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PubMed2001

Defining linear segments in protein structure.

The analysis of protein structure using secondary structure line segments has been widely used in many structure analysis and prediction methods over the past 20 years. Its use in methods that compare protein structures at this level of representation is becoming more important as an increasing number of protein structures become determined through structural genomic programmes. The standard method used to define line segments is to fit an axis through each secondary structure element. This approach has difficulties, however, both with inconsistent definitions of secondary structure and the problem of fitting a single straight line to a bent structure. The procedure described here avoids these problems by finding a set of line segments independently of any external secondary structure definition. This allows the segments to be used as a novel basis for secondary structure definition by taking the average rise/residue along each axis to characterise the segment. This practice has the advantage that secondary structures are described by a single (continuous) value that is not restricted to the conventional classes of alpha-helix, 310 and beta-strand. This latter property allows structures without "classic" secondary structures to be encoded as line segments that can be used in comparison algorithms. When compared over a large number of pairs of homologous proteins, the current method was found to be slightly more consistent than a widely used method based on hydrogen bonds.

Algorithms↗
PubMed1997

Design of a knowledge-based force field for off-lattice simulations of protein structure.

Prediction of protein structure from amino-acid sequence still continues to be an unsolved problem of theoretical molecular biology. One approach to solve it is to construct an appropriate (free) energy function that recognizes the native structures of some selected proteins (whose native structures are known) as the ones distinctively lowest in (free) energy and then to carry out a search of the lowest-energy structure of a new protein. In order to reduce the complexity of the problem and the cost of energy evaluation, the so-called united-residue representation of the polypeptide chain is often applied, in which each amino-acid residue is represented by only a few interaction sites. Once the global energy minimum of the simplified chain has been found, the all-atom structure can easily and reliably be constructed. The search of the lowest-energy structure is usually carried out by means of Monte Carlo methods, though use of more efficient global-optimization methods, especially those of deformation of original energy surface is potentially promising. Monte Carlo search of the conformational space can be accelerated greatly, if the chain is superposed on a discrete lattice (the on-lattice approach). On the other hand, the on-lattice approach prohibits the use of many efficient global-optimization methods, because they require both energy and its space derivatives. The on-lattice methods in which the chain is embedded in the continuous 3D space are, therefore, also worth developing. In this paper we summarize the work on the design and implementation of an off-lattice united-residue force field that is underway in our group, in cooperation with Professor HA. Scheraga of Cornell University, U.S.A.

Models, Molecular↗
PubMed2004

CooPPS: a system for the cooperative prediction of protein structures.

Predicting the three-dimensional structure of proteins is a difficult task. In the last few years several approaches have been proposed for performing this task taking into account different protein chemical and physical properties. As a result, a growing number of protein structure prediction tools is becoming available, some of them specialized to work on either some aspects of the predictions or on some categories of proteins; however, they are still not sufficiently accurate and reliable for predicting all kinds of proteins. In this context, it is useful to jointly apply different prediction tools and combine their results in order to improve the quality of the predictions. However, several problems have to be solved in order to make this a viable possibility. In this paper a framework and a tool is proposed which allows: (i) definition of a common reference applicative domain for different prediction tools; (ii) characterization of prediction tools through evaluating some quality parameters; (iii) characterization of the performances of a team of predictors jointly applied over a prediction problem; (iv) the singling out of the best team for a prediction problem; and (v) the integration of predictor results in the team in order to obtain a unique prediction. A system implementing the various steps of the proposed framework (CooPPS) has been developed and several experiments for testing the effectiveness of the proposed approach have been carried out.

Algorithms↗
PubMed2002

Local structure-based sequence profile database for local and global protein structure predictions.

MOTIVATION: A large body of evidence suggests that protein structural information is frequently encoded in local sequences-sequence-structure relationships derived from local structure/sequence analyses could significantly enhance the capacities of protein structure prediction methods. In this paper, the prediction capacity of a database (LSBSP2) that organizes local sequence-structure relationships encoded in local structures with two consecutive secondary structure elements is tested with two computational procedures for protein structure prediction. The goal is twofold: to test the folding hypothesis that local structures are determined by local sequences, and to enhance our capacity in predicting protein structures from their amino acid sequences. RESULTS: The LSBSP2 database contains a large set of sequence profiles derived from exhaustive pair-wise structural alignments for local structures with two consecutive secondary structure elements. One computational procedure makes use of the PSI-BLAST alignment program to predict local structures for testing sequence fragments by matching the testing sequence fragments onto the sequence profiles in the LSBSP2 database. The results show that 54% of the test sequence fragments were predicted with local structures that match closely with their native local structures. The other computational procedure is a filter system that is capable of removing false positives as possible from a set of PSI-BLAST hits. An assessment with a large set of non-redundant protein structures shows that the PSI-BLAST + filter system improves the prediction specificity by up to two-fold over the prediction specificity of the PSI-BLAST program for distantly related protein pairs. Tests with the two computational procedures above demonstrate that local sequence-structure relationships can indeed enhance our capacity in protein structure prediction. The results also indicate that local sequences encoded with strong local structure propensities play an important role in determining the native state folding topology.

Algorithms↗
PubMed2005

Rapid assessment of protein structural stability and fold validation via NMR.

In structural proteomics, it is necessary to efficiently screen in a high-throughput manner for the presence of stable structures in proteins that can be subjected to subsequent structure determination by X-ray or NMR spectroscopy. Here we illustrate that the (1)H chemical distribution in a protein as detected by (1)H NMR spectroscopy can be used to probe protein structural stability (e.g., the presence of stable protein structures) of proteins in solution. Based on experimental data obtained on well-structured proteins and proteins that exist in a molten globule state or a partially folded alpha-helical state, a well-defined threshold exists that can be used as a quantitative benchmark for protein structural stability (e.g., foldedness) in solution. Additionally, in this chapter we describe a largely automated strategy for rapid fold validation and structure-based backbone signal assignment. Our methodology is based on a limited number of NMR experiments (e.g., HNCA and 3D NOESY-HSQC) and performs a Monte Carlo-type optimization. The novel feature of the method is the opportunity to screen for structural fragments (e.g., template scanning). The performance of this new validation tool is demonstrated with applications to a diverse set of proteins.

Calcium↗
PubMed2003

High-resolution structures of retinol-binding protein in complex with retinol: pH-induced protein structural changes in the crystal state.

The targeted delivery of non-polar ligands by binding proteins to membranes or membrane receptors involves the release of these ligands on or near the plasma membrane of target cells. Because these hydrophobic ligands are often bound inside a deep cavity of binding proteins, as shown previously for plasma retinol-binding protein (RBP), their release from these proteins might require the destabilization of the protein structure by partially denaturing conditions, such as those possibly present near plasma membranes. RBP is a plasma transport protein which delivers specifically retinol from its store sites to target cells. Here, we report the high-resolution (1.1-1.4A) crystal structures of bovine holo-RBP at five different pH values, ranging from 9 to 2. While unraveling details of the native protein structure and of the interactions with retinol at nearly atomic resolution at neutral pH, this study provides evidence for definite pH-induced modifications of several structural features of RBP. The structure most representative of the changes that holo-RBP undergoes at different pH values is that of its flexible state at pH 2. At this pH, most significant are the alteration of the arrangement of salt bridges and of the network of water molecules/H-bonds that participates in the retinol-RBP interaction, an appreciable increase of the volume of the beta-barrel cavity, a considerably higher degree of mobility of the RBP-bound ligand and of several protein regions and the disorder of a large number of solvent molecules that are ordered at neutral pH. These changes are likely to be accompanied by a modification of the pattern of charge distribution on the protein surface. All these changes, which reveal a substantially lowered conformational stability of RBP, presumably occur at the initial stages of the acidic denaturation of RBP and are possibly associated with a facilitated release of the retinol molecule from its carrier protein.

Animals↗
PubMed2001

A computer system to perform structure comparison using TOPS representations of protein structure.

We describe the design and implementation of a fast topology-based method for protein structure comparison. The approach uses the TOPS topological representation of protein structure, aligning two structures using a common discovered pattern and generating measure of distance derived from an insert score. Heavy use is made of a constraint-based pattern-matching algorithm for TOPS diagrams that we have designed and described elsewhere (Bioinformatics 15(4) (1999) 317). The comparison system is maintained at the European Bioinformatics Institute and is available over the Web at tops.ebi.ac.uk/tops. Users submit a structure description in Protein Data Bank (PDB) format and can compare it with structures in the entire PDB or a representative subset of protein domains, receiving the results by email.

Algorithms↗
PubMed2004

Close agreement between the orientation dependence of hydrogen bonds observed in protein structures and quantum mechanical calculations.

Hydrogen bonding is a key contributor to the exquisite specificity of the interactions within and between biological macromolecules, and hence accurate modeling of such interactions requires an accurate description of hydrogen bonding energetics. Here we investigate the orientation and distance dependence of hydrogen bonding energetics by combining two quite disparate but complementary approaches: quantum mechanical electronic structure calculations and protein structural analysis. We find a remarkable agreement between the energy landscapes obtained from the electronic structure calculations and the distributions of hydrogen bond geometries observed in protein structures. In contrast, molecular mechanics force fields commonly used for biomolecular simulations do not consistently exhibit close correspondence to either quantum mechanical calculations or experimentally observed hydrogen bonding geometries. These results suggest a route to improved energy functions for biological macromolecules that combines the generality of quantum mechanical electronic structure calculations with the accurate context dependence implicit in protein structural analysis.

Amino Acids↗
PubMed2005

Aligning multiple protein structures by deterministic annealing.

Protein structure alignment plays a key role in protein structure prediction and fold family classification. An efficient method for multiple protein structure alignment in a mathematical manner is presented, based on deterministic annealing technique. The alignment problem is mapped onto a nonlinear continuous optimization problem (NCOP) with common consensus chain, matching assignment matrices and atomic coordinates as variables. At each step in the annealing procedure, the NCOP is decomposed into as many sub-problems as the number of protein chains, each of which is actually an independent pairwise structure alignment between a protein chain and the consensus chain and hence can be efficiently solved by the parallel computation technique. The proposed method is robust with respect to choice of iteration parameters for a wide range of proteins, and performs well in both multiple and pairwise structure alignment cases, compared with existing alignment methods.

Algorithms↗
PubMed2006

Protein Block Expert (PBE): a web-based protein structure analysis server using a structural alphabet.

Encoding protein 3D structures into 1D string using short structural prototypes or structural alphabets opens a new front for structure comparison and analysis. Using the well-documented 16 motifs of Protein Blocks (PBs) as structural alphabet, we have developed a methodology to compare protein structures that are encoded as sequences of PBs by aligning them using dynamic programming which uses a substitution matrix for PBs. This methodology is implemented in the applications available in Protein Block Expert (PBE) server. PBE addresses common issues in the field of protein structure analysis such as comparison of proteins structures and identification of protein structures in structural databanks that resemble a given structure. PBE-T provides facility to transform any PDB file into sequences of PBs. PBE-ALIGNc performs comparison of two protein structures based on the alignment of their corresponding PB sequences. PBE-ALIGNm is a facility for mining SCOP database for similar structures based on the alignment of PBs. Besides, PBE provides an interface to a database (PBE-SAdb) of preprocessed PB sequences from SCOP culled at 95% and of all-against-all pairwise PB alignments at family and superfamily levels. PBE server is freely available at http://bioinformatics.univ-reunion.fr/PBE/.

Amino Acid Motifs↗
PubMedDate not supplied

Active cross-protection induced by a recombinant baculovirus expressing chimeric infectious bursal disease virus structural proteins.

The VP2 structural gene encoded in the large genomic segment A of the variant GLS strain of infectious bursal disease virus (IBDV) was modified to encode a neutralization epitope (B69), found only on classic strains of IBDV. A chimeric cDNA clone of the large segment A, encoding VP3, VP4, and the modified variant IBDV VP2 structural proteins, was expressed in a recombinant baculovirus. The chimeric protein expressed was assessed with a panel of neutralizing monoclonal antibodies (MAbs), and it contained not only all previously MAb-defined GLS variant strain epitopes but also the B69 neutralization epitope found on classic IBDV strains. Complete active protection was afforded to specific-pathogen-free chickens by a subunit chimeric vaccine against virulent challenge with the classic IM and STC strains, as well as against the variant E/Del and GLS IBDV strains. Compared with a previously tested recombinant subunit vaccine, which incorporated unmodified baculovirus-expressed large-segment A GLS proteins, the recombinant chimeric subunit vaccine resulted in markedly improved active cross-protection against classic IBDV challenge.

Animals↗
PubMed2001

Protein structure similarities.

Comparison of protein structures can reveal distant evolutionary relationships that would not be detected by sequence information alone. This helps to infer functional properties. In recent years, many methods for pairwise protein structure alignment have been proposed and are now available on the World Wide Web. Although these methods have made it possible to compare all available protein structures, they also highlight the remaining difficulties in defining a reliable score for protein structure similarities.

Amino Acid Motifs↗
PubMed2006

A permissive secondary structure-guided superposition tool for clustering of protein fragments toward protein structure prediction via fragment assembly.

MOTIVATION: Secondary-Structure Guided Superposition tool (SSGS) is a permissive secondary structure-based algorithm for matching of protein structures and in particular their fragments. The algorithm was developed towards protein structure prediction via fragment assembly. RESULTS: In a fragment-based structural prediction scheme, a protein sequence is cut into building blocks (BBs). The BBs are assembled to predict their relative 3D arrangement. Finally, the assemblies are refined. To implement this prediction scheme, a clustered structural library representing sequence patterns for protein fragments is essential. To create a library, BBs generated by cutting proteins from the PDB are compared and structurally similar BBs are clustered. To allow structural comparison and clustering of the BBs, which are often relatively short with flexible loops, we have devised SSGS. SSGS maintains high similarity between cluster members and is highly efficient. When it comes to comparing BBs for clustering purposes, the algorithm obtains better results than other, non-secondary structure guided protein superimposition algorithms.

Algorithms↗
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↗