Search PubMed⌕ Search

Biomedical subjects

J Heringa

Publications and source records attributed to J Heringa.

At least 19 recordsLinked to original sources
PubMed2000

T-Coffee: A novel method for fast and accurate multiple sequence alignment.

We describe a new method (T-Coffee) for multiple sequence alignment that provides a dramatic improvement in accuracy with a modest sacrifice in speed as compared to the most commonly used alternatives. The method is broadly based on the popular progressive approach to multiple alignment but avoids the most serious pitfalls caused by the greedy nature of this algorithm. With T-Coffee we pre-process a data set of all pair-wise alignments between the sequences. This provides us with a library of alignment information that can be used to guide the progressive alignment. Intermediate alignments are then based not only on the sequences to be aligned next but also on how all of the sequences align with each other. This alignment information can be derived from heterogeneous sources such as a mixture of alignment programs and/or structure superposition. Here, we illustrate the power of the approach by using a combination of local and global pair-wise alignments to generate the library. The resulting alignments are significantly more reliable, as determined by comparison with a set of 141 test cases, than any of the popular alternatives that we tried. The improvement, especially clear with the more difficult test cases, is always visible, regardless of the phylogenetic spread of the sequences in the tests.

Algorithms↗
PubMed2000

Computational methods for protein secondary structure prediction using multiple sequence alignments.

Efforts to use computers in predicting the secondary structure of proteins based only on primary structure information started over a quarter century ago [1-3]. Although the results were encouraging initially, the accuracy of the pioneering methods generally did not attain the level required for using predictions of secondary structures reliably in modelling the three-dimensional topology of proteins. During the last decade, however, the introduction of new computational techniques as well as the use of multiple sequence information has lead to a dramatic increase in the success rate of prediction methods, such that successful 3D modelling based on predicted secondary structure has become feasible [e.g., Ref 4]. This review is aimed at presenting an overview of the scale of the secondary structure prediction problem and associated pitfalls, as well as the history of the development of computational prediction methods. As recent successful strategies for secondary structure prediction all rely on multiple sequence information, some methods for accurate protein multiple sequence alignments will also be described. While the main focus is on prediction methods for globular proteins, also the prediction of trans-membrane segments within membrane proteins will be briefly summarised. Finally, an integrated iterative approach tying secondary structure prediction and multiple alignment will be introduced [5].

Algorithms↗
PubMed1999

Strain in protein structures as viewed through nonrotameric side chains: I. their position and interaction.

We studied the relative spatial positioning of nonrotameric side chains with atypical and strained dihedral angles in well-refined protein tertiary structures. The analysis was confined to buried protein cores, which are less error prone to side-chain positioning. More than half of the proteins with two or more nonrotameric residues displayed clusters of two or more (and up to five) nonrotameric residues. The clusters exhibited lower average crystallographic temperature factors compared with isolated nonrotameric residues. Nonrotameric clusters showed significantly tighter packing than corresponding rotameric clusters and had distinct residue compositions that did not correlate with amino acid characteristics such as size, hydrophobicity, turn preference, and the like. Such nonrotameric residue biases would suggest that spatially concentrated strain in protein folds would be minimized by lowered vibrational energy. Furthermore, nonrotameric residues avoided helices and strands and mostly preferred coil regions. If they were in the helical conformation, then they preferred to be within N-terminal segments. Proteins 1999;37:30-43.

Amino Acids↗
PubMed1999

Strain in protein structures as viewed through nonrotameric side chains: II. effects upon ligand binding.

The relation between the spatial positioning of nonrotameric residues and ligands was studied in 112 tertiary structures of protein-ligand complexes with a crystallographic resolution of </= 1. 8 A. Nonrotameric side chains and especially clusters of interacting nonrotameric residues were found to be associated preferentially with ligand- and substrate-binding sites. Asp, Glu, His, Met, and Asn are favored nonrotameric residue types positioned in the first 9-A shell around ligands. Comparison of 20 complexes with associated apo structures suggests that ligand binding induces nonrotamericity and, hence, strain within protein-ligand complexes. The internal energy gain is not neutralized by increased hydrogen bonding or salt-bridge formation involving side chains that become nonrotameric in the complexed structure. It is suggested that the increased internal energy might aid in the formation and ejection of enzymatic products, thereby enhancing activity. These results could prove useful in protein engineering experiments aimed at altering enzymatic activity. Proteins 1999;37:44-55.

Amino Acids↗
PubMed1999

Two strategies for sequence comparison: profile-preprocessed and secondary structure-induced multiple alignment.

Multiple sequence alignment remains one of the most powerful tools for assessing sequence relateness and the identification of structurally and functionally important protein regions. In this work, two new techniques are introduced to increase the sensitivity of dynamic programming and to enable checks for alignment consistency: Profile-preprocessed and secondary structure-induced alignments. Both strategies are based upon the hierarchical dynamic programming technique and can be applied separately or used in combination. Alignments resulting from the strategies are shown in comparison with the multiple alignment methods CLUSTALX and MULTAL for distant sequence sets of the flavoxin and cupredoxin protein families.

Amino Acid Sequence↗
PubMed1998

Interaction of transmembrane helices by a knobs-into-holes packing characteristic of soluble coiled coils.

Membrane-embedded protein domains frequently exist as alpha-helical bundles, as exemplified by photosynthetic reaction centers, bacteriorhodopsin, and cytochrome C oxidase. The sidechain packing between their transmembrane helices was investigated by a nearest-neighbor analysis which identified sets of interfacial residues for each analyzed helix-helix interface. For the left-handed helix-helix pairs, the interfacial residues almost exclusively occupy positions a, d, e, or g within a heptad motif (abcdefg) which is repeated two to three times for each interacting helical surface. The connectivity between the interfacial residues of adjacent helices conforms to the knobs-into-holes type of sidechain packing known from soluble coiled coils. These results demonstrate on a quantitative basis that the geometry of sidechain packing is similar for left-handed helix-helix pairs embedded in membranes and coiled coils of soluble proteins. The transmembrane helix-helix interfaces studied are somewhat less compact and regular as compared to soluble coiled coils and tolerate all hydrophobic amino acid types to similar degrees. The results are discussed with respect to previous experimental findings which demonstrate that specific interactions between transmembrane helices are important for membrane protein folding and/or oligomerization.

Algorithms↗
PubMed1998

Detection of internal repeats: how common are they?

The exponential growth in the amount of genomic data published in recent years has led to increased efforts in analysing genomes for the presence of repeated sequences, which has in turn fostered the development of novel repeat recognition methods. This has resulted in a deepened understanding of the importance and abundance of protein and nucleotide repeats. In the past year, a shift in focus has taken place--from the significance of repeats to protein structure and function, mostly at the protein domain level, to the implication of generally much shorter repeated fragments in genetic diseases and protein malfunctioning.

Animals↗
PubMed1997

Three-dimensional domain duplication, swapping and stealing.

Examination of multidomain and/or multimeric protein structures can reveal evolutionary paths to a more complex 3D organization. Over the past few years, proteins have been shown to evolve while preserving mutual domain organization and interfaces. The recent advances in understanding domain reorganization and mobility highlight the versatility and efficiency of protein structural evolution.

Binding Sites↗
PubMed1995

A simple and fast approach to prediction of protein secondary structure from multiply aligned sequences with accuracy above 70%.

To improve secondary structure predictions in protein sequences, the information residing in multiple sequence alignments of substituted but structurally related proteins is exploited. A database comprised of 70 protein families and a total of 2,500 sequences, some of which were aligned by tertiary structural superpositions, was used to calculate residue exchange weight matrices within alpha-helical, beta-strand, and coil substructures, respectively. Secondary structure predictions were made based on the observed residue substitutions in local regions of the multiple alignments and the largest possible associated exchange weights in each of the three matrix types. Comparison of the observed and predicted secondary structure on a per-residue basis yielded a mean accuracy of 72.2%. Individual alpha-helix, beta-strand, and coil states were respectively predicted at 66.7, and 75.8% correctness, representing a well-balanced three-state prediction. The accuracy level, verified by cross-validation through jack-knife tests on all protein families, dropped, on average, to only 70.9%, indicating the rigor of the prediction procedure. On the basis of robustness, conceptual clarity, accuracy, and executable efficiency, the method has considerable advantage, especially with its sole reliance on amino acid substitutions within structurally related proteins.

Algorithms↗
PubMed1995

Increasing thermal stability of subtilisin from mutations suggested by strongly interacting side-chain clusters.

In this paper we present for seven subtilisin structures a systematic comparison of densely packed side-group clusters (defined as an ensemble of side chains with extensive internal atomic contacts as compared with those made with the surrounding protein environment and measured relative to the maximum possible for each residue type). Spatially consistent clusters are observed at structurally equivalent positions in the proteins, as revealed by careful multiple superpositioning of the respective backbone atoms. The clusters are positioned at strategic loop-connecting sites near the protein surfaces. The residues within consistent clusters displaying extensive association show varying conservation at structurally equivalent alignment sites. Suggestions for residue substitutions, as observed over the seven tertiary structures, were taken from the cluster positions and were shown to be consistent with a number of point mutations in one of the seven structures (savinase) that result in increased thermal stability.

Amino Acid Sequence↗
PubMed1994

The evolution and recognition of protein sequence repeats.

Many proteins sequences contain motifs which display similarity. The similarities between the repeats are a result of gene duplication and/or gene fusion. The evolutionary role of repeats within protein sequences is considered and some repeat examples are given ranging from tandem repeats to multiple types of repeats which are sequentially interspersed. Existing computer methods to delineate repeats in individual protein sequences are discussed and a novel sensitive repeat recognition method is introduced.

Algorithms↗
PubMed1993

The KH domain occurs in a diverse set of RNA-binding proteins that include the antiterminator NusA and is probably involved in binding to nucleic acid.

New findings are presented for the approximately 50 residue KH motif, a domain recently discovered in RNA-binding proteins. The conserved sequence is approximately 10 residues larger than previously reported. Profile searches have revealed new members of this family, including two, E. coli NusA and human GAP-associated p62 phosphoprotein, for which RNA-binding data exists. A nusA homolog was detected in the RNA polymerase gene complex of six archaebacterial species and may encode an antiterminator. All KH-containing proteins are linked with RNA and the KH motif most probably functions as a nucleic acid binding domain.

Bacterial Proteins↗
PubMed1993

A method to recognize distant repeats in protein sequences.

An automated algorithm is presented that delineates protein sequence fragments which display similarity. The method incorporates a selection of a number of local nonoverlapping sequence alignments with the highest similarity scores and a graph-theoretical approach to elucidate the consistent start and end points of the fragments comprising one or more ensembles of related subsequences. The procedure allows the simultaneous identification of different types of repeats within one sequence. A multiple alignment of the resulting fragments is performed and a consensus sequence derived from the ensemble(s). Finally, a profile is constructed from the multiple alignment to detect possible and more distant members within the sequence. The method tolerates mutations in the repeats as well as insertions and deletions. The sequence spans between the various repeats or repeat clusters may be of different lengths. The technique has been applied to a number of proteins where the repeating fragments have been derived from information additional to the protein sequences.

Algorithms↗
PubMed1992

Anatomy and evolution of proteins displaying the viral capsid jellyroll topology.

In this paper the anatomy of 25 structures containing a jellyroll motif, consisting of eight antiparallel beta-strands forming a so-called beta-barrel, was investigated. This involved performing a careful structural alignment based on hydrogen bonds for the equivalent regions of the tertiary folds and a subsequent analysis of conserved amino acids, equivalenced residue-residue contacts, and various parameters describing the size, shape and other geometrical characteristics of these regions. It was found that the jellyroll motif is best viewed as a two-sheet wedge structure rather than a barrel. The more conserved parameters are discussed. A model of evolutionary development for the jellyroll fold in the various protein and viral structures is proposed.

Amino Acid Sequence↗
PubMed1992

OBSTRUCT: a program to obtain largest cliques from a protein sequence set according to structural resolution and sequence similarity.

A program OBSTRUCT has been developed to obtain the largest possible subset according to specific constraints from a set of protein sequences whose tertiary structures have been determined crystallographically. The user can request a range in sequence similarity level and/or structural resolution. The program optionally includes sequences with known three-dimensional folds elicited from NMR data.

Protein Conformation↗