Biomedical subjects

C A Orengo

Publications and source records attributed to C A Orengo.

At least 37 records · Page 2Linked to original sources

PubMed1999

Protein folds, functions and evolution.

The evolution of proteins and their functions is reviewed from a structural perspective in the light of the current database. Protein domain families segregate unequally between the three major classes, the 32 different architectures and almost 700 folds observed to date. We find that the number of new topologies is still increasing, although 25 new structures are now determined for each new topology. The corresponding analysis and classification of function is only just beginning, fuelled by the genome data. The structural data revealed unexpected conservations and divergence of function both within and between families. The next five years will see the compilation of a definitive dictionary of protein families and their related functions, based on structural data which reveals relationships hidden at the sequence level. Such information will provide the foundation to build a better understanding of the molecular basis of biological complexity and hopefully to facilitate rational molecular design.

Animals↗

PubMed1999

Correlation of observed fold frequency with the occurrence of local structural motifs.

It is well known that some protein folds (superfolds) occur very frequently. We show that compared to other folds, most superfold structures have a higher proportion of their alpha-helical or beta-strand residues in one of three basic units of supersecondary structure (alpha-hairpin, beta-hairpin or betaalphabeta-unit). Furthermore, by taking into consideration two more complex motifs, the four-stranded Greek-key (beta4) and the betaalpha-Greek key (betaalphabetabeta), we demonstrate that the remaining superfold structures contain many of these higher order units of three-dimensional packing. The implications of these results for folding are discussed.

Models, Molecular↗

PubMed1999

The CATH Database provides insights into protein structure/function relationships.

We report the latest release (version 1.4) of the CATH protein domains database (http://www.biochem.ucl.ac.uk/bsm/cath). This is a hierarchical classification of 13 359 protein domain structures into evolutionary families and structural groupings. We currently identify 827 homologous families in which the proteins have both structual similarity and sequence and/or functional similarity. These can be further clustered into 593 fold groups and 32 distinct architectures. Using our structural classification and associated data on protein functions, stored in the database (EC identifiers, SWISS-PROT keywords and information from the Enzyme database and literature) we have been able to analyse the correlation between the 3D structure and function. More than 96% of folds in the PDB are associated with a single homologous family. However, within the superfolds, three or more different functions are observed. Considering enzyme functions, more than 95% of clearly homologous families exhibit either single or closely related functions, as demonstrated by the EC identifiers of their relatives. Our analysis supports the view that determining structures, for example as part of a 'structural genomics' initiative, will make a major contribution to interpreting genome data.

Algorithms↗

PubMed1999

Analysis and assessment of ab initio three-dimensional prediction, secondary structure, and contacts prediction.

CASP3 saw a substantial increase in the volume of ab initio 3D prediction data, with 507 datasets for fifteen selected targets and sixty-one groups participating. As with CASP2, methods ranged from computationally intensive strategies that attempt to recreate the physical and chemical forces involved in protein folding to the more recent knowledge-based approaches. These exploit information from the structure databases, extracting potentially similar fragments and/or distance constraints derived from multiple sequence alignments. The knowledge-based approaches generally gave more consistently successful predictions across the range of targets, particularly that of the Baker group (Bystroff and Baker, J Mol Biol 1998;281:565-577; Simons et al. Proteins Suppl 1999;3:171-176), which used a fragment library. In the secondary structure prediction category, the most successful approaches built on the concepts used in PHD (Rost et al. Comput Appl Biosci 1994;10:53-60), an accepted standard in this field. Like PHD, they exploit neural networks but have different strategies for incorporating multiple sequence data or position-dependent weight matrices for training the networks. Analysis of the contact data, for which only six groups participated, suggested that as yet this data provides a rather weak signal. However, in combination with other types of prediction data it can sometimes be a useful constraint for identifying the correct structure.

Animals↗

PubMed1999

From protein structure to function.

Several databases of protein structural families now exist-organised according to both evolutionary relationships and common folding arrangements. Although these lag behind sequence databases in size, the prospect of structural genomics initiatives means that they may soon include representatives of many of the sequence families. To some extent, functional information can be derived from structural similarity. For some structural families, their function is highly conserved, whereas, for others, it can only be inherited or derived on the basis of additional information (e.g. sequence patterns, common residue clusters and characteristic surface properties).

Computational Biology↗

PubMed1999

Evolution of protein function, from a structural perspective.

The recent growth in structural data, and ensuing analyses, have revealed the structural and functional versatility of protein families. With respect to enzymes, local active-site mutations, variations in surface loops and recruitment of additional domains accommodate the diverse substrate specificities and catalytic activities observed within several superfamilies. Conversely, some functions have more than one structural solution, having evolved independently several times during evolution. Combined with the existence of multi-functional genes, which have arisen by gene recruitment, these phenomena must be considered in the process of genome annotation.

Animals↗

PubMed1999

Contribution of psychosis and depression to behavioral disturbances in geropsychiatric inpatients with dementia.

BACKGROUND: Specific behavioral disturbances in dementia may be associated with underlying disorders such as the presence of psychosis and depression. The objective of this study was to examine the association of depression and psychosis with behavioral disturbances in geropsychiatric inpatients with dementia. METHODS: All admissions between October 1993 and May 1995 were reviewed to identify those patients admitted to the Houston Veterans Affairs Geropsychiatry Unit with a diagnosis of dementia; 208 patients were included in the study. Hierarchical regression models were constructed to explore the contribution of depressive and psychotic symptoms, and depression and psychosis diagnoses to Cohen-Mansfield Agitation Inventory (CMAI) scores. RESULTS: Both depression and psychotic symptoms were significantly and positively correlated with behavioral disturbances. Psychotic symptoms were associated with aggressive behavioral symptoms, and depressive symptoms were associated with constant requests for help, complaining, and negativism. Dementia severity accounted for significant variance in CMAI scores and was positively associated with behavioral disturbance; though disorder symptoms accounted for more behavioral disturbance variance than did depressive symptoms. CONCLUSIONS: Both depressive and psychotic symptoms were associated with overall behavioral disturbances in patients with dementia. Psychotic symptoms and depressive symptoms were associated with different types of behavioral disturbances. Our findings support the contention that underlying depression or psychosis may partially account for different behavioral disturbances and that not all behavioral disturbances should be globally labeled "agitation." Future studies should address symptom-specific treatment of behaviorally disturbed patients.

Aged↗

PubMed1999

A multidisciplinary ethics teaching conference on a geropsychiatric service.

This article describes an ethics case conference on a multidisciplinary geropsychiatric service, and its unique clinical, training, and research benefits. We describe the structure of the conference, the major topics addressed, the perceived advantages, and the research implications. We conclude that the care of older patients, the education of students and trainees interested in aging issues, and cutting-edge geriatric research are all advanced by such a conference.

Bioethics↗

PubMed1999

Rehospitalization of older psychiatric inpatients: an investigation of predictors.

The purpose of this study was to identify a combination of variables that could predict rehospitalization among a sample of 150 geropsychiatric inpatients. Logistic regression analyses testing a modified model identified risk factors for geropsychiatric rehospitalization and correctly classified approximately 80% of inpatients who were rehospitalized for subsequent treatment. Patients' psychiatric diagnosis (mood or schizophrenic disorder), poor general psychiatric functioning, depressive and agitated behavior at discharge, little or no supervision in living arrangements following discharge, limited social support, change in the social support system preceding hospitalization, and maladaptive family functioning could significantly predict geropsychiatric rehospitalization. The strongest independent predictor was maladaptive family functioning.

Aged↗

PubMed1999

Combining sensitive database searches with multiple intermediates to detect distant homologues.

Using data from the CATH structure classification, we have assessed the blastp, fasta, smith-waterman and gapped-blast algorithms, developed a portable normalization scheme and identified safe thresholds for database searching. Of the four methods assessed, fasta, smith-waterman and gapped-blast perform similarly, whereas the sensitivity of blastp was much lower. Introduction of an intermediate sequence search substantially improved the results. When tested on a set of relationships that could not be identified by blastp, intermediate sequences were able to find double the number of relationships identified by the smith-waterman algorithm alone. However, we found that the benefit of using intermediates varied considerably between each family and depended not only on the number of available sequences, but also their diversity. In an attempt to increase sensitivity further, a multiple intermediate sequence search (MISS) procedure was developed. When assessed on 1906 cases from a wide range of homologous families that could not be detected by the previous approaches, MISS was able to identify 241 additional relationships. MISS uses the full extent of sequence diversity to detect additional relationships, but does not consider any structure-specific information. For this reason, it is more generally applicable than fold recognition and threading methods, which require a library of known structures.

Computer Simulation↗

PubMed1999

DOMPLOT: a program to generate schematic diagrams of the structural domain organization within proteins, annotated by ligand contacts.

A program is described for automatically generating schematic linear representations of protein chains in terms of their structural domains. The program requires the co-ordinates of the chain, the domain assignment, PROSITE information and a file listing all intermolecular interactions in the protein structure. The output is a PostScript file in which each protein is represented by a set of linked boxes, each box corresponding to all or part of a structural domain. PROSITE motifs and residues involved in ligand interactions are highlighted. The diagrams allow immediate visualization of the domain arrangement within a protein chain, and by providing information on sequence motifs, and metal ion, ligand and DNA binding at the domain level, the program facilitates detection of remote evolutionary relationships between proteins.

Adenosine Diphosphate↗

PubMed1999

CORA--topological fingerprints for protein structural families.

CORA is a suite of programs for multiply aligning and analyzing protein structural families to identify the consensus positions and capture their most conserved structural characteristics (e.g., residue accessibility, torsional angles, and global geometry as described by inter-residue vectors/contacts). Knowledge of these structurally conserved positions, which are mostly in the core of the fold and of their properties, significantly improves the identification and classification of newly-determined relatives. Information is encoded in a consensus three-dimensional (3D) template and relatives found by a sensitive alignment method, which employs a new scoring scheme based on conserved residue contacts. By encapsulating these critical "core" features, templates perform more reliably in recognizing distant structural relatives than searches with representative structures. Parameters for 3D-template generation and alignment were optimized for each structural class (mainly-alpha, mainly-beta, alpha-beta), using representative superfold families. For all families selected, the templates gave significant improvements in sensitivity and selectivity in recognizing distant structural relatives. Furthermore, since templates contain less than 70% of fold positions and compare fewer positions when aligning structures, scans are at least an order of magnitude faster than scans using selected structures. CORA was subsequently tested on eight other broad structural families from the CATH database. Diagnostics plots are generated automatically and provide qualitative assistance for classifying newly determined relatives. They are demonstrated here by application to the large globin-like fold family. CORA templates for both homologous superfamilies and fold families will be stored in CATH and used to improve the classification and analysis of newly determined structures.

Models, Molecular↗

PubMed1999

Genome analysis: Assigning protein coding regions to three-dimensional structures.

We describe the results of a procedure for maximizing the number of sequences that can be reliably linked to a protein of known three-dimensional structure. Unlike other methods, which try to increase sensitivity through the use of fold recognition software, we only use conventional sequence alignment tools, but apply them in a manner that significantly increases the number of relationships detected. We analyzed 11 genomes and found that, depending on the genome, between 23 and 32% of the ORFs had significant matches to proteins of known structure. In all cases, the aligned region consisted of either >100 residues or >50% of the smaller sequence. Slightly higher percentages could be attained if smaller motifs were also included. This is significantly higher than most previously reported methods, even those that have a fold-recognition component. We survey the biochemical and structural characteristics of the most frequently occurring proteins, and discuss the extent to which alignment methods can realistically assign function to gene products.

Algorithms↗

PubMed1998

Classifying a protein in the CATH database of domain structures.

The CATH database of protein domain structures classifies structures according to their (C)lass, (A)rchitecture, (T)opology or fold and (H)omologous family (http://www.biochem.ucl.ac.uk/bsm/cath). Although the protocol used is mostly automatic, manual inspection is used to check assignments at some critical stages, such as the detection of very distantly related homologues and anologues and the assignment of novel architectures. Described in this article is a recently established facility to search the database with the coordinates of a newly determined structure. The CATH server first locates domain boundaries and then uses automatic sequence and structure comparison methods to assign this new structure to one or more of the domain families within CATH. Diagnostic reports are generated, together with multiple structural alignments for close relatives. The Server can be accessed over the World Wide Web (WWW) and mirror sites are planned to improve access.

Amino Acid Sequence↗

PubMed1998

Protein folds and functions.

BACKGROUND: The recent rapid increase in the number of available three-dimensional protein structures has further highlighted the necessity to understand the relationship between biological function and structure. Using structural classification schemes such as SCOP, CATH and DALI, it is now possible to explore global relationships between protein fold and function, something which was previously impractical. RESULTS: Using a relational database of CATH data we have generated fold distributions for arbitrary selections of proteins automatically. These distributions have been examined in the light of protein function and bound ligand. Different enzyme classes are not clearly reflected in distributions of protein class and architecture, whereas the type of bound ligand has a much more dramatic effect. CONCLUSIONS: The availability of structural classification data has enabled this novel overview analysis. We conclude that function at the top level of the EC number enzyme classification is not related to fold, as only a very few specific residues are actually responsible for enzyme activity. Conversely, the fold is much more closely related to ligand type.

Binding Sites↗

PubMed1998

The efficacy and tolerability of divalproex sodium in elderly demented patients with behavioral disturbances.

Behavioral disturbances are commonly encountered in elderly demented patients. The records of all patients admitted to a geropsychiatric inpatient unit within a 2-year period who had a primary diagnosis of dementia and an accompanying behavioral disturbance treated with divalproex sodium were reviewed. Of the 13 patients identified, all tolerated divalproex sodium without significant side-effects. General psychiatric symptoms, overall agitation, physical aggression and non-aggressive physical agitation decreased significantly, but verbal agitation did not. Divalproex sodium is well tolerated and may be effective in ameliorating certain behavioral disturbances in elderly demented patients with agitation.

Aged↗

PubMed1998

Contemporary approaches to protein structure classification.

In a similar manner to sequence database searching, it is also possible to compare three-dimensional protein structure. Such methods can be extremely useful because a structural similarity may represent a distant evolutionary relationship that is undetectable by sequence analysis. In this review, we summarise the most popular structure comparison methods, show how they can be used for database searching, and then describe some of the most advanced attempts to develop comprehensive protein structure classifications. With such data, it is possible to identify distant evolutionary relationships, provide libraries of unique folds for structure prediction, estimate the total number of folds that exist, and investigate the preference for certain types of structures over others.

Databases, Factual↗

PubMed1998

The contribution of cognitive impairment, medical burden, and psychopathology to the functional status of geriatric psychiatric inpatients.

In order to define the contributions of cognitive impairment, medical burden, and psychopathology to the functional status of geriatric psychiatric patients, a forward-looking, retrospective study of 106 consecutive admissions to a geriatric psychiatric unit at the Houston Veterans Affairs Medical Center Hospital was done. It was found that psychopathology and cognitive status, but not medical burden, contributed to the variance in functional status of geriatric psychiatric inpatients for both admission scores and for changes in scores during hospitalization. Improvements in cognitive state and psychopathology were associated with improvements in functional status during hospitalization.

Aged↗