Structure and function analysis of flexible alignment regions in proteins
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ABSTRACT:
SUBMITTER: Pirovano W
PROVIDER: S-EPMC2764137 | biostudies-literature | 2009 Jan
REPOSITORIES: biostudies-literature
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Project description:BackgroundProteins have evolved subject to energetic selection pressure for stability and flexibility. Structural similarity between proteins that have gone through conformational changes can be captured effectively if flexibility is considered. Topologically unrelated proteins that preserve secondary structure packing interactions can be detected if both flexibility and Sequential permutations are considered. We propose the FlexSnap algorithm for flexible non-topological protein structural alignment.ResultsThe effectiveness of FlexSnap is demonstrated by measuring the agreement of its alignments with manually curated non-sequential structural alignments. FlexSnap showed competitive results against state-of-the-art algorithms, like DALI, SARF2, MultiProt, FlexProt, and FATCAT. Moreover on the DynDom dataset, FlexSnap reported longer alignments with smaller rmsd.ConclusionsWe have introduced FlexSnap, a greedy chaining algorithm that reports both sequential and non-sequential alignments and allows twists (hinges). We assessed the quality of the FlexSnap alignments by measuring its agreements with manually curated non-sequential alignments. On the FlexProt dataset, FlexSnap was competitive to state-of-the-art flexible alignment methods. Moreover, we demonstrated the benefits of introducing hinges by showing significant improvements in the alignments reported by FlexSnap for the structure pairs for which rigid alignment methods reported alignments with either low coverage or large rmsd.AvailabilityAn implementation of the FlexSnap algorithm will be made available online at http://www.cs.rpi.edu/~zaki/software/flexsnap.
| S-EPMC2846951 | biostudies-literature
Project description:We have recently developed a flexible protein structure alignment program (FATCAT) that identifies structural similarity, at the same time accounting for flexibility of protein structures. One of the most important applications of a structure alignment method is to aid in functional annotations by identifying similar structures in large structural databases. However, none of the flexible structure alignment methods were applied in this task because of a lack of significance estimation of flexible alignments. In this paper, we developed an estimate of the statistical significance of FATCAT alignment score, allowing us to use it as a database-searching tool. The results reported here show that (1) the distribution of the similarity score of FATCAT alignment between two unrelated protein structures follows the extreme value distribution (EVD), adding one more example to the current collection of EVDs of sequence and structure similarities; (2) introducing flexibility into structure comparison only slightly influences the sensitivity and specificity of identifying similar structures; and (3) the overall performance of FATCAT as a database searching tool is comparable to that of the widely used rigid-body structure comparison programs DALI and CE. Two examples illustrating the advantages of using flexible structure alignments in database searching are also presented. The conformational flexibilities that were detected in the first example may be involved with substrate specificity, and the conformational flexibilities detected in the second example may reflect the evolution of structures by block building.
| S-EPMC2279924 | biostudies-literature
Project description:Nano-scale alignment of several proteins with freedom of motion is equivalent to an enormous increase in effective local concentration of proteins and will enable otherwise impossible weak and/or cooperative associations between them or with their ligands. For this purpose, a DNA backbone made of six oligodeoxynucleotide (ODN) chains is designed in which five double-stranded segments are connected by four single-stranded flexible linkers. A desired protein with an introduced cysteine is connected covalently to the 5'-end of azido-ODN by catalyst-free click chemistry. Then, six protein-ODN conjugates are assembled with their complementary nucleotide sequences into a single multi-protein-DNA complex, and six proteins are aligned along the DNA backbone. Flexible alignment of proteins is directly observed by high-speed AFM imaging, and association of proteins with weak interaction is demonstrated by fluorescence resonance energy transfer between aligned proteins.
| S-EPMC3530504 | biostudies-literature
Project description:Protein structural annotation and classification is an important and challenging problem in bioinformatics. Research towards analysis of sequence-structure correspondences is critical for better understanding of a protein's structure, function, and its interaction with other molecules. Clustering of protein domains based on their structural similarities provides valuable information for protein classification schemes. In this article, we attempt to determine whether structure information alone is sufficient to adequately classify protein structures. We present an algorithm that identifies regions of structural similarity within a given set of protein structures, and uses those regions for clustering. In our approach, called STRALCP (STRucture ALignment-based Clustering of Proteins), we generate detailed information about global and local similarities between pairs of protein structures, identify fragments (spans) that are structurally conserved among proteins, and use these spans to group the structures accordingly. We also provide a web server at http://as2ts.llnl.gov/AS2TS/STRALCP/ for selecting protein structures, calculating structurally conserved regions and performing automated clustering.
| S-EPMC2190701 | biostudies-literature
Project description:Multiple local structure comparison helps to identify common structural motifs or conserved binding sites in 3D structures in distantly related proteins. Since there is no best way to compare structures and evaluate the alignment, a wide variety of techniques and different similarity scoring schemes have been proposed. Existing algorithms usually compute the best superposition of two structures or attempt to solve it as an optimization problem in a simpler setting (e.g., considering contact maps or distance matrices). Here, we present PROPOSAL (PROteins comparison through Probabilistic Optimal Structure local ALignment), a stochastic algorithm based on iterative sampling for multiple local alignment of protein structures. Our method can efficiently find conserved motifs across a set of protein structures. Only the distances between all pairs of residues in the structures are computed. To show the accuracy and the effectiveness of PROPOSAL we tested it on a few families of protein structures. We also compared PROPOSAL with two state-of-the-art tools for pairwise local alignment on a dataset of manually annotated motifs. PROPOSAL is available as a Java 2D standalone application or a command line program at http://ferrolab.dmi.unict.it/proposal/proposal.html.
| S-EPMC4151033 | biostudies-literature
Project description:BackgroundAn algorithm is presented to compute a multiple structure alignment for a set of proteins and to generate a consensus (pseudo) protein which captures common substructures present in the given proteins. The algorithm represents each protein as a sequence of triples of coordinates of the alpha-carbon atoms along the backbone. It then computes iteratively a sequence of transformation matrices (i.e., translations and rotations) to align the proteins in space and generate the consensus. The algorithm is a heuristic in that it computes an approximation to the optimal alignment that minimizes the sum of the pairwise distances between the consensus and the transformed proteins.ResultsExperimental results show that the algorithm converges quite rapidly and generates consensus structures that are visually similar to the input proteins. A comparison with other coordinate-based alignment algorithms (MAMMOTH and MATT) shows that the proposed algorithm is competitive in terms of speed and the sizes of the conserved regions discovered in an extensive benchmark dataset derived from the HOMSTRAD and SABmark databases. The algorithm has been implemented in C++ and can be downloaded from the project's web page. Alternatively, the algorithm can be used via a web server which makes it possible to align protein structures by uploading files from local disk or by downloading protein data from the RCSB Protein Data Bank.ConclusionsAn algorithm is presented to compute a multiple structure alignment for a set of proteins, together with their consensus structure. Experimental results show its effectiveness in terms of the quality of the alignment and computational cost.
| S-EPMC2829528 | biostudies-literature
Project description:BackgroundShotgun metagenome analysis provides a robust and verifiable method for comprehensive microbiome analysis of fungal, viral, archaeal and bacterial taxonomy, particularly with regard to visualization of read mapping location, normalization options, growth dynamics and functional gene repertoires. Current read classification tools use non-standard output formats, or do not fully show information on mapping location. As reference datasets are not perfect, portrayal of mapping information is critical for judging results effectively.ResultsOur alignment-based pipeline, Wochenende, incorporates flexible quality control, trimming, mapping, various filters and normalization. Results are completely transparent and filters can be adjusted by the user. We observe stringent filtering of mismatches and use of mapping quality sharply reduces the number of false positives. Further modules allow genomic visualization and the calculation of growth rates, as well as integration and subsequent plotting of pipeline results as heatmaps or heat trees. Our novel normalization approach additionally allows calculation of absolute abundance profiles by comparison with reads assigned to the human host genome.ConclusionWochenende has the ability to find and filter alignments to all kingdoms of life using both short and long reads, and requires only good quality reference genomes. Wochenende automatically combines multiple available modules ranging from quality control and normalization to taxonomic visualization. Wochenende is available at https://github.com/MHH-RCUG/nf_wochenende .
| S-EPMC9650795 | biostudies-literature
Project description:Manganese (Mn) is an essential trace nutrient for organisms because of its role in cofactoring enzymes and providing protection against reactive oxygen species (ROS). Many bacteria require manganese to form pathogenic or symbiotic interactions with eukaryotic host cells. However, excess manganese is toxic, requiring cells to have manganese export mechanisms. Bacteria are currently known to possess two widely distributed classes of manganese export proteins, MntP and MntE, but other types of transporters likely exist. Moreover, the structure and function of MntP is not well understood. Here, we characterized the role of three structurally related proteins known or predicted to be involved in manganese transport in bacteria from the MntP, UPF0016, and TerC families. These studies used computational analysis to analyze phylogeny and structure, physiological assays to test sensitivity to high levels of manganese and ROS, and inductively coupled plasma-mass spectrometry (ICP-MS) to measure metal levels. We found that MntP alters cellular resistance to ROS. Moreover, we used extensive computational analyses and phenotypic assays to identify amino acids required for MntP activity. These negatively charged residues likely serve to directly bind manganese and transport it from the cytoplasm through the membrane. We further characterized two other potential manganese transporters associated with a Mn-sensing riboswitch and found that the UPF0016 family of proteins has manganese export activity. We provide here the first phenotypic and biochemical evidence for the role of Alx, a member of the TerC family, in manganese homeostasis. It does not appear to export manganese, but rather it intriguingly facilitates an increase in intracellular manganese concentration. These findings expand the available knowledge about the identity and mechanisms of manganese homeostasis proteins across bacteria and show that proximity to a Mn-responsive riboswitch can be used to identify new components of the manganese homeostasis machinery.
| S-EPMC5900781 | biostudies-literature
Project description:MotivationTemplate-based prediction of DNA binding proteins requires not only structural similarity between target and template structures but also prediction of binding affinity between the target and DNA to ensure binding. Here, we propose to predict protein-DNA binding affinity by introducing a new volume-fraction correction to a statistical energy function based on a distance-scaled, finite, ideal-gas reference (DFIRE) state.ResultsWe showed that this energy function together with the structural alignment program TM-align achieves the Matthews correlation coefficient (MCC) of 0.76 with an accuracy of 98%, a precision of 93% and a sensitivity of 64%, for predicting DNA binding proteins in a benchmark of 179 DNA binding proteins and 3797 non-binding proteins. The MCC value is substantially higher than the best MCC value of 0.69 given by previous methods. Application of this method to 2235 structural genomics targets uncovered 37 as DNA binding proteins, 27 (73%) of which are putatively DNA binding and only 1 protein whose annotated functions do not contain DNA binding, while the remaining proteins have unknown function. The method provides a highly accurate and sensitive technique for structure-based prediction of DNA binding proteins.AvailabilityThe method is implemented as a part of the Structure-based function-Prediction On-line Tools (SPOT) package available at http://sparks.informatics.iupui.edu/spot
| S-EPMC2905551 | biostudies-literature
Project description:BACKGROUND: UnTranslated Regions (UTRs) of mRNAs contain regulatory elements for various aspects of mRNA metabolism, such as mRNA localization, translation, and mRNA stability. Several RNA stem-loop structures in UTRs have been experimentally identified, including the histone 3' UTR stem-loop structure (HSL3) and iron response element (IRE). These stem-loop structures are conserved among mammalian orthologs, and exist in a group of genes encoding proteins involved in the same biological pathways. It is not known to what extent RNA structures like these exist in all mammalian UTRs. RESULTS: In this paper we took a systematic approach, named GLEAN-UTR, to identify small stem-loop RNA structure elements in UTRs that are conserved between human and mouse orthologs and exist in multiple genes with common Gene Ontology terms. This approach resulted in 90 distinct RNA structure groups containing 748 structures, with HSL3 and IRE among the top hits based on conservation of structure. CONCLUSION: Our result indicates that there may exist many conserved stem-loop structures in mammalian UTRs that are involved in coordinate post-transcriptional regulation of biological pathways.
| S-EPMC2413145 | biostudies-literature