共查询到20条相似文献，搜索用时 15 毫秒
1.
To improve the detection of related proteins, it is often useful to include evolutionary information for both the query and target proteins. One method to include this information is by the use of profile-profile alignments, where a profile from the query protein is compared with the profiles from the target proteins. Profile-profile alignments can be implemented in several fundamentally different ways. The similarity between two positions can be calculated using a dot-product, a probabilistic model, or an information theoretical measure. Here, we present a large-scale comparison of different profile-profile alignment methods. We show that the profile-profile methods perform at least 30% better than standard sequence-profile methods both in their ability to recognize superfamily-related proteins and in the quality of the obtained alignments. Although the performance of all methods is quite similar, profile-profile methods that use a probabilistic scoring function have an advantage as they can create good alignments and show a good fold recognition capacity using the same gap-penalties, while the other methods need to use different parameters to obtain comparable performances. 相似文献
2.
Frances M G Pearl David Lee James E Bray Daniel W A Buchan Adrian J Shepherd Christine A Orengo 《Protein science : a publication of the Protein Society》2002,11(2):233-244
An automatic sequence search and analysis protocol (DomainFinder) based on PSI-BLAST and IMPALA, and using conservative thresholds, has been developed for reliably integrating gene sequences from GenBank into their respective structural families within the CATH domain database (http://www.biochem.ucl.ac.uk/bsm/cath_new). DomainFinder assigns a new gene sequence to a CATH homologous superfamily provided that PSI-BLAST identifies a clear relationship to at least one other Protein Data Bank sequence within that superfamily. This has resulted in an expansion of the CATH protein family database (CATH-PFDB v1.6) from 19,563 domain structures to 176,597 domain sequences. A further 50,000 putative homologous relationships can be identified using less stringent cut-offs and these relationships are maintained within neighbour tables in the CATH Oracle database, pending further evidence of their suggested evolutionary relationship. Analysis of the CATH-PFDB has shown that only 15% of the sequence families are close enough to a known structure for reliable homology modeling. IMPALA/PSI-BLAST profiles have been generated for each of the sequence families in the expanded CATH-PFDB and a web server has been provided so that new sequences may be scanned against the profile library and be assigned to a structure and homologous superfamily. 相似文献
3.
Most homologous pairs of proteins have no significant sequence similarity to each other and are not identified by direct sequence comparison or profile-based strategies. However, multiple sequence alignments of low similarity homologues typically reveal a limited number of positions that are well conserved despite diversity of function. It may be inferred that conservation at most of these positions is the result of the importance of the contribution of these amino acids to the folding and stability of the protein. As such, these amino acids and their relative positions may define a structural signature. We demonstrate that extraction of this fold template provides the basis for the sequence database to be searched for patterns consistent with the fold, enabling identification of homologs that are not recognized by global sequence analysis. The fold template method was developed to address the need for a tool that could comprehensively search the midnight and twilight zones of protein sequence similarity without reliance on global statistical significance. Manual implementations of the fold template method were performed on three folds--immunoglobulin, c-lectin and TIM barrel. Following proof of concept of the template method, an automated version of the approach was developed. This automated fold template method was used to develop fold templates for 10 of the more populated folds in the SCOP database. The fold template method developed three-dimensional structural motifs or signatures that were able to return a diverse collection of proteins, while maintaining a low false positive rate. Although the results of the manual fold template method were more comprehensive than the automated fold template method, the diversity of the results from the automated fold template method surpassed those of current methods that rely on statistical significance to infer evolutionary relationships among divergent proteins. 相似文献
4.
The sequence homology detection relies on score matrices, which reflect the frequency of amino acid substitutions observed in a dataset of homologous sequences. The substitution matrices in popular use today are usually constructed without consideration of the structural context in which the substitution takes place. Here, we present amino acid substitution matrices specific for particular polar-nonpolar environment of the amino acid. As expected, these matrices [context-specific substitution matrices (CSSMs)] show striking differences from the popular BLOSUM62 matrix, which does not include structural information. When incorporated into BLAST and PSI-BLAST, CSSM outperformed BLOSUM matrices as assessed by ROC curve analyses of the number of true and false hits and by the accuracy of the sequence alignments to the hit sequences. These findings are also of relevance to profile-profile-based methods of homology detection, since CSSMs may help build a better profile. Profiles generated for protein sequences in PDB using CSSM-PSI-BLAST will be made available for searching via RPSBLAST through our web site http://lmbbi.nci.nih.gov/. 相似文献
5.
Raphael Petegrosso Zhuliu Li Molly A. Srour Yousef Saad Wei Zhang Rui Kuang 《Proteins》2019,87(6):478-491
The global connectivities in very large protein similarity networks contain traces of evolution among the proteins for detecting protein remote evolutionary relations or structural similarities. To investigate how well a protein network captures the evolutionary information, a key limitation is the intensive computation of pairwise sequence similarities needed to construct very large protein networks. In this article, we introduce label propagation on low-rank kernel approximation (LP-LOKA) for searching massively large protein networks. LP-LOKA propagates initial protein similarities in a low-rank graph by Nyström approximation without computing all pairwise similarities. With scalable parallel implementations based on distributed-memory using message-passing interface and Apache-Hadoop/Spark on cloud, LP-LOKA can search protein networks with one million proteins or more. In the experiments on Swiss-Prot/ADDA/CASP data, LP-LOKA significantly improved protein ranking over the widely used HMM-HMM or profile-sequence alignment methods utilizing large protein networks. It was observed that the larger the protein similarity network, the better the performance, especially on relatively small protein superfamilies and folds. The results suggest that computing massively large protein network is necessary to meet the growing need of annotating proteins from newly sequenced species and LP-LOKA is both scalable and accurate for searching massively large protein networks. 相似文献
6.
S. Baumgartner K. Hofmann R. Chiquet-Ehrismann P. Bucher 《Protein science : a publication of the Protein Society》1998,7(7):1626-1631
Members of the discoidin (DS) domain family, which includes the C1 and C2 repeats of blood coagulation factors V and VIII, occur in a great variety of eukaryotic proteins, most of which have been implicated in cell-adhesion or developmental processes. So far, no three-dimensional structure of a known example of this extracellular module has been determined, limiting the usefulness of identifying a new sequence as member of this family. Here, we present results of a recent search of the protein sequence database for new DS domains using generalized profiles, a sensitive multiple alignment-based search technique. Several previously unrecognized DS domains could be identified by this method, including the first examples from prokaryotic species. More importantly, we present statistical, structural, and functional evidence that the D1 domain of galactose oxidase whose three-dimensional structure has been determined at 1.7 A resolution, is a distant member of this family. Taken together, these findings significantly expand the concept of the DS domain, by extending its taxonomic range and by implying a fold prediction for all its members. The proposed alignment with the galactose oxidase sequence makes it possible to construct homology-based three-dimensional models for the most interesting examples, as illustrated by an accompanying paper on the C1 and C2 domains of factor V. 相似文献
7.
Rigden DJ Setlow P Setlow B Bagyan I Stein RA Jedrzejas MJ 《Protein science : a publication of the Protein Society》2002,11(10):2370-2381
The prfA gene product of Gram-positive bacteria is unusual in being implicated in several cellular processes; cell wall synthesis, chromosome segregation, and DNA recombination and repair. However, no homology of PrfA with other proteins has been evident. Here we report a structural relationship between PrfA and the restriction enzyme PvuII, and thereby produce models that predict that PrfA binds DNA. Indeed, wild-type Bacillus stearothermophilus PrfA, but not a catalytic site mutant, nicked one strand of supercoiled plasmid templates leaving 5'-phosphate and 3'-hydroxyl termini. This activity, much lower on linear or relaxed circular double-stranded DNA or on single-stranded DNA, is consistent with a role for this protein in chromosome segregation, DNA recombination, or DNA repair. 相似文献
8.
In protein structure prediction, a central problem is defining the structure of a loop connecting 2 secondary structures. This problem frequently occurs in homology modeling, fold recognition, and in several strategies in ab initio structure prediction. In our previous work, we developed a classification database of structural motifs, ArchDB. The database contains 12,665 clustered loops in 451 structural classes with information about phi-psi angles in the loops and 1492 structural subclasses with the relative locations of the bracing secondary structures. Here we evaluate the extent to which sequence information in the loop database can be used to predict loop structure. Two sequence profiles were used, a HMM profile and a PSSM derived from PSI-BLAST. A jack-knife test was made removing homologous loops using SCOP superfamily definition and predicting afterwards against recalculated profiles that only take into account the sequence information. Two scenarios were considered: (1) prediction of structural class with application in comparative modeling and (2) prediction of structural subclass with application in fold recognition and ab initio. For the first scenario, structural class prediction was made directly over loops with X-ray secondary structure assignment, and if we consider the top 20 classes out of 451 possible classes, the best accuracy of prediction is 78.5%. In the second scenario, structural subclass prediction was made over loops using PSI-PRED (Jones, J Mol Biol 1999;292:195-202) secondary structure prediction to define loop boundaries, and if we take into account the top 20 subclasses out of 1492, the best accuracy is 46.7%. Accuracy of loop prediction was also evaluated by means of RMSD calculations. 相似文献
9.
High divergence in protein sequences makes the detection of distant protein relationships through homology-based approaches challenging. Grouping protein sequences into families, through similarities in either sequence or 3-D structure, facilitates in the improved recognition of protein relationships. In addition, strategically designed protein-like sequences have been shown to bridge distant structural domain families by serving as artificial linkers. In this study, we have augmented a search database of known protein domain families with such designed sequences, with the intention of providing functional clues to domain families of unknown structure. When assessed using representative query sequences from each family, we obtain a success rate of 94% in protein domain families of known structure. Further, we demonstrate that the augmented search space enabled fold recognition for 582 families with no structural information available a priori. Additionally, we were able to provide reliable functional relationships for 610 orphan families. We discuss the application of our method in predicting functional roles through select examples for DUF4922, DUF5131, and DUF5085. Our approach also detects new associations between families that were previously not known to be related, as demonstrated through new sub-groups of the RNA polymerase domain among three distinct RNA viruses. Taken together, designed sequences-augmented search databases direct the detection of meaningful relationships between distant protein families. In turn, they enable fold recognition and offer reliable pointers to potential functional sites that may be probed further through direct mutagenesis studies. 相似文献
10.
We examine the informatic characteristics of amino acid representations based on physical properties. We demonstrate that sequences rewritten using contracted alphabets based on physical properties do not encode local folding information well. The best four-character alphabet can only encode approximately 57% of the maximum possible amount of structural information. This result suggests that property-based representations that operate on a local length scale are not likely to be useful in homology searches and fold-recognition exercises. 相似文献
11.
Cosenza L Rosenbach A White JV Murphy JR Smith T 《Protein science : a publication of the Protein Society》2000,9(5):916-926
Using a combination of theoretical sequence structure recognition predictions and experimental disulfide bond assignments, a three-dimensional (3D) model of human interleukin-7 (hIL-7) was constructed that predicts atypical surface chemistry in helix D that is important for receptor activation. A 3D model of hIL-7 was built using the X-ray crystal structure of interleukin-4 (IL-4) as a template (Walter MR et al., 1992, J Mol Biol. 224:1075-1085; Walter MR et al., 1992, J Biol Chem 267:20371-20376). Core secondary structures were constructed from sequences of hIL-7 predicted to form helices. The model was constructed by superimposing IL-7 helices onto the IL-4 template and connecting them together in an up-up down-down topology. The model was finished by incorporating the disulfide bond assignments (Cys3, Cys142), (Cys35, Cys130), and (Cys48, Cys93), which were determined by MALDI mass spectroscopy and site-directed mutagenesis (Cosenza L, Sweeney E, Murphy JR, 1997, J Biol Chem 272:32995-33000). Quality analysis of the hIL-7 model identified poor structural features in the carboxyl terminus that, when further studied using hydrophobic moment analysis, detected an atypical structural property in helix D, which contains Cys 130 and Cys142. This analysis demonstrated that helix D had a hydrophobic surface exposed to bulk solvent that accounted for the poor quality of the model, but was suggestive of a region in IL-7 that maybe important for protein interactions. Alanine (Ala) substitution scanning mutagenesis was performed to test if the predicted atypical surface chemistry of helix D in the hIL-7 model is important for receptor activation. This analysis resulted in the construction, purification, and characterization of four hIL-7 variants, hIL-7(K121A), hIL-7(L136A), hIL-7(K140A), and hIL-7(W143A), that displayed reduced or abrogated ability to stimulate a murine IL-7 dependent pre-B cell proliferation. The mutant hIL-7(W143A), which is biologically inactive and displaces [125I]-hIL-7, is the first reported IL-7R system antagonist. 相似文献
12.
Elofsson A 《Proteins》2002,46(3):330-339
One of the most central methods in bioinformatics is the alignment of two protein or DNA sequences. However, so far large-scale benchmarks examining the quality of these alignments are scarce. On the other hand, recently several large-scale studies of the capacity of different methods to identify related sequences has led to new insights about the performance of fold recognition methods. To increase our understanding about fold recognition methods, we present a large-scale benchmark of alignment quality. We compare alignments from several different alignment methods, including sequence alignments, hidden Markov models, PSI-BLAST, CLUSTALW, and threading methods. For most methods, the alignment quality increases significantly at about 20% sequence identity. The difference in alignment quality between different methods is quite small, and the main difference can be seen at the exact positioning of the sharp rise in alignment quality, that is, around 15-20% sequence identity. The alignments are improved by using structural information. In general, the best alignments are obtained by methods that use predicted secondary structure information and sequence profiles obtained from PSI-BLAST. One interesting observation is that for different pairs many different methods create the best alignments. This finding implies that if a method that could select the best alignment method for each pair existed, a significant improvement of the alignment quality could be gained. 相似文献
13.
D. J. Ayers P. R. Gooley A. Widmer-Cooper A. E. Torda 《Protein science : a publication of the Protein Society》1999,8(5):1127-1133
NMR offers the possibility of accurate secondary structure for proteins that would be too large for structure determination. In the absence of an X-ray crystal structure, this information should be useful as an adjunct to protein fold recognition methods based on low resolution force fields. The value of this information has been tested by adding varying amounts of artificial secondary structure data and threading a sequence through a library of candidate folds. Using a literature test set, the threading method alone has only a one-third chance of producing a correct answer among the top ten guesses. With realistic secondary structure information, one can expect a 60-80% chance of finding a homologous structure. The method has then been applied to examples with published estimates of secondary structure. This implementation is completely independent of sequence homology, and sequences are optimally aligned to candidate structures with gaps and insertions allowed. Unlike work using predicted secondary structure, we test the effect of differing amounts of relatively reliable data. 相似文献
14.
Sequence--and structure-based searching strategies have proven useful in the identification of remote homologs and have facilitated both structural and functional predictions of many uncharacterized protein families. We implement these strategies to predict the structure of and to classify a previously uncharacterized cluster of orthologs (COG3019) in the thioredoxin-like fold superfamily. The results of each searching method indicate that thioltransferases are the closest structural family to COG3019. We substantiate this conclusion using the ab initio structure prediction method rosetta, which generates a thioredoxin-like fold similar to that of the glutaredoxin-like thioltransferase (NrdH) for a COG3019 target sequence. This structural model contains the thiol-redox functional motif CYS-X-X-CYS in close proximity to other absolutely conserved COG3019 residues, defining a novel thioredoxin-like active site that potentially binds metal ions. Finally, the rosetta-derived model structure assists us in assembling a global multiple-sequence alignment of COG3019 with two other thioredoxin-like fold families, the thioltransferases and the bacterial arsenate reductases (ArsC). 相似文献
15.
L. Jaroszewski L. Rychlewski B. Zhang A. Godzik 《Protein science : a publication of the Protein Society》1998,7(6):1431-1440
Several fold recognition algorithms are compared to each other in terms of prediction accuracy and significance. It is shown that on standard benchmarks, hybrid methods, which combine scoring based on sequence-sequence and sequence-structure matching, surpass both sequence and threading methods in the number of accurate predictions. However, the sequence similarity contributes most to the prediction accuracy. This strongly argues that most examples of apparently nonhomologous proteins with similar folds are actually related by evolution. While disappointing from the perspective of the fundamental understanding of protein folding, this adds a new significance to fold recognition methods as a possible first step in function prediction. Despite hybrid methods being more accurate at fold prediction than either the sequence or threading methods, each of the methods is correct in some cases where others have failed. This partly reflects a different perspective on sequence/structure relationship embedded in various methods. To combine predictions from different methods, estimates of significance of predictions are made for all methods. With the help of such estimates, it is possible to develop a \"jury\" method, which has accuracy higher than any of the single methods. Finally, building full three-dimensional models for all top predictions helps to eliminate possible false positives where alignments, which are optimal in the one-dimensional sequences, lead to unsolvable sterical conflicts for the full three-dimensional models. 相似文献
16.
Searches using position specific scoring matrices (PSSMs) have been commonly used in remote homology detection procedures such as PSI-BLAST and RPS-BLAST. A PSSM is generated typically using one of the sequences of a family as the reference sequence. In the case of PSI-BLAST searches the reference sequence is same as the query. Recently we have shown that searches against the database of multiple family-profiles, with each one of the members of the family used as a reference sequence, are more effective than searches against the classical database of single family-profiles. Despite relatively a better overall performance when compared with common sequence-profile matching procedures, searches against the multiple family-profiles database result in a few false positives and false negatives. Here we show that profile length and divergence of sequences used in the construction of a PSSM have major influence on the performance of multiple profile based search approach. We also identify that a simple parameter defined by the number of PSSMs corresponding to a family that is hit, for a query, divided by the total number of PSSMs in the family can distinguish effectively the true positives from the false positives in the multiple profiles search approach. 相似文献
17.
Vikram Alva Michael Remmert Andreas Biegert Andrei N. Lupas Johannes Söding 《Protein science : a publication of the Protein Society》2010,19(1):124-130
Many protein classification systems capture homologous relationships by grouping domains into families and superfamilies on the basis of sequence similarity. Superfamilies with similar 3D structures are further grouped into folds. In the absence of discernable sequence similarity, these structural similarities were long thought to have originated independently, by convergent evolution. However, the growth of databases and advances in sequence comparison methods have led to the discovery of many distant evolutionary relationships that transcend the boundaries of superfamilies and folds. To investigate the contributions of convergent versus divergent evolution in the origin of protein folds, we clustered representative domains of known structure by their sequence similarity, treating them as point masses in a virtual 2D space which attract or repel each other depending on their pairwise sequence similarities. As expected, families in the same superfamily form tight clusters. But often, superfamilies of the same fold are linked with each other, suggesting that the entire fold evolved from an ancient prototype. Strikingly, some links connect superfamilies with different folds. They arise from modular peptide fragments of between 20 and 40 residues that co‐occur in the connected folds in disparate structural contexts. These may be descendants of an ancestral pool of peptide modules that evolved as cofactors in the RNA world and from which the first folded proteins arose by amplification and recombination. Our galaxy of folds summarizes, in a single image, most known and many yet undescribed homologous relationships between protein superfamilies, providing new insights into the evolution of protein domains. 相似文献
18.
蛋白质空间结构研究是分子生物学、细胞生物学、生物化学以及药物设计等领域的重要课题.折叠类型反映了蛋白质核心结构的拓扑模式,对折叠类型的识别是蛋白质序列与结构关系研究的重要内容.选取LIFCA数据库中样本量较大的53种折叠类型,应用功能域组分方法进行折叠识别.将Astral 1.65中序列一致性小于95%的样本作为检验集,全库检验结果中平均敏感性为96.42%,特异性为99.91%,马修相关系数(MCC)为0.91,各项统计结果表明:功能域组分方法可以很好地应用在蛋白质折叠识别中,LIFCA相对简单的分类规则可以很好地集中蛋白质的大部分功能特性,反映了结构与功能的对应关系. 相似文献
19.
In this study we present two methods to predict the local quality of a protein model: ProQres and ProQprof. ProQres is based on structural features that can be calculated from a model, while ProQprof uses alignment information and can only be used if the model is created from an alignment. In addition, we also propose a simple approach based on local consensus, Pcons-local. We show that all these methods perform better than state-of-the-art methodologies and that, when applicable, the consensus approach is by far the best approach to predict local structure quality. It was also found that ProQprof performed better than other methods for models based on distant relationships, while ProQres performed best for models based on closer relationship, i.e., a model has to be reasonably good to make a structural evaluation useful. Finally, we show that a combination of ProQprof and ProQres (ProQlocal) performed better than any other nonconsensus method for both high- and low-quality models. Additional information and Web servers are available at: http://www.sbc.su.se/~bjorn/ProQ/. 相似文献
20.
Kinases are a ubiquitous group of enzymes that catalyze the phosphoryl transfer reaction from a phosphate donor (usually ATP) to a receptor substrate. Although all kinases catalyze essentially the same phosphoryl transfer reaction, they display remarkable diversity in their substrate specificity, structure, and the pathways in which they participate. In order to learn the relationship between structural fold and functional specificities in kinases, we have done a comprehensive survey of all available kinase sequences (>17,000) and classified them into 30 distinct families based on sequence similarities. Of these families, 19, covering nearly 98% of all sequences, fall into seven general structural folds for which three-dimensional structures are known. These fold groups include some of the most widespread protein folds, such as Rossmann fold, ferredoxin fold, ribonuclease H fold, and TIM beta/alpha-barrel. On the basis of this classification system, we examined the shared substrate binding and catalytic mechanisms as well as variations of these mechanisms in the same fold groups. Cases of convergent evolution of identical kinase activities occurring in different folds are discussed. 相似文献