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PubMed2001

Circular dichroism studies on proteins in films and in solution: estimation of secondary structure by g-factor analysis.

Estimates of the secondary structure of a protein in solution are made by mathematical analyses of its circular dichroism (CD) spectrum below 240 nm. All current procedures require accurate determination of the concentration of the protein sample. Insoluble proteins, such as prions or amyloid, are examined as thin films or gels, but concentrations cannot be precisely defined. The ratio of a sample's CD and absorbance signals is the g-factor, an intensive property. The g-factor spectra of 19 soluble, unconjugated proteins of known structures were measured and used to derive basis spectra, characteristic of the four major structural elements, helix, sheet, turn, and remainder. Using these, the g-factor spectra of other unconjugated proteins, measured in solution or as films, can be analyzed by linear regression to give good estimates of their secondary structures when protein concentration cannot be determined.

Amino Acids↗
PubMed1996

Comparative analysis of the secondary structural motifs of P450BM-3 and the regions located upstream of the calmodulin-binding domain in the nitric oxide synthases.

The proposed method of multiple alignment of secondary structures makes it possible to estimate the multidomain enzymes' structural similarity in those cases where, following alignment, the identity appears to be inadequate or too insignificant to estimate protein relationship in spite of their functional analogy. Multiple alignment of sequences, representing the secondary structural elements of the nitric oxide synthase (NOS) N-terminal "tails", localized upstream of the calmodulin (CAM)-binding domain, and the P450 superfamily representative P450BM-3 has revealed the existence of a common secondary structural motif, standing of 60% identity between the polypeptide chain packing of NOS and the full sequence of P450BM3. This fact may point to the existence of their common ancestor. Presence of the linker olygopeptides within NOS permitted us to determine the boundary of the cytochrome-like part of NOS.

Amino Acid Sequence↗
PubMed2005

Disulfide connectivity prediction using secondary structure information and diresidue frequencies.

MOTIVATION: We describe a stand-alone algorithm to predict disulfide bond partners in a protein given only the amino acid sequence, using a novel neural network architecture (the diresidue neural network), and given input of symmetric flanking regions of N-terminus and C-terminus half-cystines augmented with residue secondary structure (helix, coil, sheet) as well as evolutionary information. The approach is motivated by the observation of a bias in the secondary structure preferences of free cysteines and half-cystines, and by promising preliminary results we obtained using diresidue position-specific scoring matrices. RESULTS: As calibrated by receiver operating characteristic curves from 4-fold cross-validation, our conditioning on secondary structure allows our novel diresidue neural network to perform as well as, and in some cases better than, the current state-of-the-art method. A slight drop in performance is seen when secondary structure is predicted rather than being derived from three-dimensional protein structures.

Algorithms↗
PubMedDate not supplied

[Relationship between tissue mitotic activity, animal age and defects in the secondary structure of DNA].

The content of defects of the secondary structure of DNA native and gamma-irradiated preparations from the intestinal mucosa and liver of adult (6-8 months) and old (24-26 months) rats was studied by the kinetic formaldehyde method. The content of the native DNA secondary structure defects does not depend on the animal and tissue mitotic activity. After gamma-irradiation in vitro (60Co, 550 R/min, 3 and 6 krad) of intestinal mucosa DNA solutions (tissues with a high mitotic activity) the content of the DNA defects is higher in old animals than in young ones. The injuring effect of gamma-rays is more pronounced in experiments with intestinal mucosa DNA than with liver DNA (tissue with a low mitotic activity). In liver DNA the content of the defects caused by gamma-rays does not depend on the animal age.

Age Factors↗
PubMed2006

The role of a metastable RNA secondary structure in hepatitis delta virus genotype III RNA editing.

RNA editing plays a critical role in the life cycle of hepatitis delta virus (HDV). The host editing enzyme ADAR1 recognizes specific RNA secondary structure features around the amber/W site in the HDV antigenome and deaminates the amber/W adenosine. A previous report suggested that a branched secondary structure is necessary for editing in HDV genotype III. This branched structure, which is distinct from the characteristic unbranched rod structure required for HDV replication, was only partially characterized, and knowledge concerning its formation and stability was limited. Here, we examine the secondary structures, conformational dynamics, and amber/W site editing of HDV genotype III RNA using a miniaturized HDV genotype III RNA in vitro. Computational analysis of this RNA using the MPGAfold algorithm indicated that the RNA has a tendency to form both metastable and stable unbranched secondary structures. Moreover, native polyacrylamide gel electrophoresis demonstrated that this RNA forms both branched and unbranched rod structures when transcribed in vitro. As predicted, the branched structure is a metastable structure that converts readily to the unbranched rod structure. Only branched RNA was edited at the amber/W site by ADAR1 in vitro. The structural heterogeneity of HDV genotype III RNA is significant because not only are both conformations of the RNA functionally important for viral replication, but the ratio of the two forms could modulate editing by determining the amount of substrate RNA available for modification.

Adenosine Deaminase↗
PubMed1994

Secondary structure of the single-stranded DNA binding protein encoded by filamentous phage Pf3 as determined by NMR.

Nuclear magnetic resonance spectroscopy was employed to study the single-stranded DNA binding protein encoded by the filamentous Pseudomonas bacteriophage Pf3. The protein is 78 amino acids long and occurs in solution predominantly as a homodimer with a molecular mass of 18 kDa. Sequence-specific 1H and 15N resonance assignments have been obtained using homo- and heteronuclear two- and three-dimensional experiments. The secondary structure of the protein monomer was determined from a qualitative interpretation of nuclear Overhauser enhancement spectra and amide exchange data. It consists of a five-stranded antiparallel beta-sheet and three beta-hairpins. Problems caused by the protein's tendency to aggregate at concentrations needed for NMR spectroscopy were largely overcome by designing a mutant (Phe36-->His) which exhibits significantly improved solubility characteristics over the wild-type protein. It is shown that this mutation only locally affects the structure of the protein; the chemical shifts of the wild-type and mutant species differ only for a few residues near the site of the mutation, and the secondary structures of the proteins are identical. The secondary structure of the Pf3 single-stranded DNA binding protein is compared to that of the Ff gene V protein, the only single-stranded DNA binding protein for which the complete three-dimensional structure is known to date [Folkers, P. J. M., Nilges, M., Folmer, R. H. A., Konings, R. N. H. & Hilbers, C. W. (1994) J. Mol. Biol. 236, 229-246; Skinner, M. M., Zhang, H., Leschnitzer, D. H., Guan, Y., Bellamy, H., Sweet, R. M., Gray, C. W., Konings, R. N. H., Wang, A. H.-J. & Terwilliger, T. C. (1994) Proc. Natl Acad. Sci. USA 91, 2071-2075]. It is found that the secondary structures of the two proteins are very similar which supports the hypothesis that a five-stranded antiparallel beta-sheet with protruding beta-hairpins is a common motif in a certain class of single-stranded DNA binding proteins. In addition, the sequence and folding predicted earlier for the DNA binding wing in the single-stranded DNA binding protein of phage Pf3 [de Jong, E. A. M., van Duynhoven, J. P. M., Harmsen, B. J. M., Tesser, G. I., Konings, R. N. H. & Hilbers, C. W. (1989) J. Mol. Biol. 206, 133-156] is borne out by the present study. It closely resembles that in the single-stranded DNA binding protein of phage Ff, which may indicate that such a wing is a recurrent motif as well.

Amino Acid Sequence↗
PubMed2004

Incorporating chemical modification constraints into a dynamic programming algorithm for prediction of RNA secondary structure.

A dynamic programming algorithm for prediction of RNA secondary structure has been revised to accommodate folding constraints determined by chemical modification and to include free energy increments for coaxial stacking of helices when they are either adjacent or separated by a single mismatch. Furthermore, free energy parameters are revised to account for recent experimental results for terminal mismatches and hairpin, bulge, internal, and multibranch loops. To demonstrate the applicability of this method, in vivo modification was performed on 5S rRNA in both Escherichia coli and Candida albicans with 1-cyclohexyl-3-(2-morpholinoethyl) carbodiimide metho-p-toluene sulfonate, dimethyl sulfate, and kethoxal. The percentage of known base pairs in the predicted structure increased from 26.3% to 86.8% for the E. coli sequence by using modification constraints. For C. albicans, the accuracy remained 87.5% both with and without modification data. On average, for these sequences and a set of 14 sequences with known secondary structure and chemical modification data taken from the literature, accuracy improves from 67% to 76%. This enhancement primarily reflects improvement for three sequences that are predicted with <40% accuracy on the basis of energetics alone. For these sequences, inclusion of chemical modification constraints improves the average accuracy from 28% to 78%. For the 11 sequences with <6% pseudoknotted base pairs, structures predicted with constraints from chemical modification contain on average 84% of known canonical base pairs.

Algorithms↗
PubMed1988

Computer-assisted primary and secondary structure analyses of DNA polymerases of herpes simplex, Epstein-Barr and varicella zoster viruses reveal conserved domains with some homology to DNA-binding domain in E. coli DNA pol I.

The primary and secondary structure of herpes simplex virus type 1 (HSV-1), varicella-zoster (VZV) and Epstein-Barr virus (EBV) DNA polymerases was calculated by means of computer programs. The comparison of HSV-1 polymerase (pol) sequence to the known primary and tertiary structure of E. coli DNA pol I revealed five short homologous sequences, one of which coincided with the alpha-helical structure of the DNA-binding domain of E. coli DNA pol. Comparison by primary and secondary structure computer programs of the three DNA polymerases coded by herpesviruses HSV-1, VZV and EBV led to the identification of polypeptide sequences shared by the three DNA pols. In a similar way, the secondary structure of the DNA pol polypeptide in the vicinity of the mutation leading to PAA resistance in HSV-1 DNA pol helped to identify the role of this sequence in the binding of phosphate donated by the nucleoside triphosphate molecule which binds to the DNA pol. Although the computer secondary structure programs are about 60% accurate, it was possible to obtain new information on the properties of certain domains in the DNA polymerases of HSV-1, VZV and EBV.

Amino Acid Sequence↗
PubMed2006

Secondary structure spatial conformation footprint: a novel method for fast protein structure comparison and classification.

BACKGROUND: Recently a new class of methods for fast protein structure comparison has emerged. We call the methods in this class projection methods as they rely on a mapping of protein structure into a high-dimensional vector space. Once the mapping is done, the structure comparison is reduced to distance computation between corresponding vectors. As structural similarity is approximated by distance between projections, the success of any projection method depends on how well its mapping function is able to capture the salient features of protein structure. There is no agreement on what constitutes a good projection technique and the three currently known projection methods utilize very different approaches to the mapping construction, both in terms of what structural elements are included and how this information is integrated to produce a vector representation. RESULTS: In this paper we propose a novel projection method that uses secondary structure information to produce the mapping. First, a diverse set of spatial arrangements of triplets of secondary structure elements, a set of structural models, is automatically selected. Then, each protein structure is mapped into a high-dimensional vector of "counts" or footprint, where each count corresponds to the number of times a given structural model is observed in the structure, weighted by the precision with which the model is reproduced. We perform the first comprehensive evaluation of our method together with all other currently known projection methods. CONCLUSION: The results of our evaluation suggest that the type of structural information used by a projection method affects the ability of the method to detect structural similarity. In particular, our method that uses the spatial conformations of triplets of secondary structure elements outperforms other methods in most of the tests.

Computational Biology↗
PubMed1983

Sequences of the 5S rRNAs of Azotobacter vinelandii, Pseudomonas aeruginosa and Pseudomonas fluorescens with some notes on 5S RNA secondary structure.

Recently published alignments of available 5 S rRNA sequences have shown that a rigid base pairing pattern, pointing to the existence of a universal five-helix secondary structure for all 5 S RNAs, can be superimposed on such alignments. For a few species, the alignment and the base pairing pattern show distortions with respect to the large majority of sequences. Their 5 S RNAs may form exceptional secondary structures, or there may just be errors in the published sequences. We have examined such a case, Pseudomonas fluorescens, and found the sequence to be in error. The corrected sequence, as well as those of the related species Azotobacter vinelandii and Pseudomonas aeruginosa, fit perfectly in the 5 S RNA sequence alignment and in the five-helix secondary structure model. There exists comparative evidence for the frequent presence of non-standard base pairs at several points of the 5 S RNA secondary structure.

Azotobacter↗
PubMed1994

The mitochondrial ribosomal RNA genes of the nematodes Caenorhabditis elegans and Ascaris suum: consensus secondary-structure models and conserved nucleotide sets for phylogenetic analysis.

The small- and large-subunit mitochondrial ribosomal RNA genes (mt-s-rRNA and mt-l-rRNA) of the nematode worms Caenorhabditis elegans and Ascaris suum encode the smallest rRNAs so far reported for metazoa. These size reductions correlate with the previously described, smaller, structurally anomalous mt-tRNAs of C. elegans and A. suum. Using primer extension analysis, the 5' end nucleotides of the mt-s-rRNA and mt-l-rRNA genes were determined to be adjacent to the 3' end nucleotides of the tRNA(Glu) and tRNA(His) genes, respectively. Detailed, consensus secondary-structure models were constructed for the mt-s-rRNA genes and the 3' 64% of mt-l-rRNA genes of the two nematodes. The mt-s-rRNA secondary-structure model bears a remarkable resemblance to the previously defined universal core structure of E. coli 16S rRNA: most of the nucleotides that have been classified as variable or semiconserved in the E. coli model appear to have been eliminated from the C. elegans and A. suum sequences. Also, the secondary structure model constructed for the 3' 64% of the mt-l-rRNA is similar to the corresponding portion of the previously defined E. coli 23S rRNA core secondary structure. The proposed C. elegans/A. suum mt-s-rRNA and mt-l-rRNA models include all of the secondary-structure element-forming sequences that in E. coli rRNAs contain nucleotides important for A-site and P-site (but not E-site) interactions with tRNAs. Sets of apparently homologous sequences within the mt-s-rRNA and mt-l-rRNA core structures, derived by alignment of the C. elegans and A. suum mt-rRNAs to the corresponding mt-rRNAs of other eukaryotes, and E. coli rRNAs were used in maximum-likelihood analyses. The patterns of divergence of metazoan phyla obtained show considerable agreement with the most prevalent metazoan divergence patterns derived from more classical, morphological, and developmental data.

Animals↗
PubMed1998

PASSML: combining evolutionary inference and protein secondary structure prediction.

MOTIVATION: Evolutionary models of amino acid sequences can be adapted to incorporate structure information; protein structure biologists can use phylogenetic relationships among species to improve prediction accuracy. Results : A computer program called PASSML ('Phylogeny and Secondary Structure using Maximum Likelihood') has been developed to implement an evolutionary model that combines protein secondary structure and amino acid replacement. The model is related to that of Dayhoff and co-workers, but we distinguish eight categories of structural environment: alpha helix, beta sheet, turn and coil, each further classified according to solvent accessibility, i.e. buried or exposed. The model of sequence evolution for each of the eight categories is a Markov process with discrete states in continuous time, and the organization of structure along protein sequences is described by a hidden Markov model. This paper describes the PASSML software and illustrates how it allows both the reconstruction of phylogenies and prediction of secondary structure from aligned amino acid sequences. AVAILABILITY: PASSML 'ANSI C' source code and the example data sets described here are available at http://ng-dec1.gen.cam.ac.uk/hmm/Passml.html and 'downstream' Web pages. CONTACT: P.Lio@gen.cam.ac.uk

Adenylate Kinase↗
PubMed1999

Improved secondary structure predictions for a nicotinic receptor subunit: incorporation of solvent accessibility and experimental data into a two-dimensional representation.

Abstract A refined prediction of the nicotinic acetylcholine receptor (nAChR) subunits' secondary structure was computed with third-generation algorithms. The four selected programs, PHD, Predator, DSC, and NNSSP, based on different prediction approaches, were applied to each sequence of an alignment of nAChR and 5-HT3 receptor subunits, as well as a larger alignment with related subunit sequences from glycine and GABA receptors. A consensus prediction was computed for the nAChR subunits through a "winner takes all" method. By integrating the probabilities obtained with PHD, DSC, and NNSSP, this prediction was filtered in order to eliminate the singletons and to more precisely establish the structure limits (only 4% of the residues were modified). The final consensus secondary structure includes nine alpha-helices (24.2% of the residues, with an average length of 13.9 residues) and 17 beta-strands (22.5% of the residues, with an average length of 6.6 residues). The large extracellular domain is predicted to be mainly composed of beta-strands, with only two helices at the amino-terminal end. The transmembrane segments are predicted to be in a mixed alpha/beta topology (with a predominance of alpha-helices), with no known equivalent in the current protein database. The cytoplasmic domain is predicted to consist of two well-conserved amphipathic helices joined together by an unfolded stretch of variable length and sequence. In general, the segments predicted to occur in a periodic structure correspond to the more conserved regions, as defined by an analysis of sequence conservation per position performed on 152 superfamily members. The solvent accessibility of each residue was predicted from the multiple alignments with PHDacc. Each segment with more than three exposed residues was assumed to be external to the core protein. Overall, these data constitute an envelope of structural constraints. In a subsequent step, experimental data relative to the extracellular portion of the complete receptor were incorporated into the model. This led to a proposed two-dimensional representation of the secondary structure in which the peptide chain of the extracellular domain winds alternatively between the two interfaces of the subunit. Although this representation is not a tertiary structure and does not lead to predictions of specific beta-beta interaction, it should provide a basic framework for further mutagenesis investigations and for fold recognition (threading) searches.

Algorithms↗
PubMed2006

Improving the sensitivity and specificity of protein homology search by incorporating predicted secondary structures.

In this paper, we improve the homology search performance by the combination of the predicted protein secondary structures and protein sequences. Previous research suggested that the straightforward combination of predicted secondary structures did not improve the homology search performance, mostly because of the errors in the structure prediction. We solved this problem by taking into account the confidence scores output by the prediction programs.

Computational Biology↗
PubMed1997

Resonance assignments, secondary structure and topology of leukaemia inhibitory factor in solution.

The chemical shift assignments and secondary structure of a murine-human chimera, MH35, of leukaemia inhibitory factor (LIF), a 180-residue protein of molecular mass 20 kDa, have been determined from multidimensional heteronuclear NMR spectra acquired on a uniformly 13C, 15N-labelled sample. Secondary structure elements were defined on the basis of chemical shifts, NH-C alpha H coupling constants; medium-range NOEs and the location of slowly exchanging amide protons. The protein contains four alpha-helices, the relative orientations of which were determined on the basis of long-range, interhelical NOEs. The four helices are arranged in an up-up-down-down orientation, as found in other four-helical bundle cytokines. The overall topology of MH35-LIF is similar to that of the X-ray crystallographic structure for murine LIF [Robinson et al. (1994) Cell, 77, 1101-1116]. Differences between the X-ray structure and the solution structure are evident in the N-terminal tail, where the solution structure has a trans-Pro17 compared with the cis-Pro17 found in the crystal structure and the small antiparallel beta-sheet encompassing residues in the N-terminus and CD loop in the crystal structure is less stable.

Amino Acid Sequence↗
PubMed1998

Use of a neural network secondary structure prediction to define targets for mutagenesis of herpes simplex virus glycoprotein B.

Herpes simplex virus glycoprotein B (HSV gB) is essential for penetration of virus into cells, for cell-to-cell spread of virus, and for cell-cell fusion. Every member of the family Herpesviridae has a gB homolog, underlining its importance. The antigenic structure of gB has been studied extensively, but little is known about which regions of the protein are important for its roles in virus entry and spread. In contrast to successes with other HSV glycoproteins, attempts to map functional domains of gB by insertion mutagenesis have been largely frustrated by the misfolding of most mutants. The present study shows that this problem can be overcome by targeting mutations to the loop regions that connect alpha-helices and beta-strands, avoiding the helices and strands themselves. The positions of loops in the primary sequence were predicted by the PHD neural network procedure, using a multiple sequence alignment of 19 alphaherpesvirus gB sequences as input. Comparison of the prediction with a panel of insertion mutants showed that all mutants with insertions in predicted alpha-helices or beta-strands failed to fold correctly and consequently had no activity in virus entry; in contrast, half the mutants with insertions in predicted loops were able to fold correctly. There are 27 predicted loops of four or more residues in gB; targeting of mutations to these regions will minimize the number of misfolded mutants and maximize the likelihood of identifying functional domains of the protein.

Amino Acid Sequence↗
PubMed2003

MANIFOLD: protein fold recognition based on secondary structure, sequence similarity and enzyme classification.

We present a protein fold recognition method, MANIFOLD, which uses the similarity between target and template proteins in predicted secondary structure, sequence and enzyme code to predict the fold of the target protein. We developed a non-linear ranking scheme in order to combine the scores of the three different similarity measures used. For a difficult test set of proteins with very little sequence similarity, the program predicts the fold class correctly in 34% of cases. This is an over twofold increase in accuracy compared with sequence-based methods such as PSI-BLAST or GenTHREADER, which score 13-14% correct first hits for the same test set. The functional similarity term increases the prediction accuracy by up to 3% compared with using the combination of secondary structure similarity and PSI-BLAST alone. We argue that using functional and secondary structure information can increase the fold recognition beyond sequence similarity.

Algorithms↗
PubMed1988

A multivariate analysis method for discriminating protein secondary structural segments.

Using discriminant analysis, three types of protein secondary structure segments--helices, beta-strands and coils--are discriminated by amino acid sequence information alone. A variable in the discriminant analysis is defined by the amino acid index used to represent the sequence data and by the calculation method used to extract a feature in this representation. Thus, the three types of secondary structure segments derived from a set of non-homologous proteins from the Protein Data Bank are analyzed by 888 variables, which correspond to the mean, standard deviation, 3.6-residue periodicity and 2-residue periodicity for the numerical profiles determined from 222 published amino acid indices. These variables are combined to obtain best discrimination of the three types of segments. When up to three variables are combined, the best discrimination rate was 75%. The variables selected consist of the mean of alpha propensity (or turn propensity), the mean of beta propensity, and the 3.6-residue periodicity of hydrophobicity. This variable selection procedure can also be applied to other types of discrimination problem, once groups of sequence data are properly organized.

Amino Acid Sequence↗