marcius's protein_structure [86 articles]

Abstract

We have constructed a map of the "protein structure space" by using the pairwise structural similarity scores calculated for all nonredundant protein structures determined experimentally. As expected, proteins with similar structures clustered together in the map and the overall distribution of structural classes of this map followed closely that of the map of the "protein fold space" we have reported previously. Consequently, proteins sharing similar molecular functions also were found to colocalize in the protein structure space map, pointing toward a ...

Abstract

Advances have recently been made in the development of implicit solvent methodologies and their application to the modeling of biomolecules, particularly with regard to generalized Born approaches, dielectric screening function formulations and models based on solvent-accessible surface areas. Interesting new developments include more refined non-polar solvation energy estimators, and implicit methods for modeling low-dielectric and heterogeneous environments such as membrane systems. These have been successfully applied to molecular dynamics simulations, the scoring of protein conformations, and the calculation of binding affinities ...

Abstract

Protein structure prediction, fold recognition, homology modeling and design rely mainly on statistical effective energy functions. Although the theoretical foundation of such functions is not clear, their usefulness has been demonstrated in many applications. Molecular mechanics force fields, particularly when augmented by implicit solvation models, provide physical effective energy functions that are beginning to play a role in this area. ...

Abstract

Empirical force field-based studies of biological macromolecules are becoming a common tool for investigating their structure-activity relationships at an atomic level of detail. Such studies facilitate interpretation of experimental data and allow for information not readily accessible to experimental methods to be obtained. A large part of the success of empirical force field-based methods is the quality of the force fields combined with the algorithmic advances that allow for more accurate reproduction of experimental observables. Presented is an overview of the ...

Abstract

Statistical thermodynamics provides a powerful theoretical framework for analyzing, understanding and predicting the conformational properties of biomolecules. The central quantity is the potential of mean force or effective energy as a function of conformation, which consists of the intramolecular energy and the solvation free energy. The intramolecular energy can be reasonably described by molecular mechanics-type functions. While the solvation free energy is more difficult to model, useful results can be obtained with simple approximations. Such functions have been used to estimate ...

Abstract

A major challenge for genomewide disease association studies is the high cost of genotyping large number of single nucleotide polymorphisms (SNP). The correlations between SNPs, however, make it possible to select a parsimonious set of informative SNPs, known as "tagging" SNPs, able to capture most variation in a population. Considerable research interest has recently focused on the development of methods for finding such SNPs. In this paper, we present an efficient method for finding tagging SNPs. The method does not involve ...

Abstract

A primary challenge for structural genomics is the automated functional characterization of protein structures. We have developed a sequence-independent method called S-BLEST (Structure-Based Local Environment Search Tool) for the annotation of previously uncharacterized protein structures. S-BLEST encodes the local environment of an amino acid as a vector of structural property values. It has been applied to all amino acids in a nonredundant database of protein structures to generate a searchable structural resource. Given a query amino acid from an experimentally determined ...

Abstract

Accompanying the discovery of an increasing number of proteins, there is the need to provide functional annotation that is both highly accurate and consistent. The Gene Ontology (GO) provides consistent annotation in a computer readable and usable form; hence, GO annotation (GOA) has been assigned to a large number of protein sequences based on direct experimental evidence and through inference determined by sequence homology. Here we show that this annotation can be extended and corrected for cases where protein structures are ...

Abstract

The RCSB Protein Data Bank (PDB) offers online tools, summary reports and target information related to the worldwide structural genomics initiatives from its portal at http://sg.pdb.org. There are currently three components to this site: Structural Genomics Initiatives contains information and links on each structural genomics site, including progress reports, target lists, target status, targets in the PDB and level of sequence redundancy; Targets provides combined target information, protocols and other data associated with protein structure determination; and Structures offers an assessment ...

Abstract

To determine how different amino acid sequences form similar protein structures, and how proteins adapt to mutations that change the volume of residues buried in their close-packed interiors, we have analysed and compared the atomic structures of nine different globins. The homology of the sequences in the two most distantly related molecules is only 16%.The principal determinants of three-dimensional structure of these proteins are the approximately 59 residues involved in helix to helix and helix to haem packings. Half of these ...

Abstract

ABSTRACT: BACKGROUND: : The number of protein structures from structural genomics centers dramatically increases in the Protein Data Bank (PDB). Many of these structures are functionally unannotated because they have no sequence similarity to proteins of known function. However, it is possible to successfully infer function using only structural similarity. RESULTS: : Here we present the PDB-UF database, a web-accessible collection of predictions of enzymatic properties using structure-function relationship. The assignments were conducted for three dimensional protein structures of unknown function ...

Abstract

A generalized computational method for folding proteins with a fully transferable potential and geometrically realistic all-atom model is presented and tested on seven helix bundle proteins. The protocol, which includes graph-theoretical analysis of the ensemble of resulting folded conformations, was systematically applied and consistently produced structure predictions of approx3 A without any knowledge of the native state. To measure and understand the significance of the results, extensive control simulations were conducted. Graph theoretic analysis provides a means for systematically identifying the ...

Abstract

Motivation: Homology models of proteins are of great interest for planning and analysing biological experiments when no experimental three-dimensional structures are available. Building homology models requires specialized programs and up-to-date sequence and structural databases. Integrating all required tools, programs and databases into a single web-based workspace facilitates access to homology modelling from a computer with web connection without the need of downloading and installing large program packages and databases. Results: SWISS-MODEL workspace is a web-based integrated service dedicated to protein ...

Abstract

Motivation: The object of this study is to propose a new method to identify small compact units that compose protein three-dimensional structures. These fragments, called protein units (PU)', are a new level of description to well understand and analyze the organization of protein structures. The method only works from the contact probability matrix, i.e. the inter Calpha-distances translated into probabilities. It uses the principle of conventional hierarchical clustering, leading to a series of nested partitions of the 3D structure. Every ...

Abstract

Predicting protein sequences that fold into specific native three-dimensional structures is a problem of great potential complexity. Although the complete solution is ultimately rooted in understanding the physical chemistry underlying the complex interactions between amino acid residues that determine protein stability, recent work shows that empirical information about these first principles is embedded in the statistics of protein sequence and structure databases. This review focuses on the use of 'knowledge-based' potentials derived from these databases in designing proteins. In addition, the ...

Abstract

The increasing use of enzymes in industrial processes and the importance of understanding protein folding and stability have led to several attempts to predict and quantify the effect of every possible amino acid exchange (mutation) on the thermostability of proteins. In this article we describe a knowledge-based discrimination function that acts as a fast and reliable guide in protein engineering and optimization. The function used consists of two parts, a pairwise energy function based on a distance- and direction-dependent atomic description ...

Abstract

PMUT allows the fast and accurate prediction (approximately 80% success rate in humans) of the pathological character of single point amino acidic mutations based on the use of neural networks. The program also allows the fast scanning of mutational hot spots, which are obtained by three procedures: (1) alanine scanning, (2) massive mutation and (3) genetically accessible mutations. A graphical interface for Protein Data Bank (PDB) structures, when available, and a database containing hot spot profiles for all non-redundant PDB structures ...

Abstract

In the present work, we use structural information to characterize a set of disease-associated single amino acid polymorphisms exhaustively. The analysis of different properties, such as substitution matrix elements, secondary structure, accessibility, free energies of transfer from water to octanol, amino acid volume, etc., suggests that many disease-causing mutations are associated with extreme changes in the value of parameters relating to protein stability. Overall, our results indicate that, while knowledge of protein structure clearly helps in understanding these mutations, a finer ...

Abstract

The SWISS-MODEL Repository is a database of annotated 3D protein structure models generated by the SWISS-MODEL homology-modelling pipeline. As of September 2005, the repository contained 675,000 models for 604,000 different protein sequences of the UniProt database. Regular updates ensure that the content of the repository reflects the current state of sequence and structure databases, integrating new or modified target sequences, and making use of new template structures. Each Repository entry consists of one or more 3D models accompanied by detailed information ...

Abstract

Structural genomics projects aim to provide an experimental or computational three-dimensional model structure for all of the tractable macromolecules that are encoded by complete genomes. To this end, pilot centres worldwide are now exploring the feasibility of large-scale structure determination. Their experimental structures and computational models are expected to yield insight into the molecular function and mechanism of thousands of proteins. The pervasiveness of this information is likely to change the use of structure in molecular biology and biochemistry. ...

Abstract

In recent years, there has been significant progress in the ability to predict the three-dimensional structure of proteins from their amino acid sequence. Progress has been due to new methods to extract the growing amount of information in sequence and structure databases and improved computational descriptions of protein energetics. This review summarizes recent advances in these areas and describes a number of novel biological applications made possible by structure prediction. Despite remaining challenges, protein structure prediction is becoming an extremely useful ...

Abstract

The prediction of functional sites in newly solved protein structures is a challenge for computational structural biology. Most methods for approaching this problem use evolutionary conservation as the primary indicator of the location of functional sites. However, sequence conservation reflects not only evolutionary selection at functional sites to maintain protein function, but also selection throughout the protein to maintain the stability of the folded state. To disentangle sequence conservation due to protein functional constraints from sequence conservation due to protein structural ...

Abstract

Structures for protein domains have increased rapidly in recent years owing to advances in structural biology and structural genomics projects. New structures are often similar to those solved previously, and such similarities can give insights into function by linking poorly understood families to those that are better characterized. They also allow the possibility of combing information to find still more proteins adopting a similar structure and sometimes a similar function, and to reprioritize families in structural genomics pipelines. We explore this ...

Abstract

The Fragnostic (http://ffas.burnham.org/Fragnostic) web tool implements a novel and useful view of protein structure space. We mined a non-redundant subset of the PDB for common fragments shared between proteins inhabiting different SCOP folds. Subsequently, we formulated an inter-fold similarity measure based on fragment sharing. Fold space is described as a graph whose nodes are folds between which the edges are drawn depending on the extent of fragment sharing. In this fashion, Fragnostic helps discover meaningful relationships between proteins belonging to different ...

Abstract

An angle <IMG SRC="/giflibrary/12/Omega.gif" BORDER="0"> is defined to serve as a metric for global side-chain orientations, which reflects the orientation of the side chain relative to the radial vector from the center of the protein to an amino acid. The side-chain orientations of buried residues exhibit characteristically different orientations than do exposed residues, in both monomeric and dimeric structures. Overall, buried side chains point mostly inward, whereas surface side chains tend to point outward from the surface. This difference in behavior also correlates ...

Abstract

Proteins possessing the same fold may undergo similar motions, particularly if these motions involve large conformational transitions. The increasing amounts of structural data provide a useful starting point with which to test this hypothesis. We have performed a total of 0.29 mus of molecular dynamics across a series of proteins within the same fold family (periplasmic binding proteinlike) in order to address to what extent similarity of motion exists. Analysis of the local conformational space on these timescales (10-20 ns) revealed ...

Abstract

The structure prediction of loops with flexible stem residues is addressed in this article. While the secondary structure of the stem residues is assumed to be known, the geometry of the protein into which the loop must fit is considered to be unknown in our methodology. As a consequence, the compatibility of the loop with the remainder of the protein is not used as a criterion to reject loop decoys. The loop structure prediction with flexible stems is more difficult than ...

Abstract

Here we present a full overview of the Critical Assessment of Protein Structure Prediction (CASP6) comparative modelling category. Prediction accuracy for the 43 comparative modelling targets was assessed through detailed numerical comparisons between predicted and experimental structures. Assessments using standard measures for model backbone quality and structural alignment accuracy highlighted a small number of groups with stand out predictions and these findings were backed up by statistical comparisons. We were able to carry out evaluations of side chain contacts predictions and ...

Abstract

A number of new and newly improved methods for predicting protein structure developed by the Jones-UCL group were used to make predictions for the 6th CASP experiment. Structures were predicted with a combination of fold recognition methods (mGen THREADER, nFOLD and THREADER) and a substantially enhanced version of FRAGFOLD, our fragment assembly method. Attempts at automatic domain parsing were made using DomPred and DomSSEA, which are based on a secondary structure parsing algorithm and additionally for DomPred, a simple local sequence ...

Abstract

Two single-method servers SPARKS 2 and SP(3) participated in automatic-server predictions in CASP 6. The overall results for all as well as detailed performance in comparative modeling targets are presented. It is shown that both SPARKS 2 and SP(3) are able to recognize their corresponding best templates for all easy comparative-modeling targets. The alignment accuracy, however, is not always the best among all the servers. Possible factors are discussed. SPARKS 2 and SP(3) fold-recognition servers as well as their executables are ...

Abstract

MOTIVATION: We investigate the relationship between the quality of models of protein structure and their usefulness as search models in molecular replacement, a widely used method to experimentally determine protein structures by X-ray crystallography. RESULTS: We used the available models submitted to the Critical Assessment of Techniques for Protein Structure Prediction to verify in which cases they can be automatically used as search templates for molecular replacement. Our results show that there is a correlation between the quality of the models ...

Abstract

Accurate high-resolution refinement of protein structure models is a formidable challenge because of the delicate balance of forces in the native state, the difficulty in sampling the very large number of alternative tightly packed conformations, and the inaccuracies in current force fields. Indeed, energy-based refinement of comparative models generally leads to degradation rather than improvement in model quality, and, hence, most current comparative modeling procedures omit physically based refinement. However, despite their inaccuracies, current force fields do contain information that is ...

Abstract

There is a large gap between the number of membrane protein (MP) sequences and that of their decoded 3D structures, especially high-resolution structures, due to difficulties in crystal preparation of MPs. However, detailed knowledge of the 3D structure is required for the fundamental understanding of the function of an MP and the interactions between the protein and its inhibitors or activators. In this paper, some computational approaches that have been used to predict MP structures are discussed and compared. ...

Abstract

Membrane proteins are crucial for many biological functions and have become attractive targets for pharmacological agents. About 10%-30% of all proteins contain membrane-spanning helices. Despite recent successes, high-resolution structures for membrane proteins remain exceptional. The gap between known sequences and known structures calls for finding solutions through bioinformatics. While many methods predict membrane helices, very few predict membrane strands. The good news is that most methods for helical membrane proteins are available and are more often right than wrong. The best ...

Abstract

We describe a computational approach to protein tertiary structure prediction that combines ideas from the three-dimensional (3D) profile method of Bowie, Lüthy and Eisenberg and the associative memory Hamiltonians of Friedrichs and Wolynes. The ultimate goal of our work is to extend and generalize the capabilities of these heuristics so as to be able to predict novel structures that might be found in nature or designed proteins. In our approach we approximate the interactions between residues through a pseudo-potential function similar ...

Abstract

Relatively little has been known about the structure of alpha-helical membrane proteins, since until recently few structures had been crystallized. These limited data have restricted structural analyses to the prediction of secondary structure, rather than tertiary folds. In order to address this, this paper describes an analysis of the 23 available membrane protein structures. A number of findings are made that are of particular relevance to transmembrane helix packing: (1) on average lipid-tail-accessible transmembrane residues are significantly more hydrophobic, less conserved ...

Abstract

Three-dimensional structures of only a handful of membrane proteins have been solved, in contrast to the thousands of structures of water-soluble proteins. Difficulties in crystallization have inhibited the determination of the three-dimensional structure of membrane proteins by x-ray crystallography and have spotlighted the critical need for alternative approaches to membrane protein structure. A new approach to the three-dimensional structure of membrane proteins has been developed and tested on the integral membrane protein, bacteriorhodopsin, the crystal structure of which had previously been ...

Abstract

Only a tiny fraction of the many hundreds of known protein complexes are also of known three-dimensional structure. The experimental difficulties surrounding structure determination of complexes make methods that are able to predict structures paramount. The challenge of predicting complex structures is daunting and raises many issues that need to be addressed. To produce the best models, new prediction methods have to somehow combine partial structures with a mixed bag of experimental data, including interactions and low-resolution electron microscopy images. ...

Abstract

Protein one-dimensional (1D) structures such as secondary structure and contact number provide intuitive pictures to understand how the native three-dimensional (3D) structure of a protein is encoded in the amino acid sequence. However, it has not been clear whether a given set of 1D structures contains sufficient information for recovering the underlying 3D structure. Here we show that the 3D structure of a protein can be recovered from a set of three types of 1D structures, namely, secondary structure, contact number ...

Abstract

Most protein structure prediction methods use templates to assist in the construction of protein models. In this paper, we analyse the current state of template-based modelling approaches and reach an estimate of the empirical limits of these methods. Our analysis show that current prediction methods are already reaching these empirical accuracy limits in the easier cases, where finding a close homologue to the native target structure is not a problem. However, we find that even in the absence of alignment errors ...