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PubMed1995

Accurate prediction of protein secondary structural class with fuzzy structural vectors.

The prerequisites for accurate prediction of protein secondary structural class (all-alpha, all-beta, alpha+beta, alpha/beta or multidomain) were studied, and a new similarity-based method is presented for the prediction of the secondary structural class of a protein from its sequence. The new method uses representatives of nuclear families as a learning set. For the sequence to be predicted, the method produces a vector of certainty factors called a fuzzy structural vector. Validation with independent test sets shows that the prediction accuracy of the proposed method has clear dependency on the representativity of the learning set. The representatives obtained from the nuclear families of the Brookhaven Protein Data Bank (PDB) were shown to give accurate predictions for PDB proteins, whilst the amino acid composition-based methods used previously achieve their maximum predictability with relatively limited learning sets, and they remain inaccurate even with highly representative learning sets. The usability of the new method is increased further by the fuzzy structural vectors, which substantially reduce the risk of misclassification and realistically describe vague secondary structural tendencies.

Algorithms↗
PubMed1989

Predicted structures of apolipoprotein II mRNA constrained by nuclease and dimethyl sulfate reactivity: stable secondary structures occur predominantly in local domains via intraexonic base pairing.

Analyses of apolipoprotein II mRNA with chemical and enzymatic probes showed that double- and single-stranded regions were distributed uniformly along the mRNA except for a large (72 nucleotides) single-stranded region containing the translation stop codon. Secondary structure models constrained by the experimental data were made by varying the distance (along the mRNA) over which base pairing was allowed. Four prominent secondary structures were seen with restrictions of 165, 330, or 659 nucleotides suggesting that such structures from via local interactions over distances of 50-120 nucleotides. Predicted long range interactions involve only 2-3 base pairs while local interactions involve helices of 4-10 base pairs. Predicted helices of greater than or equal to 4 base pairs occur primarily within exons, raising the possibility that prominent secondary structures in mRNAs may be largely due to intraexonic base pairing. Tests of single- and double-stranded domains by oligonucleotide-directed RNase H cleavage and primer extension were in accord with the structure model and with nuclease and chemical modification data. The model predicting base pairing between the coding and the 3' noncoding regions was tested by RNase H cleavage followed by oligo(dT)-cellulose chromatography to separate 5' and 3' mRNA fragments. Most (82%) of the 5' fragment remained associated with the 3' noncoding region in a structure with a tm = 50 degrees C in 0.2 M Na+ suggesting that this stem could be stable in vivo. This stem may be stable in the isolated mRNA, but would likely occur transiently in polyribosomal apolipoprotein II mRNA due to ribosome transit through the 5' side of the stem. Alternate structures may occur in this region during ribosome transit and play a role in translation termination or in determining the susceptibility of the mRNA to degradation.

Animals↗
PubMed1995

Protein secondary structure prediction by the analysis of variation and conservation in multiple alignments.

A number of methods exist for the prediction of protein secondary structure from primary sequence. One method identifies variable charged and conserved hydrophobic residues within large multiple alignments as a means of indicating outside and inside sites respectively in the protein structure. These sites are then manually fitted to secondary structure templates to generate a secondary structure prediction. Using the existing theoretical bases of this method, we present an algorithm (STAMA) which automatically carries out the initial variation/conservation analysis of the alignment. We also test the accuracy of complete predictions carried out by manual fitting of the STAMA-derived assignments to structure templates, using five large multiple alignments each including a protein of known structure. The method was found on average to predict only 57% of residues in the correct secondary structure, and was only as accurate as predictions carried out using the established and automated method of Garnier, Osguthorpe and Robson (1978) applied to a single sequence. When used in conjunction with other secondary structure prediction methods, however, the resulting consensus predictions were found to be very accurate, with 78% of the elements (alpha helices or beta strands) for which a consensus could be obtained being predicted correctly. The algorithm presented here, plus the assessment of the accuracy of prediction generated by this method, should enable this predictive approach to receive informed general use.

Algorithms↗
PubMed1982

Studies on the relationship of disulfide bonds to the formation and maintenance of secondary structure in chicken egg white lysozyme.

The dependence of secondary structure on SS content was examined to gain further insight into the role of SS bond formation in chain folding. Lysozyme was reduced to various levels, and the products were studied with respect to remaining native structure. Reductions were carried out in the absence of denaturant. Thus, the observed changes were not attributable to a general denaturing effect, but more specifically to cleavage of SS bonds. The products of reduction were found by gel filtration chromatography to contain both polymeric and monomeric forms. By "fingerprinting", the monomers gave no indication of having undergone SS interchange, and specific cleavage of native SS bonds was indicated by a stepwise disappearance of SS-containing peptides with increasing reduction level. Ion-exchange chromatography of the carboxymethylated monomers gave the three possible reduction intermediates, containing two, four, and six carboxymethylcysteine residues per mole, in addition to the fully reduced form. The intermediates exhibited circular dichroic (CD) characteristics that were clearly nonnative, indicating alteration of the secondary structure throughout all stages of reduction. Concomitantly, there were extensive losses of enzymatic activity at intermediate levels, while no activity was found for the fully reduced form. Partially and fully reduced lysozymes were also examined for their abilities to resume native secondary structure in the absence of SS formation, as would be evidenced by a reversion to native CD characteristics. Despite literature indications of native structure in the reduced protein as observed from examination of CD behavior, none was found in the present effort, under a variety of experimental conditions. These observations are consistent with an essential role of SS bonds in forming and maintaining a major portion of the native secondary structure in lysozyme.

Animals↗
PubMed1990

Alignment of protein sequences using secondary structure: a modified dynamic programming method.

A method for comparison of protein sequences based on their primary and secondary structure is described. Protein sequences are annotated with predicted secondary structures (using a modified Chou and Fasman method). Two lettered code sequences are generated (Xx, where X is the amino acid and x is its annotated secondary structure). Sequences are compared with a dynamic programming method (STRALIGN) that includes a similarity matrix for both the amino acids and secondary structures. The similarity value for each paired two-lettered code is a linear combination of similarity values for the paired amino acids and their annotated secondary structures. The method has been applied to eight globin proteins (28 pairs) for which the X-ray structure is known. For protein pairs with high primary sequence similarity (greater than 45%), STRALIGN alignment is identical to that obtained by a dynamic programming method using only primary sequence information. However, alignment of protein pairs with lower primary sequence similarity improves significantly with the addition of secondary structure annotation. Alignment of the pair with the least primary sequence similarity of 16% was improved from 0 to 37% 'correct' alignment using this method. In addition, STRALIGN was successfully applied to seven pairs of distantly related cytochrome c proteins, and three pairs of distantly related picornavirus proteins.

Amino Acid Sequence↗
PubMed1987

Prediction of the secondary structures of stefins and cystatins, the low-molecular mass protein inhibitors of cysteine proteinases.

A procedure for classifying proteins of known sequence into structurally similar groups was developed on the basis of the Argos parametric approach. It is shown that stefins and cystatins constitute two structurally well resolved, but homologous groups of proteins. Furthermore, it is very probable that segments of secondary structures within each family are conserved, although significant differences between stefins and cystatins are indicated at the level of secondary structure. Next, secondary structures of all sequenced stefins and cystatins were predicted and used in the construction of secondary structures of the "typical stefin" and the "typical cystatin". Results were interpreted in the light of evolution and inhibition mechanism: Alignment of the "typical stefin" versus the "typical cystatin" secondary structure segments suggests that the divergence of stefin and cystatin families did not occur by a gene fusion event, but only by a mechanism of substitution, insertion and/or deletion. The central region of low-molecular mass cystatins, which is assumed to interact with cysteine proteinases, is predicted to be in a beta-sheet conformation. This resembles the beta-sheet in the active site of "standard mechanism" serine proteinases inhibitors.

Amino Acid Sequence↗
PubMed2006

Non-protein amino acids in the design of secondary structure scaffolds.

The use of stereochemically constrained amino acids permits the design of short peptides as models for protein secondary structures. Amino acid residues that are restrained to a limited range of backbone torsion angles (phi-psi) may be used as folding nuclei in the design of helices and beta-hairpins. alpha-Amino-isobutyric acid (Aib) and related Calphaalpha dialkylated residues are strong promoters of helix formation, as exemplified by a large body of experimentally determined structures of helical peptides. DPro-Xxx sequences strongly favor type II' turn conformations, which serve to nucleate registered beta-hairpin formation. Appropriately positioned DPro-Xxx segments may be used to nucleate the formation of multistranded antiparallel beta-sheet structures. Mixed (alpha/beta) secondary structures can be generated by linking rigid modules of helices and beta-hairpins. The approach of using stereochemically constrained residues promotes folding by limiting the local structural space at specific residues. Several aspects of secondary structure design are outlined in this chapter, along with commonly used methods of spectroscopic characterization.

Aminoisobutyric Acids↗
PubMed1999

Using imperfect secondary structure predictions to improve molecular structure computations.

MOTIVATION: Until ab initio structure prediction methods are perfected, the estimation of structure for protein molecules will depend on combining multiple sources of experimental and theoretical data. Secondary structure predictions are a particularly useful source of structural information, but are currently only approximately 70% correct, on average. Structure computation algorithms which incorporate secondary structure information must therefore have methods for dealing with predictions that are imperfect. EXPERIMENTS PERFORMED: We have modified our algorithm for probabilistic least squares structural computations to accept 'disjunctive' constraints, in which a constraint is provided as a set of possible values, each weighted with a probability. Thus, when a helix is predicted, the distances associated with a helix are given most of the weight, but some weights can be allocated to the other possibilities (strand and coil). We have tested a variety of strategies for this weighting scheme in conjunction with a baseline synthetic set of sparse distance data, and compared it with strategies which do not use disjunctive constraints. RESULTS: Naive interpretations in which predictions were taken as 100% correct led to poor-quality structures. Interpretations that allow disjunctive constraints are quite robust, and even relatively poor predictions (58% correct) can significantly increase the quality of computed structures (almost halving the RMS error from the known structure). CONCLUSIONS: Secondary structure predictions can be used to improve the quality of three-dimensional structural computations. In fact, when interpreted appropriately, imperfect predictions can provide almost as much improvement as perfect predictions in three-dimensional structure calculations.

Algorithms↗
PubMed2007

Similarity of RNA secondary structures.

In this article, we propose a relatively similar measure to compare RNA secondary structures. We first transform an RNA secondary structure into a special sequence representation. Then, on the basis of symbolic sequence complexity, we obtain the relative distance of RNA secondary structures. The examination of similarities/dissimilarities of a set of RNA secondary structures at the 3'-terminus of different viruses illustrates the utility of the approach.

Base Sequence↗
PubMed2005

Combining prediction of secondary structure and solvent accessibility in proteins.

Owing to the use of evolutionary information and advanced machine learning protocols, secondary structures of amino acid residues in proteins can be predicted from the primary sequence with more than 75% per-residue accuracy for the 3-state (i.e., helix, beta-strand, and coil) classification problem. In this work we investigate whether further progress may be achieved by incorporating the relative solvent accessibility (RSA) of an amino acid residue as a fingerprint of the overall topology of the protein. Toward that goal, we developed a novel method for secondary structure prediction that uses predicted RSA in addition to attributes derived from evolutionary profiles. Our general approach follows the 2-stage protocol of Rost and Sander, with a number of Elman-type recurrent neural networks (NNs) combined into a consensus predictor. The RSA is predicted using our recently developed regression-based method that provides real-valued RSA, with the overall correlation coefficients between the actual and predicted RSA of about 0.66 in rigorous tests on independent control sets. Using the predicted RSA, we were able to improve the performance of our secondary structure prediction by up to 1.4% and achieved the overall per-residue accuracy between 77.0% and 78.4% for the 3-state classification problem on different control sets comprising, together, 603 proteins without homology to proteins included in the training. The effects of including solvent accessibility depend on the quality of RSA prediction. In the limit of perfect prediction (i.e., when using the actual RSA values derived from known protein structures), the accuracy of secondary structure prediction increases by up to 4%. We also observed that projecting real-valued RSA into 2 discrete classes with the commonly used threshold of 25% RSA decreases the classification accuracy for secondary structure prediction. While the level of improvement of secondary structure prediction may be different for prediction protocols that implicitly account for RSA in other ways, we conclude that an increase in the 3-state classification accuracy may be achieved when combining RSA with a state-of-the-art protocol utilizing evolutionary profiles. The new method is available through a Web server at http://sable.cchmc.org.

Amino Acid Sequence↗
PubMed2000

Studies on the relationships between the synonymous codon usage and protein secondary structural units.

The relationship between the synonymous codon usage and protein secondary structural elements (alpha helices and beta sheets) were reinvestigated by taking structural information of proteins from Protein Data Bank (PDB) and their corresponding mRNA sequences from GenBank for four different organisms E. coli, B. subtilis, S. cerevisiae, and Homo sapiens. It was observed that synonymous codon families have non-random codon usage, but there does not exist any species invariant universal correlation between the synonymous codon usage and protein secondary structural elements. The secondary structural units of proteins can be distinguished from the occurrences of bases at the second codon position.

Amino Acids↗
PubMed1981

A computer method for construction of secondary structure from polynucleotide sequence. Possible structure of the bacterial replication origin.

A computer method to search the possible secondary structure of a long polynucleotide was developed. As a criterion for the stabilization of a secondary structure, free energy originating from base-pairing was employed, since the structure in solution would be at the free energy minimum. The method is summarized as follows: all possible helices are collected from a given nucleotide sequence under restrictions that the length of a helix is greater than N0 bases (e.g., four bases) and the free energy of the helix calculated according to free energies of two successive sequence-dependent basepairs is lower than E0 (e.g., -5 kcal/mol). The search of secondary structures of low free energy is performed by connecting one helix to another without allowing any base-pairing between loops. For connecting single-stranded regions, destabilizing free energy of 2--3 kcal/mol is added. The method was first applied to several tRNAs and the clover-leaf structure of tRNA was obtained as a free energy minimum. Then, possible secondary structures of the replication origin regions of the Escherichia coli and Salmonella typhimurium chromosomes were examined by the method, assuming that one of the strands in the origin region takes a specific secondary structure. The lowest-energy structure for the E. coli origin was found to be approximately identical to that for the S. typhimurium origin region.

Base Sequence↗
PubMedDate not supplied

[Molecular dynamics of bending fluctuations in the protein secondary structures].

A comparative study of the dynamics of protein secondary structure elements by the example of alpha-helices of myoglobin, barnase, polylysine, and polyglycine and beta-layers of barnase and GFP was carried out by the methods of molecular dynamics. The effective Young's moduli of both free secondary structure elements and those built in the protein globule were determined. A heterogeneity of the elastic properties of the secondary structure elements was found. The melting of myoglobin alpha-helix in a virtual viscous medium was studied.

Bacterial Proteins↗
PubMed2004

Secondary structure prediction of interacting RNA molecules.

Computational tools for prediction of the secondary structure of two or more interacting nucleic acid molecules are useful for understanding mechanisms for ribozyme function, determining the affinity of an oligonucleotide primer to its target, and designing good antisense oligonucleotides, novel ribozymes, DNA code words, or nanostructures. Here, we introduce new algorithms for prediction of the minimum free energy pseudoknot-free secondary structure of two or more nucleic acid molecules, and for prediction of alternative low-energy (sub-optimal) secondary structures for two nucleic acid molecules. We provide a comprehensive analysis of our predictions against secondary structures of interacting RNA molecules drawn from the literature. Analysis of our tools on 17 sequences of up to 200 nucleotides that do not form pseudoknots shows that they have 79% accuracy, on average, for the minimum free energy predictions. When the best of 100 sub-optimal foldings is taken, the average accuracy increases to 91%. The accuracy decreases as the sequences increase in length and as the number of pseudoknots and tertiary interactions increases. Our algorithms extend the free energy minimization algorithm of Zuker and Stiegler for secondary structure prediction, and the sub-optimal folding algorithm by Wuchty et al. Implementations of our algorithms are freely available in the package MultiRNAFold.

Algorithms↗
PubMed1994

Secondary structure characterization of microparticulate insulin powders.

The secondary structure content of microparticulate insulin powders produced by the supercritical antisolvent (SAS) precipitation technique was investigated via Raman spectroscopy. Precipitate samples were generated at 25 and 35 degrees C processing temperatures. Both precipitate samples gave amide I band spectra that were shifted roughly +10 cm-1 relative to the commercial powder. The corresponding secondary structure estimates had significantly increased beta-sheet contents with concomitant decreases in alpha-helix contents relative to the commercial protein; the sum of beta-turn and random coil content remained essentially unchanged. The magnitude of the perturbation was slightly greater for the 35 degrees C sample. Dissolution of the commercial powder and precipitates in 0.01 M HCl yielded solution structure estimates similar to that of the commercial powder. An analysis of insulin in dimethyl sulfoxide, the suspending solvent in the SAS process, indicated that some, but not all, of the structural change observed for the precipitate samples may be attributed to solvent exposure. These results are suggestive of extensive beta-sheet-mediated intermolecular interactions in precipitate states, consistent with analyses of irreversible protein aggregate/fibril states. Interestingly, unlike irreversible protein aggregates, the insulin powders recover essentially full biological activity on reconstitution.

Chemical Phenomena↗
PubMed1999

Putative secondary structures of unusually long strepsipteran SSU rRNAs and its phylogenetic implications.

We constructed the putative secondary structures of the small subunit rRNAs (SSU rRNA) from three strepsipteran insects. The primary sequences of the strepsipteran SSU rRNAs are unusually long due to unique and long insertions. In spite of these insertions, the basic shapes of their secondary structures are well maintained as shown in those of other eukaryotes, because these insertions appear mainly in the variable regions. The secondary structures for the V1, V3, V5, V8, and V9 regions are well conserved, even though the primary structures of V1, V5, and V8 regions are quite variable. However, the predicted secondary structures for the V2, V4, and V7 regions are quite different from those of other insects. In the V4 and V7 regions, helices specific to the Strepsiptera exist. These helices have not been reported in other organisms so far. Similarly, four eukaryotic specific helices (E8-1, E10-2, E23-4 and E45-1) not reported in insects exist in the V2, V4, and V8 regions. These helices are formed by the inserted sequences. The secondary structures of the expanded segments of the strepsipteran SSU rRNA were applied to infer the phylogenetic position of Strepsiptera, one of the most enigmatic problems in insect phylogeny. Only the secondary structure of the V7 region showed the weak Strepsiptera/Diptera sister-group relationship.

Animals↗
PubMed1981

Periodicity in DNA primary structure is defined by secondary structure of the coded protein.

A 10.5-base periodicity found earlier is inherent in both eu- and prokaryotic coding nucleotide sequences. In the case of noncoding eukaryotic sequences no periodicity is found, so the 10.5-base oscillation seemingly does not correlate with the nucleosomal organization of DNA. It is shown that the DNA fragments, coding the alpha-helical protein segments, manifest the pronounced 10.5-base periodicity, while those regions of DNA which code the beta-structure have a 6-base oscillation. The repeating pattern of nucleotide sequences can be used for comparison of the DNA segments with low degree of homology.

Animals↗
PubMed1997

Determination of secondary structure of normal fibrin from human peripheral blood.

The secondary structure of human fibrin from normal donors and from bovine and suilline plasma was studied by Fourier transform ir spectroscopy and a quantitative analysis of its secondary structure was suggested. For this purpose, a previously experimented spectrum deconvolution procedure based on the use of the Conjugate Gradient Minimisation Algorithm with the addition of suitable constraints was applied to the analysis of conformation-sensitive amide bands. This procedure was applied to amide I and III analysis of bovine and suilline fibrin, obtained industrially, and to amide III analysis of human fibrin clots. The analysis of both amide I and III in the first case was useful in order to test the reliability of the method. We found bovine, suilline, and human fibrin to contain about 30% alpha-helix (amide I and III components at 1653 cm-1, and 1312 and 1284 cm-1, respectively), 40% beta-sheets (amide I and III components at 1625 and 1231 cm-1, respectively) and 30% turns (amide I and III components at 1696, 1680, 1675 cm-1, and 1249 cm-1, respectively). The precision of the quantitative determination depends on the amount of these structures in the protein. Particularly, the coefficient of variation is < 10% for percentage values of amide I and III components > 15 and 5%, respectively. The good agreement of our quantitative data, obtained separately by amide I and amide III analysis, and consistent with a previous fibrinogen (from commercial sources) study that reports only information about fibrin beta-sheet content obtained by factor analysis, leads us to believe that the amounts of secondary structures found (alpha-helix, beta-sheets, and turns) are accurate.

Algorithms↗