Monocyte distribution width (MDW) and DECAF: two simple tools to determine the prognosis of severe COPD exacerbation.

Monocyte distribution width (MDW) has been associated with inflammation and poor prognosis in various acute diseases. Chronic obstructive pulmonary disease (COPD) exacerbations (ECOPD) are associated with mortality. The objective of this study was to evaluate the utility of the MDW as a predictor of ECOPD prognosis.

Structural adaptation of enzymes to low temperatures.

A systematic comparative analysis of 21 psychrophilic enzymes belonging to different structural families from prokaryotic and eukaryotic organisms is reported. The sequences of these enzymes were multiply aligned to 427 homologous proteins from mesophiles and thermophiles. The net flux of amino acid exchanges from meso/thermophilic to psychrophilic enzymes was measured.

Strain in protein structures as viewed through nonrotameric side chains: II. effects upon ligand binding.

The relation between the spatial positioning of nonrotameric residues and ligands was studied in 112 tertiary structures of protein-ligand complexes with a crystallographic resolution of View Article and Find Full Text PDF

Strain in protein structures as viewed through nonrotameric side chains: I. their position and interaction.

We studied the relative spatial positioning of nonrotameric side chains with atypical and strained dihedral angles in well-refined protein tertiary structures. The analysis was confined to buried protein cores, which are less error prone to side-chain positioning. More than half of the proteins with two or more nonrotameric residues displayed clusters of two or more (and up to five) nonrotameric residues.

Recognizing very distant sequence relationships among proteins by family profile analysis.

Family profile analysis (FPA), described in this paper, compares all available homologous amino acid sequences of a target family with the profile of a probe family while conventional sequence profile analysis (Gribskov M, Lüthy R, Eisenberg D. Meth Enzymol 1990;183:146-159) considers only a single target sequence in comparison with the probe family. The increased input of sequence information in FPA expands the range for sequence-based recognition of structural relationships.

Reliability of atomic displacement parameters in protein crystal structures.

Mean standard errors in atomic displacement parameters (ADPs) resulting from protein crystal structure determinations are estimated by comparing the ADPs of protein-chain pairs of identical sequence within the same crystal or within different crystals displaying the same or different space groups. The estimated ADP standard errors increase nearly linearly as the resolution decreases - an unexpected result given the nonlinear dependence of the resolution on the amount of diffraction data. The estimated ADP standard errors are larger for side-chain and solvent-exposed atoms than for main-chain and buried atoms and, surprisingly, are also larger for residues in the helical secondary structure relative to other local backbone conformations.

Easy method to predict solvent accessibility from multiple protein sequence alignments.

An easy and uncomplicated method to predict the solvent accessibility state of a site in a multiple protein sequence alignment is described. The approach is based on amino acid exchange and compositional preference matrices for each of three accessibility states: buried, exposed, and intermediate. Calculations utilized a modified version of the 3D_ali databank, a collection of multiple sequence alignments anchored through protein tertiary structural superpositions.

Automated protein sequence database classification. II. Delineation Of domain boundaries from sequence similarities.

Motivation: Decomposing each protein into modular domains is a basic prerequisite to classify accurately structural units in biological molecules. Boundaries between domains are indicated by two similar amino acid sequence segments located within the same protein (repeats) or within homologous proteins at notably different distances from their respective N- or C-termini.

Results: We have developed an automated method that combines such positional constraints derived from various detected pairwise sequence similarities to delineate the modular organization of proteins.

Automated protein sequence database classification. I. Integration of compositional similarity search, local similarity search, and multiple sequence alignment.

Motivation: Genome sequencing projects require the periodic application of analysis tools that can classify and multiply align related protein sequence domains. Full automation of this task requires an efficient integration of similarity and alignment techniques.

Results: We have developed a fully automated process that classifies entire protein sequence databases, resulting in alignment of the homologous sequences.

Are knowledge-based potentials derived from protein structure sets discriminative with respect to amino acid types?

The parametric description of residue environments through solvent accessibility, backbone conformation, or pairwise residue-residue distances is the key to the comparison between amino acid types at protein sequence positions and residue locations in structural templates (condition of protein sequence-structure match). For the first time, the research results presented in this study clarify and allow to quantify, on a rigorous statistical basis, to what extent the amino acid type-specific distributions of commonly used environment parameters are discriminative with respect to the 20 amino acid types. Relying on the Bahadur theory, we estimate the probability of error in a single-sequence-structure alignment based on weak or absent discriminative power in a learning database of protein structure.

Accessibility to internal cavities and ligand binding sites monitored by protein crystallographic thermal factors.

Protein structures are flexible both in solution and in the solid state. X-ray crystallographically determined thermal factors monitor the flexibility of protein atoms. A method utilizing such factors is proposed to delineate protein regions through which a ligand can exchange between binding site and bulk solvent.

Relationships between protein sequence and structure patterns based on residue contacts.

The identification of correlations between sequence patterns and structural motifs is a prerequisite in the development of protein structure prediction methods. The prediction accuracy indicates whether these correlations are discerned. We present an approach to identify long-range relationships between sequence patterns and structural motifs by varying the granulation of the structure description.

Protein-protein crystal-packing contacts.

Protein-protein contacts in monomeric protein crystal structures have been analyzed and compared to the physiological protein-protein contacts in oligomerization. A number of features differentiate the crystal-packing contacts from the natural contacts occurring in multimeric proteins. The area of the protein surface patches involved in packing contacts is generally smaller and its amino acid composition is indistinguishable from that of the protein surface accessible to the solvent.

Applying experimental data to protein fold prediction with the genetic algorithm.

Specific residue interactions as revealed from a few and readily available experiments can be quite important in shaping a protein's tertiary topology by complementing basic and general folding principles. This experimental information is employed in structure prediction (mainchain topology) based on sequence knowledge and the genetic algorithm with its ability to optimize simultaneously many parameters. Examples investigated include the distribution of cysteinyl S-S bonds, protein side-chain ligands to iron-sulfur cages, cofactor-ligands, crosslinks amongst side-chains, and conserved hydrophobic and catalytic residues.

Probing Flp: a new approach to analyze the structure of a DNA recognizing protein by combining the genetic algorithm, mutagenesis and non-canonical DNA target sites.

A topological and functional overview of a DNA recognition protein with unknown structure can be achieved by combining three different, but complementary approaches: modeling by the genetic algorithm, functional analysis of mutated variants, and testing the target DNA using non-canonical oligonucleotides. As an example we choose the Flp protein, a site-specific recombinase from Saccharomyces cerevisiae. We derive the topological outline including the DNA binding cleft, examine DNA binding regions by deletional and mutational analysis, and analyze the DNA binding site using 7-deazaadenine, 7-deazaguanine, inosine and 4-O-methylthymine as probes.

Correlation between side chain mobility and conformation in protein structures.

Thermal factors of protein atoms as determined by X-ray crystallographic techniques show a tendency to be larger in side chains with unfavourable local conformations rather than in those displaying conformational energy minima. It follows that side chain atoms are more mobile if they are in a non-rotameric configuration and that the stereochemistry of protein structures cannot be fully assessed or simulated without consideration of thermal factors that monitor flexibility in various regions of the protein. The observations should also prove useful in protein folding and design.

Prediction of membrane protein topology utilizing multiple sequence alignments.

A technique for prediction of protein membrane topology (intra- and extracellular sidedness) has been developed. Membrane-spanning segments are first predicted using an algorithm based upon multiply aligned amino acid sequences. The compositional differences in the protein segments exposed at each side of the membrane are then investigated.

Hydrophobic patches on protein subunit interfaces: characteristics and prediction.

Hydrophobic patches, defined as clusters of neighboring apolar atoms deemed accessible on a given protein surface, have been investigated on protein subunit interfaces. The data were taken from known tertiary structures of multimeric protein complexes. Amino acid composition and preference, patch size distribution, and patch contact complementarity across associating subunits were examined and compared with hydrophobic patches found on the solvent-accessible surface of the multimeric complexes.

Protein thermal stability, hydrogen bonds, and ion pairs.

Researchers in both academia and industry have expressed strong interest in comprehending the mechanisms responsible for enhancing the thermostability of proteins. Many and different structural principles have been postulated for the increased stability. Here, 16 families of proteins with different thermal stability were theoretically examined by comparing their respective fractional polar atom surface areas and the number and type of hydrogen bonds and salt links between explicit protein atoms.

NADP-dependent enzymes. II: Evolution of the mono- and dinucleotide binding domains.

Nicotinamide adenine dinucleotides [NAD and NADP with both referred to as NAD(P)] are among the more diffuse redox cofactors. Despite their stereochemical similarity where the only difference is a phosphomonoester on the ribose near the adenine of NADP, they show different biochemical reactivities with NAD behaving as an oxidant and NADP as a reductant. NAD(P)-dependent enzymes generally share a common open alpha/beta fold with few exceptions only recently structurally characterized.

NADP-dependent enzymes. I: Conserved stereochemistry of cofactor binding.

The ubiquitous redox cofactors nicotinamide adenine dinucleotides [NAD and NADP] are very similar molecules, despite their participation in substantially different biochemical processes. NADP differs from NAD in only the presence of an additional phosphate group esterified to the 2'-hydroxyl group of the ribose at the adenine end and yet NADP is confined with few exceptions to the reactions of reductive biosynthesis, whereas NAD is used almost exclusively in oxidative degradations. The discrimination between NAD and NADP is therefore an impressive example of the power of molecular recognition by proteins.

Seventy-five percent accuracy in protein secondary structure prediction.

In this study we present an accurate secondary structure prediction procedure by using an query and related sequences. The most novel aspect of our approach is its reliance on local pairwise alignment of the sequence to be predicted with each related sequence rather than utilization of a multiple alignment. The residue-by-residue accuracy of the method is 75% in three structural states after jack-knife tests.

Protein thermal stability: hydrogen bonds or internal packing?

Thermally stable proteins are of interest for several reasons. They can be used to improve the efficiency of many industrial processes and provide insight into the general mechanisms of protein folding and stabilization. Comparison of tertiary structural properties of several protein families with members of different thermostability should help to delineate the role of individual factors in achieving stability at high temperature.

The future of protein secondary structure prediction accuracy.

Background: The accuracy of secondary structure prediction for a protein from knowledge of its sequence has been significantly improved by about 7% to the 70-75% range by inclusion of information residing in sequences similar to the query sequence. The scientific literature has been inconsistent, if not negative, regarding chances for further improvement from the vast knowledge to be provided by genome sequencing efforts.

Results: By applying a prediction technique that is particularly sensitive to added sequence information to a standard set of query sequences with related primary structures taken from chronologically successive releases of the SWISS-PROT database, it is shown that prediction accuracy can be expected to reach 80-85% with a large 10-fold increase in present sequence knowledge.