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Biomedical subjects

M B Swindells

Publications and source records attributed to M B Swindells.

At least 19 recordsLinked to original sources
PubMed1995

Protein folds: towards understanding folding from inspection of native structures.

Following a short summary of some of the principal features of folded proteins, the results of two complementary studies of protein structure are presented, the first concerned with the factors which influence secondary structure propensity and the second an analysis of protein topology. In an attempt to deconvolute the physical contributions to secondary structure propensities, we have calculated intrinsic phi, psi propensities, derived from the coil regions of proteins. Comparison of intrinsic phi, psi propensities with their equivalent secondary structure values show correlations for both helix and strand. This suggests that the local dipeptide, steric and electrostatic interactions have a major influence on secondary structure propensity. We then proceed to inspect the distribution of protein domain folds observed to date. Several folds occur very commonly, so that 46% of the current non-homologous database comprises only nine folds. The implications of these results for protein folding are discussed.

Computer Simulation↗
PubMed1995

A procedure for the automatic determination of hydrophobic cores in protein structures.

An algorithm is described for automatically detecting hydrophobic cores in proteins of known structure. Three pieces of information are considered in order to achieve this goal. These are: secondary structure, side-chain accessibility, and side-chain-side-chain contacts. Residues are considered to contribute to a core when they occur in regular secondary structure and have buried side chains that form predominantly nonpolar contacts with one another. This paper describes the algorithm's application to families of proteins with conserved topologies but low sequence similarities. The aim of this investigation is to determine the efficacy of the algorithm as well as to study the extent to which similar cores are identified within a common topology.

Algorithms↗
PubMed1995

A procedure for detecting structural domains in proteins.

A procedure is described for detecting domains in proteins of known structure. The method is based on the intuitively simple idea that each domain should contain an identifiable hydrophobic core. By applying the algorithm described in the companion paper (Swindells MB, 1995, Protein Sci 4:93-102) to identify distinct cores in multi-domain proteins, one can use this information to determine both the number and the location of the constituent domains. Tests have shown the procedure to be effective on a number of examples, even when the domains are discontinuous along the sequence. However, deficiencies also occur when hydrophobic cores from different domains continue through the interface region and join one another.

Aconitate Hydratase↗
PubMed1995

Structural similarity between the pleckstrin homology domain and verotoxin: the problem of measuring and evaluating structural similarity.

An unexpected structural similarity is described between the pleckstrin homology (PH) domain and verotoxin. This similarity has escaped detection primarily due to the differences in topology that exist between the two proteins. By comparing this result with two previously reported similarities for the PH domain, one with the lipocalins and another with the FK506 binding protein, we discuss the problems of measuring and assessing structural similarities.

Amino Acid Sequence↗
PubMed1995

Intrinsic phi, psi propensities of amino acids, derived from the coil regions of known structures.

Many different factors contribute to secondary structure propensities, including phi, psi preferences, side-chain interactions, steric effects and hydrophobic tertiary contacts. To deconvolute these competing factors, we have adopted a novel approach which quantifies the intrinsic phi, psi propensities for residues in coil regions (that is, residues not in alpha-helix and not in beta-strand). Comparisons of intrinsic phi, psi propensities with their equivalent secondary structure propensities show that while correlations for helix are relatively weak, those for strand are much stronger. This paper describes our new phi, psi propensities and provides an explanation for the variations observed.

Amino Acids↗
PubMed1994

Loopy similarities.

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Amino Acid Sequence↗
PubMed1994

Finding your fold.

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Binding Sites↗
PubMed1993

Prediction of a novel topology in the N-terminal, 14 kDa fragment of Ada protein.

Previously determined protein structures have been analysed, in order to find folding motifs similar to that proposed by NMR spectroscopy, for the N-terminal, 14 kDa fragment of the Ada protein. The analyses reveal only limited similarities with the NMR-derived structural data and strongly suggest that this region of the Ada protein adopts a previously unobserved topology. Characteristic structural features, which arise from the inferred chain connectivity, are examined through comparisons with other structures. Using this information, the topology of the Ada protein 14 kDa fragment has been predicted in order to provide structural data not yet attainable from NMR experiments.

Amino Acid Sequence↗
PubMed1993

Classification of doubly wound nucleotide binding topologies using automated loop searches.

A classification is presented of doubly wound alpha/beta nucleotide binding topologies, whose binding sites are located in the cleft formed by a topological switch point. In particular, the switch point loop nearest the N-terminus is used to identify specific structural classes of binding protein. This yields seven structurally distinct loop conformations, which are subsequently used as motifs for scanning the Protein Data Bank. The searches, which are effective at identifying functional relationships within a large database of structures, reveal a remarkable and previously unnoticed similarity between the coenzyme binding sites of flavodoxin and tryptophan synthetase, even though there is no sequence or topological similarity between them.

Amino Acid Sequence↗
PubMed1993

A study of structural determinants in the interleukin-1 fold.

The structures of interleukin-1 beta, basic fibroblast growth factor and Erythrina trypsin inhibitor have been analysed in order to determine whether the hydrophobic core remains conserved, even when the structures have extremely low sequence similarities. We find that there are significant differences in the way each protein achieves a satisfactory arrangement of core residues and that positions which contribute to the core of one structure are not guaranteed to contribute to the integrity of another. Furthermore, the side-chain packing arrangements of these core residues vary significantly between the three structures. During this analysis the side-chain rotamers for three independently determined interleukin-1 beta structures were also compared. It was found that although buried residues are generally in agreement the remaining residues frequently occupy different rotamers in the three structures. This suggests that although meaningful studies are possible for buried side-chains the results obtained from equivalent analyses of accessible residues should be treated with caution. These results are discussed with specific reference to the optimization of side-chain packing in proteins of known structure.

Amino Acid Sequence↗
PubMed1992

Structure prediction and modelling.

Cracking the second fundamental code of molecular biology (how the tertiary structure of a protein is determined by its amino acid sequence) remains an elusive goal. However, the impetus to establish credible approximations, if not a definitive solution to this relationship, has never been greater. In the past year significant progress has been made through a series of novel approaches. This review describes the most important developments and outlines how they can be usefully employed by those whose specialization lies outside the field.

Models, Molecular↗