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PLOS COMPUTATIONAL BIOLOGY 2011年第10期7卷 1-16页

作者： Eddy, Sean R. HHMI Janelia Farm Res Campus Ashburn VA USA

Profile hidden Markov models (profile HMMs) and probabilistic inference methods have made important contributions to the theory of sequence database homology search. However, practical use of profile HMM methods has been hindered by the computational expense of existing software implementations. Here I describe an acceleration heuristic for profile HMMs, the "multiple segment Viterbi" (MSV) algorithm. The MSV algorithm computes an optimal sum of multiple ungapped local alignment segments using a striped vector-parallel approach previously described for fast Smith/Waterman alignment. MSV scores follow the same statistical distribution as gapped optimal local alignment scores, allowing rapid evaluation of significance of an MSV score and thus facilitating its use as a heuristic filter. I also describe a 20-fold acceleration of the standard profile HMM Forward/Backward algorithms using a method I call "sparse rescaling". These methods are assembled in a pipeline in which high-scoring MSV hits are passed on for reanalysis with the full HMM Forward/Backward algorithm. This accelerated pipeline is implemented in the freely available HMMER3 software package. Performance benchmarks show that the use of the heuristic MSV filter sacrifices negligible sensitivity compared to unaccelerated profile HMM searches. HMMER3 is substantially more sensitive and 100- to 1000-fold faster than HMMER2. HMMER3 is now about as fast as blast for protein searches.

关键词： Sequence alignment blast algorithm Hidden Markov models Database searching Multiple alignment calculation Computer software Computational pipelines Heuristic alignment procedure

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Knotted vs. Unknotted Proteins: Evidence of Knot-Promoting Loops

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PLOS COMPUTATIONAL BIOLOGY 2010年第7期6卷 e1000864-e1000864页

作者： Potestio, Raffaello Micheletti, Cristian Orland, Henri SISSA I-34014 Trieste Italy DEMOCRITOS CNR IOM Trieste Italy Italian Inst Technol SISSA Unit Trieste Italy CEA Inst Phys Theor Gif Sur Yvette France

Knotted proteins, because of their ability to fold reversibly in the same topologically entangled conformation, are the object of an increasing number of experimental and theoretical studies. The aim of the present investigation is to assess, on the basis of presently available structural data, the extent to which knotted proteins are isolated instances in sequence or structure space, and to use comparative schemes to understand whether specific protein segments can be associated to the occurrence of a knot in the native state. A significant sequence homology is found among a sizeable group of knotted and unknotted proteins. In this family, knotted members occupy a primary sub-branch of the phylogenetic tree and differ from unknotted ones only by additional loop segments. These "knot-promoting'' loops, whose virtual bridging eliminates the knot, are found in various types of knotted proteins. Valuable insight into how knots form, or are encoded, in proteins could be obtained by targeting these regions in future computational studies or excision experiments.

关键词： Protein structure comparison Sequence alignment Phylogenetic analysis Protein structure Proteomic databases Protein folding Protein structure databases blast algorithm

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Annotation Error in Public Databases: Misannotation of Molecular Function in Enzyme Superfamilies

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PLOS COMPUTATIONAL BIOLOGY 2009年第12期5卷 e1000605-e1000605页

作者： Schnoes, Alexandra M. Brown, Shoshana D. Dodevski, Igor Babbitt, Patricia C. Univ Calif San Francisco Grad Grp Biophys San Francisco CA 94143 USA Univ Calif San Francisco Dept Bioengn & Therapeut Sci San Francisco CA 94143 USA Univ Zurich Dept Biochem Zurich Switzerland Univ Calif San Francisco Dept Pharmaceut Chem San Francisco CA 94143 USA Univ Calif San Francisco Calif Inst Quantitat Biosci San Francisco CA 94143 USA

Due to the rapid release of new data from genome sequencing projects, the majority of protein sequences in public databases have not been experimentally characterized;rather, sequences are annotated using computational analysis. The level of misannotation and the types of misannotation in large public databases are currently unknown and have not been analyzed in depth. We have investigated the misannotation levels for molecular function in four public protein sequence databases (UniProtKB/Swiss-Prot, GenBank NR, UniProtKB/TrEMBL, and KEGG) for a model set of 37 enzyme families for which extensive experimental information is available. The manually curated database Swiss-Prot shows the lowest annotation error levels (close to 0% for most families);the two other protein sequence databases (GenBank NR and TrEMBL) and the protein sequences in the KEGG pathways database exhibit similar and surprisingly high levels of misannotation that average 5%-63% across the six superfamilies studied. For 10 of the 37 families examined, the level of misannotation in one or more of these databases is >80%. Examination of the NR database over time shows that misannotation has increased from 1993 to 2005. The types of misannotation that were found fall into several categories, most associated with "overprediction'' of molecular function. These results suggest that misannotation in enzyme superfamilies containing multiple families that catalyze different reactions is a larger problem than has been recognized. Strategies are suggested for addressing some of the systematic problems contributing to these high levels of misannotation.

关键词： Genome annotation Hidden Markov models Genomic databases Dehydration (medicine) Sequence databases blast algorithm Enzymes Genomics

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PLOS COMPUTATIONAL BIOLOGY 2008年第5期4卷 e1000063-e1000063页

作者： Song, Nan Joseph, Jacob M. Davis, George B. Durand, Dannie Carnegie Mellon Univ Dept Biol Sci Pittsburgh PA 15213 USA Carnegie Mellon Univ Sch Comp Sci Pittsburgh PA 15213 USA

We address the problem of homology identification in complex multidomain families with varied domain architectures. The challenge is to distinguish sequence pairs that share common ancestry from pairs that share an inserted domain but are otherwise unrelated. This distinction is essential for accuracy in gene annotation, function prediction, and comparative genomics. There are two major obstacles to multidomain homology identification: lack of a formal definition and lack of curated benchmarks for evaluating the performance of new methods. We offer preliminary solutions to both problems: 1) an extension of the traditional model of homology to include domain insertions;and 2) a manually curated benchmark of well-studied families in mouse and human. We further present Neighborhood Correlation, a novel method that exploits the local structure of the sequence similarity network to identify homologs with great accuracy based on the observation that gene duplication and domain shuffling leave distinct patterns in the sequence similarity network. In a rigorous, empirical comparison using our curated data, Neighborhood Correlation outperforms sequence similarity, alignment length, and domain architecture comparison. Neighborhood Correlation is well suited for automated, genome-scale analyses. It is easy to compute, does not require explicit knowledge of domain architecture, and classifies both single and multidomain homologs with high accuracy. Homolog predictions obtained with our method, as well as our manually curated benchmark and a web-based visualization tool for exploratory analysis of the network neighborhood structure, are available at http://***. Our work represents a departure from the prevailing view that the concept of homology cannot be applied to genes that have undergone domain shuffling. In contrast to current approaches that either focus on the homology of individual domains or consider only families with identical domain archit

关键词： Sequence alignment Protein domains blast algorithm Evolutionary genetics Multiple alignment calculation Gene duplication Genome analysis Genomics

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A probabilistic model of local sequence alignment that simplifies statistical significance estimation

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PLOS COMPUTATIONAL BIOLOGY 2008年第5期4卷 e1000069-e1000069页

作者： Eddy, Sean R. Howard Hughes Med Inst Ashburn VA USA

Sequence database searches require accurate estimation of the statistical significance of scores. Optimal local sequence alignment scores follow Gumbel distributions, but determining an important parameter of the distribution (lambda) requires time-consuming computational simulation. Moreover, optimal alignment scores are less powerful than probabilistic scores that integrate over alignment uncertainty ("Forward'' scores), but the expected distribution of Forward scores remains unknown. Here, I conjecture that both expected score distributions have simple, predictable forms when full probabilistic modeling methods are used. For a probabilistic model of local sequence alignment, optimal alignment bit scores ("Viterbi'' scores) are Gumbel-distributed with constant lambda = log 2, and the high scoring tail of Forward scores is exponential with the same constant lambda. Simulation studies support these conjectures over a wide range of profile/sequence comparisons, using 9,318 profile-hidden Markov models from the Pfam database. This enables efficient and accurate determination of expectation values (E-values) for both Viterbi and Forward scores for probabilistic local alignments.

关键词： Sequence alignment Hidden Markov models Tails blast algorithm Multiple alignment calculation Probability distribution Database searching Statistical distributions

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Malleable Machines in Transcription Regulation: The Mediator Complex

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PLOS COMPUTATIONAL BIOLOGY 2008年第12期4卷 e1000243-e1000243页

作者： Toth-Petroczy, Agnes Oldfield, Christopher J. Simon, Istvan Takagi, Yuichiro Dunker, A. Keith Uversky, Vladimir N. Fuxreiter, Monika Hungarian Acad Sci Inst Enzymol Biol Res Ctr Budapest Hungary Indiana Univ Sch Med Dept Biochem & Mol Biol Ctr Computat Biol & Bioinformat Indianapolis IN USA Indiana Univ Sch Med Inst Intrinsically Disordered Prot Res Indianapolis IN USA Russian Acad Sci Inst Biol Instrumentat Pushchino 142292 Moscow Region Russia

The Mediator complex provides an interface between gene-specific regulatory proteins and the general transcription machinery including RNA polymerase II (RNAP II). The complex has a modular architecture (Head, Middle, and Tail) and cryoelectron microscopy analysis suggested that it undergoes dramatic conformational changes upon interactions with activators and RNAP II. These rearrangements have been proposed to play a role in the assembly of the preinitiation complex and also to contribute to the regulatory mechanism of Mediator. In analogy to many regulatory and transcriptional proteins, we reasoned that Mediator might also utilize intrinsically disordered regions (IDRs) to facilitate structural transitions and transmit transcriptional signals. Indeed, a high prevalence of IDRs was found in various subunits of Mediator from both Saccharomyces cerevisiae and Homo sapiens, especially in the Tail and the Middle modules. The level of disorder increases from yeast to man, although in both organisms it significantly exceeds that of multiprotein complexes of a similar size. IDRs can contribute to Mediator's function in three different ways: they can individually serve as target sites for multiple partners having distinctive structures;they can act as malleable linkers connecting globular domains that impart modular functionality on the complex;and they can also facilitate assembly and disassembly of complexes in response to regulatory signals. Short segments of IDRs, termed molecular recognition features (MoRFs) distinguished by a high protein-protein interaction propensity, were identified in 16 and 19 subunits of the yeast and human Mediator, respectively. In Saccharomyces cerevisiae, the functional roles of 11 MoRFs have been experimentally verified, and those in the Med8/Med18/Med20 and Med7/Med21 complexes were structurally confirmed. Although the Saccharomyces cerevisiae and Homo sapiens Mediator sequences are only weakly conserved, the arrangements of the disordere

关键词： Saccharomyces cerevisiae Yeast Transcriptional control Intrinsically disordered proteins Sequence alignment blast algorithm Transcription factors Protein sequencing

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A primer on python for life science researchers

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PLOS COMPUTATIONAL BIOLOGY 2007年第11期3卷 2052-2057页

作者： Bassi, Sebastian Univ Nacl Quilmes Buenos Aires DF Argentina

The article presents a tutorial on the Python computer program language for life science researchers. It introduces Biophython which is used for computational molecular biology. It states that Python provides free acc... 详细信息

关键词： Programming languages blast algorithm Language Bioinformatics Syntax Computer software High level languages Source code

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Automated protein subfamily identification and classification

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PLOS COMPUTATIONAL BIOLOGY 2007年第8期3卷 1526-1538页

作者： Brown, Duncan P. Krishnamurthy, Nandini Sjoelander, Kimmen Univ Calif Berkeley Dept Bioengn Berkeley CA 94720 USA

Function prediction by homology is widely used to provide preliminary functional annotations for genes for which experimental evidence of function is unavailable or limited. This approach has been shown to be prone to systematic error, including percolation of annotation errors through sequence databases. Phylogenomic analysis avoids these errors in function prediction but has been difficult to automate for high- throughput application. To address this limitation, we present a computationally efficient pipeline for phylogenomic classification of proteins. This pipeline uses the SCI- PHY ( Subfamily Classification in Phylogenomics) algorithm for automatic subfamily identification, followed by subfamily hidden Markov model ( HMM) construction. A simple and computationally efficient scoring scheme using family and subfamily HMMs enables classification of novel sequences to protein families and subfamilies. Sequences representing entirely novel subfamilies are differentiated from those that can be classified to subfamilies in the input training set using logistic regression. Subfamily HMM parameters are estimated using an information- sharing protocol, enabling subfamilies containing even a single sequence to benefit from conservation patterns defining the family as a whole or in related subfamilies. SCI- PHY subfamilies correspond closely to functional subtypes defined by experts and to conserved clades found by phylogenetic analysis. Extensive comparisons of subfamily and family HMM performances show that subfamily HMMs dramatically improve the separation between homologous and non- homologous proteins in sequence database searches. Subfamily HMMs also provide extremely high specificity of classification and can be used to predict entirely novel subtypes. The SCI- PHY Web server at http:// phylogenomics. berkeley. edu/ SCI- PHY/ allows users to upload a multiple sequence alignment for subfamily identification and subfamily HMM construction. Biologists wishing to provi

关键词： Hidden Markov models Sequence alignment Multiple alignment calculation Phylogenetics Phylogenetic analysis Protein domains Trees blast algorithm

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Detecting key structural features within highly recombined genes

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PLOS COMPUTATIONAL BIOLOGY 2007年第1期3卷 137-150页

作者： Wertz, John E. McGregor, Karen F. Bessen, Debra E. New York Med Coll Dept Microbiol & Immunol Valhalla NY 10595 USA Thames Valley Univ Microbiol Res Grp London England

Many microorganisms exhibit high levels of intragenic recombination following horizontal gene transfer events. Furthermore, many microbial genes are subject to strong diversifying selection as part of the pathogenic process. A multiple sequence alignment is an essential starting point for many of the tools that provide fundamental insights on gene structure and evolution, such as phylogenetics;however, an accurate alignment is not always possible to attain. In this study, a new analytic approach was developed in order to better quantify the genetic organization of highly diversified genes whose alleles do not align. This blast-based method, denoted blast Miner, employs an iterative process that places short segments of highly similar sequence into discrete datasets that are designated "modules." The relative positions of modules along the length of the genes, and their frequency of occurrence, are used to identify sequence duplications, insertions, and rearrangements. Partial alleles of sof from Streptococcus pyogenes, encoding a surface protein under host immune selection, were analyzed for module content. High-frequency Modules 6 and 13 were identified and examined in depth. Nucleotide sequences corresponding to both modules contain numerous duplications and inverted repeats, whereby many codons form palindromic pairs. Combined with evidence for a strong codon usage bias, data suggest that Module 6 and 13 sequences are under selection to preserve their nucleic acid secondary structure. The concentration of overlapping tandem and inverted repeats within a small region of DNA is highly suggestive of a mechanistic role for Module 6 and 13 sequences in promoting aberrant recombination. Analysis of pbp2X alleles from Streptococcus pneumoniae, encoding cell wall enzymes that confer antibiotic resistance, supports the broad applicability of this tool in deciphering the genetic organization of highly recombined genes. blast Miner shares with phylogenetics the important pr

关键词： blast algorithm Sequence alignment Alleles Multiple alignment calculation Computer software Streptococcus pyogenes DNA recombination Homologous recombination

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Recent evolutions of multiple sequence alignment algorithms

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PLOS COMPUTATIONAL BIOLOGY 2007年第8期3卷 1405-1408页

作者： Notredame, Cedric Parc Sci Luminy CNRS Inst Struct Biol & Microbiol UPR2589 Marseille France

The article discusses the developments on multiple sequence alignment (MSA) algorithms used in biological modeling. It states that an MSA algorithm is intended for assembling alignments that reflect the biological relationship between sequences. The scoring schemes used by pairwise alignment algorithm can be divided into categories namely, matrix-based and consistency-based algorithms. The purpose of template-based alignment model is said to be the use of dataset as a starting point for exploring and retrieving related information in public databases.

关键词： Multiple alignment calculation Sequence alignment algorithms Phylogenetic analysis Protein structure comparison RNA structure blast algorithm Trees

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