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Results for “Models, Structural”

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At least 253 records · Page 14Linked to original sources

PubMed1996

HOLE: a program for the analysis of the pore dimensions of ion channel structural models.

A method (HOLE) that allows the analysis of the dimensions of the pore running through a structural model of an ion channel is presented. The algorithm uses a Monte Carlo simulated annealing procedure to find the best route for a sphere with variable radius to squeeze through the channel. Results can be displayed in a graphical fashion or visualized with most common molecular graphical packages. Advances include a method to analyze the anisotropy within a pore. The method can also be used to predict the conductance of channels using a simple empirically corrected ohmic model. As an example the program is applied to the cholera toxin B-subunit pentamer. The compatibility of the crystal structure and conductance data is established.

Algorithms↗

PubMed2002

Potassium channels: structures, models, simulations.

Potassium channels have been studied intensively in terms of the relationship between molecular structure and physiological function. They provide an opportunity to integrate structural and computational studies in order to arrive at an atomic resolution description of mechanism. We review recent progress in K channel structural studies, focussing on the bacterial channel KcsA. Structural studies can be extended via use of computational (i.e. molecular simulation) approaches in order to provide a perspective on aspects of channel function such as permeation, selectivity, block and gating. Results from molecular dynamics simulations are shown to be in good agreement with recent structural studies of KcsA in terms of the interactions of K(+) ions with binding sites within the selectivity filter of the channel, and in revealing the importance of filter flexibility in channel function. We discuss how the KcsA structure may be used as a template for developing structural models of other families of K channels. Progress in this area is explored via two examples: inward rectifier (Kir) and voltage-gated (Kv) potassium channels. A brief account of structural studies of ancillary domains and subunits of K channels is provided.

Amino Acid Sequence↗

PubMed1990

A structural model for the genome of echovirus 22.

We have proposed previously that the structural model for the echovirus 22 genome is a single-stranded RNA molecule that has folded back upon itself to form a stable "hairpin" at the 5'-terminus. The vRNA of echovirus 22 has been characterized further by digestion with selective ribonucleases, electrophoresis in composite gels, hydrodynamic studies in density gradients of Cs2SO4 and sucrose, thermal denaturation and 3'-terminal ribonucleotide analysis. Based on these observations, the genome of echovirus 22 is a single-stranded RNA molecule having a region of secondary structure located at the 5'-terminus that may be characterized as a snapback hairpin with hydrogen-bonded base-pairing. In addition, a VPg-like protein is attached (presumably to the 5'-end of the RNA) and the 3'-terminus contains a polyadenylic acid tract [poly (A)].

Carrier Proteins↗

PubMed1995

Structural modeling of differential diagnosis, treatment, and results for allergic rhinitis.

This paper analyzed the relationship among the differential diagnosis, treatment, and results for allergic rhinitis using the covariance structural model. The data were collected from 274 patients with suspected allergic rhinitis who visited the Otorlaryngology Department of the Paik Hospital during 1991-1993. After each patient's characteristics was categorized and combined into several common factors, covariance structure analysis was performed to analyze the structural relationships among the differential diagnosis, treatment, and results of treatment using the significant factors obtained from discriminant analysis. The significant characteristics influenced the diagnosis were the results of skin test from mite/animal, and from mugworts, the results from laboratory tests, rhinorrhea and sneezing, and nasal polyps. The significant characteristics that influenced the method of treatment were: nasal polyps, headache/general symptom, family history/medication, and septal deviation. Headache/general symptom was the only significantly influencing factor for the treatment results.

Diagnosis, Differential↗

PubMed1986

Physician utilization of computers in medical practice: policy implications based on a structural model.

The development of policies regarding computer-based medical technology is hampered by a lack of knowledge about the process by which such applications are adopted and utilized by physicians. This study was designed to test a model of the process by which physicians change their practice behavior by utilizing a computer-based hospital information system (HIS). A structural model was developed, estimated, and tested using data from 270 members of the medical staff of a 1160 bed, private teaching hospital. The overall model consists of a measurement model which assumes that the observed variables are generated by a smaller number of unobserved variables or factors; and a structural equation model that relates exogenous and endogenous variables. The model indicates that consultation with other physicians on a hospital service leads to greater exposure to potential computer applications resulting in less concern about the potential impact of computers on medical practice. Physicians who are more knowledgeable about computers are far more likely to tailor the system to their individual practice by developing their own personal order sets for use on the HIS. All of these factors result in increased use of the HIS by physicians. A number of policy implications related to the introduction of new computer-based technology into medical practice settings are discussed.

Attitude to Computers↗

PubMed1998

Stress and low birth weight: a structural modeling approach using real life stressors.

This study presents a structural equation model describing the influence of stressful life experiences on low birth weight. Data were gathered prospectively in two waves from 5295 inner-city women as part of a city-wide preterm birth prevention project. Using interviews and the medical record, over 200 measures were gathered on each mother and her infant, where each measure was included because of its relevance documented in the risk factor literature. Seventeen of these measures reflected real life stressful experiences and through measurement modeling, eleven of these measures were chosen to represent three underlying measures of stress: economic stress, family stress, and the lack of social support. This study incorporates these psychosocial stressors into a full structural equation model to show their influence on addictive behavior and low birth weight. The full model emerged from tests of alternative causal conceptualizations of how these stressors influence each other and low birth weight--whether their influence on low birth weight in simple and direct, or whether their influence is mediated by addictive behaviors. The model was tested on the first wave, a sample of 3205, and cross-validated on the second wave, a sample of 2090. The model shows that economic stress influences both social support and family stress, but has no direct influence on low birth weight: that social support, or its absence, influences addictive behavior, but has no direct influence on low birth weight, and that family stress influences addictive behavior, and consistent with 30 years of research on humans, has no direct influence on low birth weight. Finally, the mother's history of medical risks shows an independent influence on low birth weight, while her age does not. Age, however, shows a strong influence on addictive behavior. The study demonstrates how structural equation modeling can be used to create and test alternative conceptualizations of how stress affects low birth weight. There are strong implications for planners of prenatal care programs.

Female↗

PubMed2002

Structural modeling of contrast sensitivity in adulthood.

Structural equation modeling was used to assess the utility of the sensorineural model of contrast sensitivity proposed by Sekuler et al. [Vision Res. 24, 689 (1984)] to account for spatial vision in adulthood. In Study 1, visual acuity and contrast sensitivity (1.5-18 c/deg) were measured in 84 people between the ages of 19 and 81 yr. No three-filter model fitted the data well. Although a two-filter model was associated with good fit indices, parameter estimates for both filters were inconsistent with physiological and behavioral data. In Study 2, acuity and contrast sensitivity (1.5-18 c/deg) were assessed in 95 observers between the ages of 23 and 73 yr. All measures were gathered once per month over a three-month period. The Sekuler et al. three-filter model did not fit the data from any time of measure, but a two-filter, bandpass model provided a consistent and excellent fit for all three waves. The model suggests that age-related change in the neural mechanisms underlying contrast sensitivity is minimal once acuity is controlled. Discrepancies between this conclusion and that reported by Sekuler et al. may be related to test type, psychophysical method, reliability, and sample selection.

Adult↗

PubMed1985

Structural model for interferons.

Secondary structures of leucocyte alpha 1- and alpha 2-interferons and of fibroblast beta-interferon are calculated using the molecular theory of protein secondary structures. The common secondary structure calculated for alpha- and beta-interferons is used to predict the three-dimensional structures of fragments 1-110 and 111-166 of the chains (which are supposed to be quasi-independent domains). The predicted structure of the active domain I (1-110) is an 'up-and-down' tetrahelical complex (in which the second helix is shorter than the others and can be absent in alpha 1-interferon) similar to the mirror image of myohaemoerythrin. The predicted structure of domain II (111-166) is either a three-stranded beta-sheet screened from one side by two alpha-helices or a three-helical complex (similar to that in the N-domain of papain), the first structure being more consistent with the circular dichroism data of alpha-interferon and its C-end fragment.

Circular Dichroism↗

PubMed1993

Model structures and action of interleukin 1 and its antagonist.

A comparison has been made between the homology and hydrophobicity profiles of six interleukin amino acid sequences and that of the human interleukin 1 beta (IL-1 beta) for which a crystal structure exists. The resulting sequence alignment was used to build model structures for the sequences for three IL-1 alpha, two IL-1 beta and an interleukin receptor antagonist. Analysis of these structures demonstrates that the interleukin molecule has a strong electric dipole which is generated by the topological position of the amino acids in the sequence. Electrostatic surface calculations implicate a particular residues (Lys145) as being fundamental to interleukin activity and this supports site-directed mutation evidence that this residue is required for activity.

Amino Acid Sequence↗

PubMed1992

Terminating a macromolecular helix. Structural model for the minor proteins of bacteriophage M13.

Analysis of the results of X-ray diffraction, electron microscopy and s sequence studies of filamentous bacteriophage M13 are used to construct structural models for the minor proteins gp7 and gp9 at the end of the virus assembled first, and a portion of gp6 at the end of the virus that binds host. Comparison of the sequence of the major coat protein, gp8, with those of gp7, gp9 and gp6 indicates that significant portions of these three proteins have sequences similar to that of gp8. Assuming that sequence similarity is indicative of structural similarity, gp7, gp9 and portions of gp6 are modeled based on what is known about the structure of gp8. These molecular models are analyzed to predict the packing of the minor proteins with the terminal gp8 proteins (the last gp8 proteins at either end of the helix). This analysis indicates that the gp8 proteins integrated into the virus first may have a structure distinct from those in the body of the virus particle. The gp8 proteins at the end assembled last appear to have a conformation very similar to that of the integral coat proteins. These models place specific constraints on models for the process of viral assembly.

Amino Acid Sequence↗

PubMed1997

An age-structured model for pertussis transmission.

The vaccination program for pertussis (whooping cough) in the United States consists of giving multiple doses of pertussis vaccine to young children. A demographic model with a steady-state age distribution is used as a basis for building an epidemiologic model for the transmission of pertussis. This age-structured model includes vaccination of infants and children for pertussis with waning of both infection-acquired and vaccine-induced immunity. Computer simulations of the mathematical model between 1940 and 2040 show the changes that took place during the implementation phase of the U.S. program and predict only minor future changes in the age distribution and incidence of pertussis if the vaccination program is maintained at the 1995 level. The sensitivities of these results to changes in demographic and epidemiologic parameters, vaccine efficacy, duration of protection, and levels of vaccination coverage are investigated.

Adolescent↗

PubMed1998

Large-scale protein structure modeling of the Saccharomyces cerevisiae genome.

The function of a protein generally is determined by its three-dimensional (3D) structure. Thus, it would be useful to know the 3D structure of the thousands of protein sequences that are emerging from the many genome projects. To this end, fold assignment, comparative protein structure modeling, and model evaluation were automated completely. As an illustration, the method was applied to the proteins in the Saccharomyces cerevisiae (baker's yeast) genome. It resulted in all-atom 3D models for substantial segments of 1,071 (17%) of the yeast proteins, only 40 of which have had their 3D structure determined experimentally. Of the 1,071 modeled yeast proteins, 236 were related clearly to a protein of known structure for the first time; 41 of these previously have not been characterized at all.

Fungal Proteins↗

PubMed2001

A proposed structural model for amyloid fibril elongation: domain swapping forms an interdigitating beta-structure polymer.

We propose a model illustrating how proteins, which differ in their overall sequences and structures, can form the propagating, twisted beta-sheet conformations, characteristic of amyloids. Some cases of amyloid formation can be explained through a "domain swapping" event, where the swapped segment is either a beta-hairpin or an unstable conformation which can partially unfold and assume a beta-hairpin structure. As in domain swapping, here the swapped beta-hairpin is at the edge of the structure, has few (if any) salt bridges and hydrogen bonds connecting it to the remainder of the structure and variable extents of buried non-polar surface areas. Additionally, in both cases the swapped piece constitutes a transient "building block" of the structure, with a high population time. Whereas in domain swapping the swapped fragment has been shown to be an alpha-helix, loop, strand or an entire domain, but so far not a beta-hairpin, despite the large number of cases in which it was already detected, here swapping may involve such a structural motif. We show how the swapping of beta-hairpins would form an interdigitated, twisted beta-sheet conformation, explaining the remarkable high stability of the protofibril in vitro. Such a swapping mechanism is attractive as it involves a universal mechanism in proteins, critical for their function, namely hinge-bending motions. Our proposal is consistent with structural superpositioning of mutational variants. While the overall r.m.s.d.s of the wild-type and mutants are small, the proposed hinge-bending region consistently shows larger deviations. These larger deviations illustrate that this region is more prone to respond to the mutational changes, regardless of their location in the sequence or in the structure. Nevertheless, above all, we stress that this proposition is hypothetical, since it is based on assumptions lacking definitive experimental support.

Amyloid↗

PubMed2004

A structural model of the plant acyl-acyl carrier protein thioesterase FatB comprises two helix/4-stranded sheet domains, the N-terminal domain containing residues that affect specificity and the C-terminal domain containing catalytic residues.

Plant acyl-acyl carrier protein thioesterases (TEs) terminate the acyl-acyl carrier protein track of fatty acid biosynthesis and play an essential role in determining the amount and composition of fatty acids entering the storage lipid pool. A combination of bioinformatics tools was used to predict a three-dimensional model for Arabidopsis FatB (AtFatB), which comprises a fold similar to that of Escherichia coli TEII, an enzyme that is functionally similar to plant TEs but lacks significant sequence similarity and displays different inhibitor sensitivity. The catalytic residues in AtFatB, Cys-264 and His-229, localize to the same region of the model as catalytic residues found in other enzymes with helix/multi-stranded sheet motifs (hot dog folds). Based on the model, we identified Asn-227 as a possible third member of the proposed papain-like catalytic triad. The conversion of Asn-227 to Ala resulted in a loss of detectable activity (>200-fold reduction), similar to the result seen for the equivalent mutation in papain. Mapping of plant TE specificity-affecting mutations onto the structural model showed that these mutations all cluster around the catalytic triad. Also, superposition of the crystallographically determined structures of the complexes of 4-hydroxybenzoyl-CoA TE with substrate and beta-hydroxydecanoyl thiol ester dehydrase with inhibitor onto the AtFatB model showed that the substrate and inhibitor localize to the same region as the AtFatB catalytic triad in their respective structures. Together these data corroborate the structural model and show that the hot dog fold is common to enzymes from both prokaryotes and eukaryotes and that this fold supports at least three different catalytic mechanisms.

Amino Acid Sequence↗

PubMed1990

Uncertainties in pharmacokinetic modeling for perchloroethylene. I. Comparison of model structure, parameters, and predictions for low-dose metabolism rates for models derived by different authors.

In recent years physiologically based pharmacokinetic models have come to play an increasingly important role in risk assessment for carcinogens. The hope is that they can help open the black box between external exposure and carcinogenic effects to experimental observations, and improve both high-dose to low-dose and interspecies projections of risk. However, to date, there have been only relatively preliminary efforts to assess the uncertainties in current modeling results. In this paper we compare the physiologically based pharmacokinetic models (and model predictions of risk-related overall metabolism) that have been produced by seven different sets of authors for perchloroethylene (tetrachloroethylene). The most striking conclusion from the data is that most of the differences in risk-related model predictions are attributable to the choice of the data sets used for calibrating the metabolic parameters. Second, it is clear that the bottom-line differences among the model predictions are appreciable. Overall, the ratios of low-dose human to bioassay rodent metabolism spanned a 30-fold range for the six available human/rat comparisons, and the seven predicted ratios of low-dose human to bioassay mouse metabolism spanned a 13-fold range. (The greater range for the rat/human comparison is attributable to a structural assumption by one author group of competing linear and saturable pathways, and their conclusion that the dangerous saturable pathway constitutes a minor fraction of metabolism in rats.) It is clear that there are a number of opportunities for modelers to make different choices of model structure, interpretive assumptions, and calibrating data in the process of constructing pharmacokinetic models for use in estimating "delivered" or "biologically effective" dose for carcinogenesis risk assessments. We believe that in presenting the results of such modeling studies, it is important for researchers to explore the results of alternative, reasonably likely approaches for interpreting the available data--and either show that any conclusions they make are relatively insensitive to particular interpretive choices, or to acknowledge the differences in conclusions that would result from plausible alternative views of the world.

Animals↗

PubMed2000

Building 3D-structural model of kappa opioid receptor and studying its interaction mechanism with dynorphin A(1-8).

AIM: To construct the 3D-structural model of human kappa opioid receptor (HKOR) and study its interacting mechanism with dynorphin A(1-8) (Dyn8). METHODS: Comparative molecular modeling was applied to build the 7 transmembrane (TM) helical domain of HKOR using the bovine rhodopsin (OPSD) model as a template. Molecular dynamics was performed to minimize the HKOR model and to simulate the 3D-structure of Dyn8 based on the NMR results of dynorphin A(1-14). The extracellular loops (EL) were built by self-constructed database searching. DOCK4.0 program was performed to construct Dyn8 complex with HKOR. RESULTS: (1) The model of HKOR was obtained and validated by theoretical and experimental data. (2) The Dyn8-HKOR interacting mechanism is reasonably explained: Side chain of residue Asp138 interacts with protonated nitrogen atom at the N-terminal residues of Dyn8 through electrostatic and hydrogen bonding, which play an important role in ligand binding with receptor. (3) Negatively charged amino acids in the second extracellular loop (EL2) as Asp223 and Glu209 interact with the C-terminal positively charged residues in Dyn8, and Glu209 is a likely determinant of peptide ligand specificity. CONCLUSION: Some amino acid residues positioned in EL2, TM3, TM4, and TM5 form the binding site and therefore determine the selectivity of kappa peptide agonist.

Amino Acid Sequence↗

PubMed2003

Sites for interaction between Gal80p and Gal1p in Kluyveromyces lactis: structural model of galactokinase based on homology to the GHMP protein family.

The induction of transcription of the galactose genes in yeast involves the galactose-dependent binding of ScGal3p (in Saccharomyces cerevisiae) or KlGal1p (in Kluyveromyces lactis) to Gal80p. This binding abrogates Gal80's inhibitory effect on the activation domain of Gal4p, which can then activate transcription. Here, we describe the isolation and characterization of new interaction mutants of K.lactis GAL1 and GAL80 using a two-hybrid screen. We present the first structural model for Gal1p to be based on the published crystal structures of other proteins belonging to the GHMP (galactokinase, homoserine kinase, mevalonate kinase and phosphomevalonate kinase) kinase family and our own X-ray diffraction data of Gal1p crystals at 3A resolution. The locations of the various mutations in the modelled Gal1p structure identify domains involved in the interaction with Gal80p and provide a structural explanation for the phenotype of constitutive GAL1 mutations.

Amino Acid Sequence↗

PubMed1996

Functional implications of the modeled structure of maspin.

The tumor suppressor maspin (mammary-specific serpin) is an unstable serpin that does not undergo the stressed to relaxed transition typical of proteinase inhibitory serpins and, consequently, is not likely to function as a serine proteinase inhibitor. This suggests that the positioning and configuration of the reactive site loop (RSL) of maspin are likely to resemble those of ovalbumin, the best studied non-inhibitory serpin. Accordingly, the tertiary structure of maspin has been modeled on the crystal structure of native ovalbumin. Biochemical data and the modeled theoretical structure of maspin reveal the absence of disulfide bonds in the molecule and the presence of an unstable RSL that adopts a distorted helical structure. We confirm that the RSL is extremely sensitive to limited proteolysis and suggest that this may provide a structural basis for the proteolytic inactivation of maspin, a process that is likely to modulate the activity of maspin in biological systems.

Amino Acid Sequence↗