Biomedical subjects

F S Domingues

Publications and source records attributed to F S Domingues.

10 recordsLinked to original sources

PubMed2001

Assessment of the CASP4 fold recognition category.

We present the assessment of the CASP4 fold recognition category. The tasks we had to execute include the splitting of multidomain targets into single domains, the classification of target domains in terms of prediction categories, the numerical evaluation of predictions, the mapping of numerical scores to quality indices, the ranking of predictors, the selection of top-performing groups, and the analysis and critical discussion of the state of the art in this field. The 125 fold recognition groups were assessed by a total score that summarizes their performance over all targets and a quality score reflecting the average quality of the submitted models. Most of the top-performing groups achieved respectable results on both scores simultaneously. Several groups submitted models that were much closer to the respective target structures than any of the known folds in the Protein Data Bank. The CASP4 assessment included the automated servers of the parallel CAFASP experiment. For the total score, the highest rank achieved by a fully automated server is 12. Two thirds of the predictors have rather low scores.

Computer Simulation↗

PubMed2000

The role of protein structure in genomics.

The genome projects produce an enormous amount of sequence data that needs to be annotated in terms of molecular structure and biological function. These tasks have triggered additional initiatives like structural genomics. The intention is to determine as many protein structures as possible, in the most efficient way, and to exploit the solved structures for the assignment of biological function to hypothetical proteins. We discuss the impact of these developments on protein classification, gene function prediction, and protein structure prediction.

Databases, Factual↗

PubMed2000

Structure-based evaluation of sequence comparison and fold recognition alignment accuracy.

The biological role, biochemical function, and structure of uncharacterized protein sequences is often inferred from their similarity to known proteins. A constant goal is to increase the reliability, sensitivity, and accuracy of alignment techniques to enable the detection of increasingly distant relationships. Development, tuning, and testing of these methods benefit from appropriate benchmarks for the assessment of alignment accuracy.Here, we describe a benchmark protocol to estimate sequence-to-sequence and sequence-to-structure alignment accuracy. The protocol consists of structurally related pairs of proteins and procedures to evaluate alignment accuracy over the whole set. The set of protein pairs covers all the currently known fold types. The benchmark is challenging in the sense that it consists of proteins lacking clear sequence similarity. Correct target alignments are derived from the three-dimensional structures of these pairs by rigid body superposition. An evaluation engine computes the accuracy of alignments obtained from a particular algorithm in terms of alignment shifts with respect to the structure derived alignments. Using this benchmark we estimate that the best results can be obtained from a combination of amino acid residue substitution matrices and knowledge-based potentials.

Algorithms↗

PubMed2000

ProSup: a refined tool for protein structure alignment.

We investigated and optimized a method for structure comparison which is based on rigid body superimposition. The method maximizes the number of structurally equivalent residues while keeping the root mean square deviation constant. The resulting number of equivalent residues then provides an adequate similarity measure, which is easy to interpret. We demonstrate that the approach is able to detect remote structural similarity. We show that the number of equivalent residues is a suitable measure for ranking database searches and that the results are in good agreement with expert knowledge protein structure classification. Structure comparison frequently has multiple solutions. The approach that we use provides a range of alternative alignments rather a single solution. We discuss the nature of alternative solutions on several examples.

Algorithms↗

PubMed2000

Structure-derived substitution matrices for alignment of distantly related sequences.

Sequence alignment is a standard method to infer evolutionary, structural, and functional relationships among sequences. The quality of alignments depends on the substitution matrix used. Here we derive matrices based on superimpositions from protein pairs of similar structure, but of low or no sequence similarity. In a performance test the matrices are compared with 12 other previously published matrices. It is found that the structure-derived matrices are applicable for comparisons of distantly related sequences. We investigate the influence of evolutionary relationships of protein pairs on the alignment accuracy.

Models, Molecular↗

PubMed1999

An attempt to analyse progress in fold recognition from CASP1 to CASP3.

The Critical Assessment of Techniques for Protein Structure Prediction (CASP) experiment has been conducted for the third time. An obvious question is whether there has been progress from CASP1 to CASP3. An analysis depends on many variables, including prediction category, number and difficulty of targets, methods used to evaluate prediction success, and the rules for submission. It also depends on whether progress is measured in terms of all predictions submitted or in terms of the best predictions for each target. The progress made by individual groups is another interesting issue. In view of this complexity and the limited amount of data, an objective estimate of progress is difficult to obtain. Despite such difficulties, some estimate of progress is desirable. Here, we present an attempt to quantify progress in the fold-recognition category from CASP1 to CASP3. The numbers indicate clear progress from CASP1 to CASP2 but no improvement from CASP2 to CASP3. However, we argue that the targets in CASP3 are more difficult compared with CASP2, which translates into better performance of CASP3 over CASP2.

Autoantigens↗

PubMed1999

Automated large scale evaluation of protein structure predictions.

Evaluation and assessment are critical issues in CASP experiments. Automated procedures are necessary to compare a large number of predictions with the target folds. The evaluation has to reveal the maximum extent of similarity between predictions and targets, it should be applicable across prediction categories, and it should be transparent and accessible to a wide community. Here we present an automated evaluation scheme which is an attempt to meet these requirements. In the implementation and execution of this scheme we had to solve or circumvent problems of convergence, where algorithms fail to find optimum solutions, problems of ambiguity where no unique optimum solution exists, and problems in ranking and interpretation. Key features of this implementation are (1) the root mean square deviation of structure superimposition is kept close to a constant value throughout the evaluation and (2) all structural matches found between two folds are taken into account. We discuss these points in detail and describe the numerical criteria used in the CASP3 evaluation.

Algorithms↗

PubMed1999

Sustained performance of knowledge-based potentials in fold recognition.

We describe the results obtained using fold recognition techniques in our third participation in the CASP experiment. The approach relies on knowledge-based potentials for alignment production and fold identification. As indicated by the increase in alignment quality and fold identification reliability, the predictions improved from CASP1 to CASP3. In particular, we identified structural relationships in which no known evolutionary link exists. Our predictions are based on single sequences rather than multiple sequence alignments. Additionally, we voluntarily submitted only a single model for each target because, in our view, submission of a single model is the most stringent test. We describe the methods used, the strategy adopted in the predictions, and the prediction results and discuss future work.

Algorithms↗

PubMed1998

Analysis of x-ray diffraction patterns from amyloid of biopsied vitreous humor and kidney of transthyretin (TTR) Met30 familial amyloidotic polyneuropathy (FAP) patients: axially arrayed TTR monomers constitute the protofilament.

Familial amyloidotic polyneuropathy (FAP) is characterized by deposits of amyloid fibers in which the major protein component is transthyretin (TTR). Nearly fifty mutations have been reported for the TTR in hereditary FAP. Protein crystallography of mutant TTRs has shown that the molecular structures of the variant molecules are similar to those found in the wild type. On this basis, the FAP fibers were initially proposed to consist of native-like TTR tetramers. In the current paper, we used x-ray fiber diffraction to study the structure of FAP fibers from biopsy samples of vitreous humor and kidney. The reflections of the vitreous sample showed a cross-beta diffraction pattern. All the meridional reflections were indexed by a one-dimensional, 29 A-period lattice, and the equatorial reflections were indexed by an apparent one-dimensional 67 A-period lattice. The x-ray intensity distribution indicated that the unit structure, which is similar to a TTR monomer, is composed of a pair of beta-sheets consisting of four hydrogen-bonded beta-chains per sheet, with the beta-chains oriented approximately normal to the fiber axis. The axial disposition of these units, with a 29 A-period, constitutes the protofilament; and a tetrameric lateral assembly of the protofilaments containing the core domain of the approximately 20 A-wide beta-sheet structure constitutes the FAP amyloid fiber. An inter-fiber separation of 75 A in these concentrated samples accounts for the apparent one-dimensional lattice perpendicular to the fiber axis. In the delipidated kidney FAP sample, the diffraction pattern indicated a pair of beta-sheets, suggesting that the protofilament structure in kidney is similar to that in vitreous humor. In the non-delipidated sample the successive sharp reflections indexed to a one-dimensional, 48.9 A-lattice, and the electron density projection showed a density elevation at the center of a lipid bilayer. This suggests that lipid may be associated with the monomeric TTR in the kidney FAP protofilament.

Amyloid↗

PubMed1997

Protein folds from pair interactions: a blind test in fold recognition.

We submitted nine predictions to CASP2 using our fold recognition program ProFIT. Two of these structures were still unsolved by the end of the experiment, six had a recognizable fold, and one fold was new. Four predictions of the six recognizable folds were correct. Two models were excellent in terms of alignment quality (T0031, T0004): in one the alignment was partially correct (T0014), and one fold was correctly identified (T0038). We discuss improvements of the program and analyze the prediction results.

Aldose-Ketose Isomerases↗