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M J Sternberg

Publications and source records attributed to M J Sternberg.

At least 109 records · Page 6Linked to original sources
PubMed1989

A relational database of protein structures designed for flexible enquiries about conformation.

A relational database of protein structure has been developed to enable rapid and flexible enquiries about the occurrence of many aspects of protein architecture. The coordinates of 294 proteins from the Brookhaven Data Bank have been processed by standard computer programs to generate many additional terms that quantify aspects of protein structure. These terms include solvent accessibility, main-chain and side-chain dihedral angles, and secondary structure. In a relational database, the information is stored in tables with columns holding the different terms and rows holding the different entries for the terms. The different relational base tables store the information about the protein coordinate set, the different chains in the protein, the amino acid residues and ligands, the atomic coordinates, the salt bridges, the hydrogen bonds, the disulphide bridges and the close tertiary contacts. The database was established under ORACLE management system. Enquiries are constructed in ORACLE using SQL (structured query language) which is simple to use and alleviates the need for extensive computer programs. A single table can be searched for entries that meet various criteria, e.g. all protein solved to better than a given resolution. The power of the database occurs when several tables, or the entries in a single table, are cross-correlated. For example the dihedral angles of proline in the fourth position in an alpha-helix in high resolution structures can be rapidly obtained. The structural database provides a powerful tool to obtain empirical rules about protein conformation. This database of protein structures is part of a joint project between Birkbeck College and Leeds University to establish an integrated data resource of protein sequences and structures (ISIS) that encodes the complex patterns of residues and coordinates that define protein conformation. The entire data resource (ISIS) will provide a system to guide all areas of protein modelling including structure prediction, site-directed mutagenesis and de novo protein design. The availability of ISIS is described in the paper.

Computer Simulation↗
PubMed1989

Prediction of beta-turns in proteins using neural networks.

The use of neural networks to improve empirical secondary structure prediction is explored with regard to the identification of the position and conformational class of beta-turns, a four-residue chain reversal. Recently an algorithm was developed for beta-turn predictions based on the empirical approach of Chou and Fasman using different parameters for three classes (I, II and non-specific) of beta-turns. In this paper, using the same data, an alternative approach to derive an empirical prediction method is used based on neural networks which is a general learning algorithm extensively used in artificial intelligence. Thus the results of the two approaches can be compared. The most severe test of prediction accuracy is the percentage of turn predictions that are correct and the neural network gives an overall improvement from 20.6% to 26.0%. The proportion of correctly predicted residues is 71%, compared to a chance level of about 58%. Thus neural networks provide a method of obtaining more accurate predictions from empirical data than a simpler method of deriving propensities.

Algorithms↗
PubMed1989

Can a simple function for the dielectric response model electrostatic effects in globular proteins?

The relationship between the effective dielectric constant that models the electrostatic effect from a charged side chain in a protein was evaluated both experimentally and theoretically. Experimental values were obtained from the shifts in pKa that resulted from point mutations of side chains in subtilisin. Theoretical values were obtained from an iterative solution to Poisson's equation that considers the dielectric response of the protein and the solvent together with charge positions. There is no simple relationship between the effective dielectric constant and the distance from the charge responsible for the interactions. For some charge positions a linear but not a direct proportional relationship of the effective dielectric with distance of separation was observed. Thus, simple models such as a linear distance-dependence for the dielectric response are not suitable to evaluate electrostatic effects in proteins.

Algorithms↗
PubMed1989

A predicted three-dimensional structure for the human immunodeficiency virus binding domains of CD4 antigen.

A predicted three-dimensional structure of the two N-terminal extracellular domains of human CD4 antigen, a cell surface glycoprotein, is reported. This region of CD4, particularly the first domain, has been identified as containing the binding region for the envelope gp120 protein of the human immunodeficiency virus. The model was predicted based on the sequence homology of each domain with the variable light chain of immunoglobulins. The framework beta-sheet regions were taken from the crystal coordinates of REI. For one region in the first domain of CD4 there was an ambiguity in the alignment with REI and two alternate models are presented. Loops connecting the framework were modelled from fragments selected from a database of main chain coordinates from all known protein structures. Residues identified as involved in binding gp120 have been located in several other studies within the first domain of CD4. Epitopes from eight monoclonal antibodies have been mapped onto residues in both domains. Competition of these antibodies with each other and with gp120 can be interpreted from the structural model.

Amino Acid Sequence↗
PubMed1988

Predictions of linear T-cell and B-cell epitopes in proteins encoded by HIV-1, HIV-2 and SIVMAC and the conservation of these sites between strains.

An important consideration in the design of vaccines to prevent HIV-1 infection effective against different strains is the amino acid sequence conservation of antigenic determinants. Even one amino acid change can destroy the antigenicity of a site for the antibody or T-cell receptor. The comparisons of predicted T- and B-cell epitopes between human HIV-1, HIV-2 and monkey SIVMAC AIDS viruses are presented. The three major gene products (env, gag and pol) were examined. A number of epitopes were identical between strains of HIV-1. Our analysis highlights the problem of designing an effective HIV-1 and HIV-2 vaccine and also the problem of testing human vaccines in monkey models.

Amino Acid Sequence↗
PubMed1988

Analysis and prediction of the location of catalytic residues in enzymes.

The catalytic residues of an enzyme are defined as the amino acids directly involved in chemical catalysis. They mainly act as a general acid--base, electrophilic or nucleophilic catalyst or they polarize and stabilize the transition state. An analysis of the structural features of 36 catalytic residues in 17 enzymes of known structure and with defined mechanism is reported. Residues that bind metal ions (Zn2+ and Cu2+) are considered separately. The features examined are: residue type, location in secondary structure, separation between the residues, accessibility to solvent, intra-protein electrostatic interactions, mobility as evaluated from crystallographic temperature factors, polarity of the environment and the sequence conservation between homologous enzymes of residues that were sequentially or spatially close to the catalytic residue. In general the environment of catalytic residues is similar to that of polar side chains that have low accessibility to solvent. Two algorithms have been developed to identify probable catalytic residues. Scanning an alignment of homologous enzyme sequences for peaks of sequence conservation identifies 13 out of the 16 catalytic residues with 50 residues overpredicted. When the conservation of the spatially close residues is used instead, a different set of 13 residues are identified with 47 residues overpredicted. A combination of the two algorithms identifies 11 residues with 36 residues overpredicted.

Algorithms↗
PubMed1987

Analysis of the relationship between side-chain conformation and secondary structure in globular proteins.

The relationship between the preferred side-chain dihedral angles and the secondary structure of a residue was examined. The structures of 61 proteins solved to a resolution of 2.0 A (1 A = 0.1 nm) or better were analysed using a relational database to store the information. The strongest feature observed was that the chi 1 distribution for most side-chains in an alpha-helix showed an absence of the g- conformation and a shift towards the t conformation when compared to the non-alpha/beta structures. The exceptions to this tendency were for short polar side-chains that form hydrogen bonds with the main-chain which prefer g+. Shifts in the chi 1 preferences for residues in the beta-sheet were observed. Other side-chain dihedral angles (chi 2, chi 3, chi 4) were found to be influenced by the main-chain. This paper presents more accurate distributions for the side-chain dihedral angles which were obtained from the increased number of proteins determined to high resolution. The means and standard deviations for chi 1 and chi 2 angles are presented for all residues according to the secondary structure of the main-chain. The means and standard deviations are given for the most popular conformations for side-chains in which chi 3 and chi 4 rotations affect the position of C atoms.

Amino Acid Sequence↗
PubMed1987

A strategy for the rapid multiple alignment of protein sequences. Confidence levels from tertiary structure comparisons.

An algorithm is presented for the multiple alignment of protein sequences that is both accurate and rapid computationally. The approach is based on the conventional dynamic-programming method of pairwise alignment. Initially, two sequences are aligned, then the third sequence is aligned against the alignment of both sequences one and two. Similarly, the fourth sequence is aligned against one, two and three. This is repeated until all sequences have been aligned. Iteration is then performed to yield a final alignment. The accuracy of sequence alignment is evaluated from alignment of the secondary structures in a family of proteins. For the globins, the multiple alignment was on average 99% accurate compared to 90% for pairwise comparison of sequences. For the alignment of immunoglobulin constant and variable domains, the use of many sequences yielded an alignment of 63% average accuracy compared to 41% average for individual variable/constant alignments. The multiple alignment algorithm yields an assignment of disulphide connectivity in mammalian serotransferrin that is consistent with crystallographic data, whereas pairwise alignments give an alternative assignment.

Algorithms↗
PubMed1987

Prediction of antigenic determinants and secondary structures of the major AIDS virus proteins.

Criteria for the design of peptide vaccines to prevent AIDS are presented. The best vaccine candidates contain both B and T lymphocyte-defined epitopes in regions conserved in sequence between viral isolates. We propose that attention should focus on proteins specified by the gag and, possibly, pol genes in addition to the env gene envelope glycoproteins being actively studied. The predictions of B- and T-epitopes are refined by consideration of secondary structure prediction and inter-isolate sequence variability to suggest peptides from env, gag and pol that would be the best vaccine candidates.

Amino Acid Sequence↗
PubMed1987

Prediction of protein secondary structure and active sites using the alignment of homologous sequences.

The prediction of protein secondary structure (alpha-helices, beta-sheets and coil) is improved by 9% to 66% using the information available from a family of homologous sequences. The approach is based both on averaging the Garnier et al. (1978) secondary structure propensities for aligned residues and on the observation that insertions and high sequence variability tend to occur in loop regions between secondary structures. Accordingly, an algorithm first aligns a family of sequences and a value for the extent of sequence conservation at each position is obtained. This value modifies a Garnier et al. prediction on the averaged sequence to yield the improved prediction. In addition, from the sequence conservation and the predicted secondary structure, many active site regions of enzymes can be located (26 out of 43) with limited over-prediction (8 extra). The entire algorithm is fully automatic and is applicable to all structural classes of globular proteins.

Algorithms↗
PubMed1986

Prediction of protein structure from amino acid sequence.

Methods of predicting protein conformation from amino acid sequence are reviewed. Several widely used algorithms to predict local secondary structure are first discussed. Four general approaches to predict the tertiary structure are then described: (1) energy calculations from an open chain; (2) recognition of sequence homology with a known structure; (3) uses of a sequence template that dictates a particular fold; (4) docking alpha-helices and beta-strands. Throughout this review, the likely success of these methods is considered.

Amino Acid Sequence↗
PubMed1985

Electrostatic interactions in globular proteins: calculation of the pH dependence of the redox potential of cytochrome c551.

An equal mixture of oxidized and reduced cytochrome c551 experiences a change in the potential of the haem iron when one of the propionates attached to the haem is ionized. The change is 65 mV, which corresponds to an effective dielectric between the propionate and the iron of 27. It has been possible to use the algorithm of Warwicker & Watson (1982) to calculate the change in the potential at the haem iron arising from the change in ionization of the propionate. This gives the extra work required to oxidize or reduce the iron. The change in potential that we calculate is 90 mV, which corresponds to an effective dielectric of 19.5, between the propionate and the iron. In comparison with other commonly used dielectric models the agreement is very good.

Bacterial Proteins↗
PubMed1984

Modelling the ATP-binding site of oncogene products, the epidermal growth factor receptor and related proteins.

A three-dimensional model for the ATP-binding site of the oncogene product v-src is proposed by the use of interactive computer graphics. A similar model would apply to sequence related proteins such as other oncogene products, the epidermal growth factor receptor, cAMP-dependent protein kinase and the cell division control protein CDC28. The model was proposed on the basis of the conservation of certain key residues between the oncogene product family of proteins and several nucleotide binding proteins of known structures.

Adenosine Triphosphate↗
PubMed1984

Electrostatic interactions in globular proteins. Different dielectric models applied to the packing of alpha-helices.

The alpha-helix has an electric dipole arising from the alignment of peptide dipoles parallel to the helix axis. The effect of this alpha-helix dipole in the stabilization of the tertiary structure of globular proteins is examined using three of the commonly used dielectric models. These models are; (1) the uniform dielectric model, (2) the distance dependent dielectric model and (3) the cavity dielectric model. Of these the cavity model is the most reasonable since it attempts to describe the markedly different dielectric responses of the solvent and the protein. The protein is set at a low continuous dielectric value and the solvent is set at a high continuous dielectric value. It is found that for the cavity model of the dielectric the calculated interaction energy between two helices is strongly dependent upon how exposed the helix termini are to solvent. For helices with exposed termini the calculations using the cavity model yield electrostatic interaction energies which are lower by an order of magnitude than those obtained using the uniform dielectric model.

Electricity↗
PubMed1981

Analysis and predication of structural motifs in the glycolytic enzymes.

Protein crystallography has determined the three-dimensional structures of 10 of the 13 enzymes of the glycolytic pathway. Diagrams and details of these enzyme structures are given in the paper. Most of the enzyme domains are variations and extensions of a many (4--9)-stranded, predominantly or totally parallel, beta-sheet that is shielded from solvent by alpha-helices (i.e. alpha/beta structures). There are strong structural similarities between the domains of some, but not all, of the enzymes. In particular the dinucleotide binding fold of lactate dehydrogenase and the beta-barrel of triose phosphate isomerase are found in other domains. General rules governing the topology and packing of alpha-helices against a beta-sheet provide a basis for the combinatorial prediction of the tertiary fold of glycolytic domains from their amino acid sequence and observed secondary structure. The predication algorithm demonstrates that there are severe restrictions on the number of possible structures. However, these restrictions do not fully explain some of the remarkable structural similarities between different enzymes that probably result from evolution from a common ancestor.

Animals↗