversity. This suggests that the more domains a protein has, the more interactions or more variability it will be capable of. (SCOPExplorer is available for download at http://scopexplorer.ulsan.ac.kr).     

The isotopic exchange of oxygen as a tool for detection of the glycation sites in proteins

A nonenzymatic reaction of reducing sugars with the free amino group located at the N terminus of the polypeptide chain or in the lysine side chain results in glycation of proteins. The fragments of glycated proteins obtained by enzymatic hydrolysis could be considered as the biomarkers of both the aging process and diabetes mellitus. Here we propose a new method for the identification of peptide-derived Amadori products in the enzymatic digest of glycated proteins. The products of enzymatic hydrolysis of the model protein ubiquitin were incubated with H₂¹⁸O under microwave activation. We observed that at these conditions the Amadori compounds selectively exchange one oxygen atom in the hexose moiety. The characteristic isotopic pattern of Amadori products treated with H₂¹⁸O allows fast and convenient identification of this group of compounds, whereas nonglycated peptides are not susceptible to isotopic exchange.     

GENECODIS: a web-based tool for finding significant concurrent annotations in gene lists

We present GENECODIS, a web-based tool that integrates different sources of information to search for annotations that frequently co-occur in a set of genes and rank them by statistical significance. The analysis of concurrent annotations provides significant information for the biologic interpretation of high-throughput experiments and may outperform the results of standard methods for the functional analysis of gene lists. GENECODIS is publicly available at .     

TRIAL: a tool for finding distant structural similarities

Finding structural similarities in distantly related proteins can reveal functional relationships that can not be identified using sequence comparison. Given two proteins A and B and threshold ε ?, we develop an algorithm, TRiplet-based Iterative ALignment (TRIAL) for computing the transformation of B that maximizes the number of aligned residues such that the root mean square deviation (RMSD) of the alignment is at most ε ?. Our algorithm is designed with the specific goal of effectively handling proteins with low similarity in primary structure, where existing algorithms perform particularly poorly. Experiments show that our method outperforms existing methods. TRIAL alignment brings the secondary structures of distantly related proteins to similar orientations. It also finds larger number of secondary structure matches at lower RMSD values and increased overall alignment lengths. Its classification accuracy is up to 63 percent better than other methods, including CE and DALI. TRIAL successfully aligns 83 percent of the residues from the smaller protein in reasonable time while other methods align only 29 to 65 percent of the residues for the same set of proteins.     

SMotif: a server for structural motifs in proteins

SMotif is a server that identifies important structural segments or motifs for a given protein structure(s) based on conservation of both sequential as well as important structural features such as solvent inaccessibility, secondary structural content, hydrogen bonding pattern and residue packing. This server also provides three-dimensional orientation patterns of the identified motifs in terms of inter-motif distances and torsion angles. These motifs may form the common core and therefore, can also be employed to design and rationalize protein engineering and folding experiments. AVAILABILITY: SMotif server is available via the URL http://caps.ncbs.res.in/SMotif/index.html. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.     

Three-dimensional window analysis for detecting positive selection at structural regions of proteins

Detection of natural selection operating at the amino acid sequencelevel is important in the study of molecular evolution. Single-siteanalysis and one-dimensional window analysis can be used todetect selection when the biological functions of amino acidsites are unknown. Single-site analysis is useful when selectionoperates more or less constantly over evolutionary time, butless so when selection operates temporarily. One-dimensionalwindow analysis is more sensitive than single-site analysiswhen the functions of amino acid sites in close proximity inthe linear sequence are similar, although this is not alwaysthe case. Here I present a three-dimensional window analysismethod for detecting selection given the three-dimensional structureof the protein of interest. In the three-dimensional structure,the window is defined as the sphere centered on the -carbonof an amino acid site. The window size is the radius of thesphere. The sites whose -carbons are included in the windoware grouped for the neutrality test. The window is moved withinthe three-dimensional structure by sequentially moving the centralsite along the primary amino acid sequence. To detect positiveselection, it may also be useful to group the surface-exposedsites in the window separately. Three-dimensional window analysisappears not only to be more sensitive than single-site analysisand one-dimensional window analysis but also to provide similarspecificity for inferring positive selection in the analysesof the hemagglutinin and neuraminidase genes of human influenzaA viruses. This method, however, may fail to detect selectionwhen it operates only on a particular site, in which case single-siteanalysis may be preferred, although a large number of sequencesis required.     

GeneSyn: a tool for detecting conserved gene order across genomes

SUMMARY: GeneSyn is a software tool that allows automatic detection of conserved gene order from annotated genomes. AVAILABILITY: Available free of charge for Unix/Linux/Cygwin platforms at ftp://159.149.110.11/pub/GeneSyn_1.0/ SUPPLEMENTARY INFORMATION: ftp://159.149.110.11/pub/GeneSyn_1.0/     

A tool for the prediction of functionally important sites in proteins using a library of functional templates

Understanding and characterizing the biochemical and evolutionary information within the wealth of protein sequence and structural data, particularly at functionally important sites, is very important. A comprehensive analysis of physico-chemical properties and evolutionary conservation patterns at the molecular and biological function level is expected to yield important clues for identifying similar sites in as-yet uncharacterized proteins. We present a library of protein functional templates (PFTs) designed to represent the compositional and evolutionary conservation patterns of functional sites at the molecular and biological function level. Subsequently we developed LIMACS (LInear MAtching of Conservation Scores), a software tool that uses the template library for the prediction of functionally important sites in a multiple sequence alignment, transferring the molecular function annotation from the most-similar functional site in the template library to a predicted site.     

Physical basis of structural and catalytic Zn-binding sites in proteins

Zn²⁺, an element that is essential to all life forms, can play a catalytic or a solely structural role. Previous works have shown that Zn²⁺ binds preferentially to water molecules and His in catalytic sites, but to Cys⁻ instructural sites, but the molecular basis for the observed ligand preference is unclear. Here, we show that the different Zn²⁺ roles are also reflected in the different bond distances to Zn²⁺ in structural and catalytic sites. We reveal the physical basis for the observed differences between structural and catalytic Zn sites: In most catalytic sites, water is found bound to Zn²⁺ as it transfers the least charge to Zn²⁺ and is less bulky compared to the protein ligands, enabling Zn²⁺ to serve as a Lewis acid in catalysis. In most structural sites, however, ≥ 2 Cys⁻ are found bound to Zn²⁺, as Cys⁻ transfers the most charge to Zn²⁺ and reduces the Zn charge to such an extent that Zn²⁺ can no longer act as a Lewis acid; furthermore, steric repulsion among the bulky Cys(S⁻) prevents Zn²⁺ from accommodating another ligand. Based on the observed ligand preference and Zn-ligand distance differences between structural and catalytic Zn sites, we present a simple method for distinguishing the two types of sites and for verifying the catalytic role of Zn²⁺. Finally, we discuss how the physical bases revealed aid in designing potential drug molecules that target Zn proteins.     

Marker-inferred relatedness as a tool for detecting heritability in nature

This paper presents a perspective of how inferred relatedness, based on genetic marker data such as microsatellites or amplified fragment length polymorphisms (AFLPs), can be used to demonstrate quantitative genetic variation in natural populations. Variation at two levels is considered: among pairs of individuals within populations, and among pairs of subpopulations within a population. In the former, inferred pairwise relatedness, combined with trait measures, allow estimates of heritability 'in the wild'. In the latter, estimates of QST are obtained, in the absence of known heritabilities, via estimates of pairwise FST. Estimators of relatedness based on the 'Kronecker operator' are given. Both methods require actual variation of relationship, a rarely studied aspect of population structure, and not necessarily present. Some conditions for appropriate population structures in the wild are identified, in part through a review of recent studies.