Sesam: A relational database for structure and sequence of macromolecules

Huysmans, Martina; Richelle, Jean

doi:10.1002/prot.340110108

Cited by 41 publications

(12 citation statements)

References 49 publications

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“…& Wodak, S. J., unpublished results). Information on the proteins is extracted from the protein database SESAM (Huysmans et al, 1991), which contains sequence and structure information on proteins from the Brookhaven databank (Bernstein et al, 1977).…”

Section: Protein Structure Datamentioning

confidence: 99%

Stability Changes upon Mutation of Solvent- accessible Residues in Proteins Evaluated by Database-derived Potentials

Gilis

Rooman

1996

Journal of Molecular Biology

158

123

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The stability changes in peptides and proteins caused by the substitution of a single amino acid, which can be measured experimentally by the Bruxelles, CP160/16 a.v. F. Roosevelt change in folding free energy, are evaluated here using effective potentials derived from known protein structures. The analysis is focused on 1050 Brussels Belgium mutations of residues that are accessible to the solvent. These represent in total 106 mutations, introduced at different sites in barnase, bacteriophage T4 lysozyme and chymotrypsin inhibitor 2, and in a synthetic helical peptide. Assuming that the mutations do not modify the backbone structure, the changes in folding free energies are computed using various types of database-derived potentials and are compared with the measured ones. Distance-dependent residue-residue potentials are found to be inadequate for estimating the stability changes caused by these mutations, as they are dominated by hydrophobic interactions, which do not play an essential role at the protein surface. On the contrary, the potentials based on backbone torsion angle propensities yield quite good results. Indeed, for a subset of 96 out of the 106 mutations, the computed and measured changes in folding free energy correlate with a linear correlation coefficient of 0.87. Moreover, the ten mutations that are excluded from the correlation either seem to cause modifications of the backbone structure or to involve strong hydrophobic interactions, which are atypical for solvent-accessible residues. We find furthermore that raising the ionic strength of the solvent used for measuring the changes in folding free energies improves the correlation, as it tends to mask the electrostatic interactions. When adding to these 106 mutations 44 mutations performed in staphylococcal nuclease and chemotactic protein, which were first discarded because some of them were suspected to affect the backbone conformation or the denatured state, the correlation between measured and computed folding free energy changes remains quite good: the correlation coefficient is 0.86 for 135 out of the 150 mutations. The success of the backbone torsion potentials in predicting stability changes indicates that the approximations made for deriving these potentials are adequate. It suggests moreover that the local interactions along the chain dominate at the protein surface.

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Section: Protein Structure Datamentioning

confidence: 99%

Stability Changes upon Mutation of Solvent- accessible Residues in Proteins Evaluated by Database-derived Potentials

Gilis

Rooman

1996

Journal of Molecular Biology

158

123

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“…BIPED [47,48] and SESAM [49] are the first examples of operational relational protein sequence and structure databases. They are both based on commercial, general, relational database management systems.…”

Section: Model Building By Homology and Design Of Site-directed Mutatmentioning

confidence: 99%

Prediction and analysis of structure, stability and unfolding of thermolysin-like proteases

Vriend¹,

Eijsink²

1993

J Computer-Aided Mol Des

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Bacillus neutral proteases (NPs) form a group of well-characterized homologous enzymes, that exhibit large differences in thermostability. The three-dimensional (3D) structures of several of these enzymes have been modelled on the basis of the crystal structures of the NPs of B. thermoproteolyticus (thermolysin) and B. cereus. Several new techniques have been developed to improve the model-building procedures. Also a 'model-building by mutagenesis' strategy was used, in which mutants were designed just to shed light on parts of the structures that were particularly hard to model. The NP models have been used for the prediction of site-directed mutations aimed at improving the thermostability of the enzymes. Predictions were made using several novel computational techniques, such as position-specific rotamer searching, packing quality analysis and property-profile database searches. Many stabilizing mutations were predicted and produced: improvement of hydrogen bonding, exclusion of buried water molecules, capping helices, improvement of hydrophobic interactions and entropic stabilization have been applied successfully. At elevated temperatures NPs are irreversibly inactivated as a result of autolysis. It has been shown that this denaturation process is independent of the protease activity and concentration and that the inactivation follows first-order kinetics. From this it has been conjectured that local unfolding of (surface) loops, which renders the protein susceptible to autolysis, is the rate-limiting step. Despite the particular nature of the thermal denaturation process, normal rules for protein stability can be applied to NPs. However, rather than stabilizing the whole protein against global unfolding, only a small region has to be protected against local unfolding. In contrast to proteins in general, mutational effects in proteases are not additive and their magnitude is strongly dependent on the location of the mutation. Mutations that alter the stability of the NP by a large amount are located in a relatively weak region (or more precisely, they affect a local unfolding pathway with a relatively low free energy of activation). One weak region, that is supposedly important in the early steps of NP unfolding, has been determined in the NP of B. stearothermophilus. After eliminating this weakest link a drastic increase in thermostability was observed and the search for the second-weakest link, or the second-lowest energy local unfolding pathway is now in progress. Hopefully, this approach can be used to unravel the entire early phase of unfolding.

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“…BIPED was a relational database capable of asking a variety of questions relating primarily to geometry, for example, questions about hydrogen bonds, disul®de bridges, and torsional angles. The relational database SESAM (Huysmans et al, 1991) followed, and included various energy parameters used in modeling and conformational energy calculations. The ®rst object-oriented database was that of Gray et al (1990) which was later used to search for hydrophobic subdomains ).…”

Section: Past Progressmentioning

confidence: 99%

Macromolecular Structure Databases: Past Progress and Future Challenges

Weissig

Shindyalov

Bourne

1998

Acta Crystallogr D Biol Cryst

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Databases containing macromolecular structure data provide a crystallographer with important tools for use in solving, re®ning and understanding the functional signi®cance of their protein structures. Given this importance, this paper brie¯y summarizes past progress by outlining the features of the signi®cant number of relevant databases developed to date. One recent database, PDB+, containing all current and obsolete structures deposited with the Protein Data Bank (PDB) is discussed in more detail. PDB+ has been used to analyze the self-consistency of the current (1 January 1998) corpus of over 7000 structures. A summary of those ®ndings is presented (a full discussion will appear elsewhere) in the form of global and temporal trends within the data. These trends indicate that challenges exist if crystallographers are to provide the community with complete and consistent structural results in the future. It is argued that better information management practices are required to meet these challenges.

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Sesam: A relational database for structure and sequence of macromolecules

Cited by 41 publications

References 49 publications

Stability Changes upon Mutation of Solvent- accessible Residues in Proteins Evaluated by Database-derived Potentials

Stability Changes upon Mutation of Solvent- accessible Residues in Proteins Evaluated by Database-derived Potentials

Prediction and analysis of structure, stability and unfolding of thermolysin-like proteases

Macromolecular Structure Databases: Past Progress and Future Challenges

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