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PubMed1991

Predicting the three-dimensional folding of transfer RNA with a computer modeling protocol.

We have developed a computer modeling protocol that can be used to predict the three-dimensional folding of a ribonucleic acid on the basis of limited amounts of secondary and tertiary data. This protocol extends the use of distance geometry beyond the domain of NMR data in which it is usually applied. The use of this algorithm to fold the molecule eliminates operator subjectivity and reproducibly predicts the overall dimensions and shape of the transfer RNA molecule. By use of a replacement pseudoatom set based on helical substructures, a series of transfer RNA foldings have been completed that utilize only the primary structure, the phylogenetically deduced secondary structure, and five long-range interactions that were determined without reference to the crystal structure. In a control set of foldings, all the interactions suspected to exist in 1969 have been included. In all cases, the modeling process consistently predicts the global arrangement of the helical domains and to a lesser extent the general path of the backbone of transfer RNA.

Computer Simulation↗
PubMed1991

Identification of antibody epitopes within the CB-11 peptide of type II collagen. II. Computer modelling studies of peptides and the interpretation of epitope scanning results.

Computer modelling techniques were used to investigate the structure of 8-mers from the CB-11 peptide of bovine type II collagen which were recognised by sera from rats which had previously been injected with bovine type II collage. It was discovered that all the hydrophobic peptides recognised by the rat sera were predicted to have collagenous-like secondary structures. The primary structure of the 8-mers which were recognised was also compared against the sequences in the OWL protein sequence database. The combined results of the computer modelling and sequence analysis suggested that the sequence Gly-Pro-Gly-Phe-Pro is a minimal B cell epitope of the CB-11 fragment of bovine type II collagen.

Amino Acid Sequence↗
PubMed1992

Computer modeling of gibberellin-DNA binding.

Computer modeling and molecular mechanics performed on the intercalation complexes of selected gibberellins or biosynthetic precursors with DNA dinucleotides revealed that under appropriate conditions the ligands insert (intercalate) between the base-paired double-stranded dinucleotide, 5'-dTdA-3'. Stabilization of the double-stranded dinucleotide after docking of a gibberellin between base pairs is inferred by the sum negative energy of hydrogen bonding and van der Waals contacts and the entropic changes which accompany the formation of each ligand-dinucleotide complex. In addition, the interactions of the gibberellins and dinucleotides, with the gibberellic acid-dinucleotide complex serving as the prototype, show optimum geometry and stereochemical hydrogen bonding recognition which are dependent upon the complementary chirality and stereochemistry of the individual components. Whether or not the gibberellins directly influence the uncoiling of DNA or gene expression at the transcriptional level via an intercalation mechanism is a matter of conjecture, albeit one that warrants intensive investigation.

Computer Simulation↗
PubMed1990

Analysis of glycosylated serum protein changes using a computer model.

UNLABELLED: The authors devised a computer model of albumin glycosylation based on irreversible glycosylation reaction of first-order kinetics. The dynamism of glycosylated albumin changes in relation to glycaemic profiles was compared with an earlier model of haemoglobin glycosylation. A non-linear regression analysis was employed to calculate the parameters of the model in three groups of patients. CONCLUSIONS: 1. Erythrocyte pool stratification accounts for the smaller clinical difference between glycosylated protein and haemoglobin than would correspond to their respective half-life values. 2. Glycosylated proteins are probably eliminated more rapidly than non-glycosylated proteins. 3. Higher levels of glycosylated proteins are occasionally at variance with model calculations, a fact which is probably due to other factors.

Computer Simulation↗
PubMed1977

A Monte Carlo computer model to investigate patient scheduling.

A Monte Carlo computer model was developed to investigate various types of patient appointment schedules for a single channel queue. Input parameters included the incidence of no-shows, the rate of unscheduled walk-ins, the frequency distribution of physician examination times, and the string of appointment times. The results included the frequency distributions of physician utilization rates and the total waiting time of all patients. Five hospital clinics were simulated. Even increment schedules yielded the best trade-off between physician utilization and patient waiting.

Appointments and Schedules↗
PubMed1991

An evaluation of eight computer models of mammalian inner hair-cell function.

Eight computer models of auditory inner hair cells have been evaluated. From an extensive literature on mammalian species, a subset of well-reported auditory-nerve properties in response to tone-burst stimuli were selected and tested for in the models. This subset included tests for: (a) rate-level functions for onset and steady-state responses; (b) two-component adaptation; (c) recovery of spontaneous activity; (d) physiological forward masking; (e) additivity; and (f) frequency-limited phase locking. As models of hair-cell functioning are increasingly used as the front end of speech-recognition devices, the computational efficiency of each model was also considered. The evaluation shows that no single model completely replicates the subset of tests. Reasons are given for our favoring the Meddis model [R. Meddis, J. Acoust. Soc. Am. 83, 1056-1063 (1988)] both in terms of its good agreement with physiological data and its computational efficiency. It is concluded that this model is well suited to provide the primary input to speech recognition devices and models of central auditory processing.

Animals↗
PubMed1976

Subsite mapping of enzymes. Application of the depolymerase computer model to two alpha-amylases.

In the preceding paper (Allen and Thoma, 1976) we developed a depolymerase computer model, which uses a minimization routine to establish a subsite map for a depolymerase. In the present paper we show how the model is applied to experimental data for two alpha-amylases. Michaelis parameters and bond-cleavage frequencies for substrates of chain lengths up to twelve glucosyl units have been reported for Bacillus amyloliquefaciens, and a subsite map has been proposed for this enzyme [Thoma et al. (1971) J. Biol. Chem. 246, 5621-5635]. By applying the computer model to the experimental data, we have arrived at a ten-subsite map. We find that a significant improvement in this map is achieved by allowing the hydrolytic rate coefficient to vary as a function of the number of occupied subsites comprising the enzyme-binding region. The bond-cleavage frequencies, the enzyme is found to have eight subsites. A partial subsite map is arrived at, but the entire binding region cannot be mapped because Michaelis parameters are complicated by transglycosylation reactions. The hydrolytic rate coefficients for this enzyme are not constant.

Amino Acid Sequence↗
PubMed1991

3-D computer model of subcortical structures of human brain.

Three-dimensional computer model of thalamus and adjacent formations of human brain has been elaborated on the basis of sagittal slices from the Schaltenbrand-Bailey stereotactic atlas. The model includes 120 morphologically distinguishable structures and consists of more than 16 million points (volume elements) each of them being associated with the particular structure in the brain. The model is stored in the long-term computer memory. A special software has been developed to facilitate utilizing the model obtained. The software facilitates synthesizing arbitrary cross-sections through the brain and provides the correspondence between the stereotactic coordinates of any point and its position on the screen of monitor. The coordinates of the point in the system of stereotactic atlas and the name of the structure, the point belongs to, are also supplied. It is also possible to get magnified images of cross-sections and to get isometrical images. The system enables the neurosurgeon to improve the planning and execution of stereotactic operations, and will also be helpful for education.

Brain↗
PubMed1991

Three-dimensional model of Escherichia coli ribosomal 5 S RNA as deduced from structure probing in solution and computer modeling.

The conformation of Escherichia coli 5 S rRNA was investigated using chemical and enzymatic probes. The four bases were monitored at one of their Watson-Crick positions with dimethylsulfate (at C(N-3) and A(N-1], with a carbodiimide derivative (at G(N-1) and U(N-3] and with kethoxal (at G(N-1, N-2]. Position N-7 of purine was probed with diethylpyrocarbonate (at A(N-7] and dimethylsulfate (at G(N-7]. Double-stranded or stacked regions were tested with RNase V1 and unpaired guanine residues with RNase T1. We also used lead(II) that has a preferential affinity for interhelical and loop regions and a high sensitivity for flexible regions. Particular care was taken to use uniform conditions of salt, magnesium, pH and temperature for the different enzymatic chemical probes. Derived from these experimental data, a three dimensional model of the 5 S rRNA was built using computer modeling which integrates stereochemical constraints and phylogenetic data. The three domains of 5 S rRNA secondary structure fold into a Y-shaped structure that does not accommodate long-range tertiary interactions between domains. The three domains have distinct structural and dynamic features as revealed by the chemical reactivity and the lead(II)-induced hydrolysis: domain 2 (loop B/helix III/loop C) displays a rather weak structure and possesses dynamic properties while domain 3 (helix V/region E/helix IV/loop D) adopts a highly structured and overall helical conformation. Conserved nucleotides are not crucial for the tertiary folding but maintain an intrinsic structure in the loop regions, especially via non-canonical pairing (A.G, G.U, G.G, A.C, C.C), which can close the loops in a highly specific fashion. In particular, nucleotides in the large external loop C fold into an organized conformation leading to the formation of a five-membered loop motif. Finally, nucleotides at the hinge region of the Y-shape are involved in a precise array of hydrogen bonds based on a triple interaction between U14, G69 and G107 stabilizing the quasi-colinearity of helices II and V. The proposed tertiary model is consistent with the localization of the ribosomal protein binding sites and possesses strong analogy with the model proposed for Xenopus laevis 5 S rRNA, indicating that the Y-shape model can be generalized to all 5 S rRNAs.

Base Sequence↗
PubMed1991

Stereochemical complementarity of progesterone and cavities between base pairs in partially unwound double stranded DNA using computer modeling and energy calculations to determine degree of fit.

Computer modeling was applied for the first time to investigate previously reported complementarity of progesterone and cavities formed between base pairs in partially unwound double stranded DNA. Computer graphics enabled a more objective assessment of complementarity; energy calculations provided a rigorous method to evaluate degree of fit. Graphics confirmed that the complementarity was virtually "lock and key", i.e. close contacts were formed between van der Waals surfaces in the progesterone/DNA complexes and hydrogen bonds were formed between the two carbonyl groups on opposite ends of the steroid and phosphate groups on adjacent strands of DNA. Molecular mechanics calculations revealed that insertion of the steroid resulted in a relatively stable complex i.e. both van der Waals and electrostatic energies were lowered due to favorable steric interactions and stereospecific hydrogen bonds, respectively. Three published X-ray crystal structures of progesterone exhibited similar complementarity. Ent-progesterone which does not occur naturally possessed very poor complementarity. These findings confirm that the structure of progesterone is directly reflected in the stereochemistry of DNA. While no mechanistic explanation for these results is proffered, we hypothesize that such complementarity must have played a decisive role in the evolution of steroid hormone structure and function.

Base Composition↗
PubMed1977

A computational model of cerebellar cortex and peripheral muscle.

A computational model, suitable for analytical or machine simulation studies, is developed for a specific cerebellar loop, the pathway from muscle fibre stretch receptors to the cerebellar cortex and back again. The model adheres to physiological data from the cat, and employs features from several existing models, including a single neuron model developed and tested earlier. Also included is a mechanical equivalent to an idealised muscle, in this case a rectangular array of muscle fibres which map 1-to-1 onto the array of compartments which form the cerebellar cortex. Much of the literature on cerebellar models is briefly reviewed, as are several key physiological experiments.

Animals↗
PubMed1992

Intra-blood-brain barrier synthesis of IgG: comparison of IgG synthesis formulas in a computer model and in 1,629 consecutive specimens.

We evaluated four formulas for estimating the intra-blood-brain barrier (IBBB) synthesis of IgG in a computer model of two types of BBB damage and in 1,629 consecutively received pairs of CSF and serum. These four formulas were the IgG synthesis rate (SR), IgG(loc) (ie, local), IgG index, and IgG extended index. Results from the 1,629 specimens and the computer model of type 2 BBB damage (partial or total loss of selective filtration) accurately predicted problems encountered with the IgG SR in clinical practice. In both the model and with the results from the 1,629 specimens, the combination of the IgG(loc) and IgG index formulas minimized the possibility of false-positive and false-negative results and yielded the most reliable results for IBBB synthesis of IgG in the presence or absence of increased permeability of the BBB. Additional studies with detailed clinical correlations will allow an accurate assessment of how effectively this combination of formulas can help to rule in or out the diagnosis of a particular disease or inflammatory condition of the CNS.

Albumins↗
PubMedDate not supplied

Computer modelling studies of ribonuclease T1-2'-deoxy-2'-fluoroguanylyl- (3',5')-cytidine complex.

The mode of binding of the substrate analog 2'-deoxy-2'-fluoroguanylyl- (3',5')-cytidine (GfpC) to RNase T1 was determined by computer modelling studies. The results obtained are in good agreement with the observations of 1H-nmr studies. The modes of binding of the substrate analog GfpC and the substrate GpC to the enzyme RNase T1 have been compared. Though the guanine base favours to occupy the same site of the enzyme in both the complexes, significant differences are observed in the local environment around the 2'-substituent group of guanosine ribose moiety. In the RNase T1-GpC complex, the 2'-OH group is in close proximity to the side chain carboxylic acid of Glu58 which leads to the formation of a hydrogen bond. However, in the RNase T1-GfpC complex, 2'-fluorine is positioned away from Glu58 due to electrostatic repulsion and instead forms a hydrogen bond with His40 imidazolium group. The results obtained rule out the possibility of His40 serving as the base group in catalysis as suggested by 1H-nmr studies and further support the primary role assigned to Glu58 as the general base group by earlier computer modelling and the recent site directed mutagenesis studies. This study also implies that the 2'-deoxy-2'-fluoro substrate analog may not serve as a good model for determining the amino acid residue which serves as the general base group in ribonuclease catalysed reactions.

Binding Sites↗
PubMed1977

A computational model of pulmonary gas transport incorporating effective diffusion.

A computational model of gas transport in the lung is described which remedies many of the deficiencies of previous models, as listed by Chang and Farhi (1973), in that it allows for fluctuating lung dimensions, gas exchange, simultaneous convection and diffusion, and the enhanced effective diffusion that occurs when convective flow is also present. The results of calculations using the model are presented, showing the maximum effect of Taylor diffusion. The actual magnitude of Taylor diffusion, suitably modified to allow for the disturbed conditions within the lung, is considered in the light of recent experiments.

Carbon Dioxide↗
PubMed1991

Computer modelling of neural tube defects.

Neurulation, the curling of the neuroepithelium to form the neural tube, is an essential component of the development of animal embryos. Defects of neural tube formation, which occur with an overall frequency of one in 500 human births, are the cause of severe and distressing congenital abnormalities. However, despite the fact that there is increasing information from animal experiments about the mechanisms which effect neural tube formation, much less is known about the fundamental causes of neural tube defects (NTD). The use of computer models provides one way of gaining clues about the ways in which neurulation may be compromised. Here we employ one computer model to examine the robustness of different cellular mechanisms which are thought to contribute to neurulation. The model, modified from that of Odell et al (Odell, G.M., Oster, G., Alberch, P. and Burnside, B., (1981)) mimics neurulation by laterally propagating a wave of apical contraction along an active zone within a ring of cells. We link the results to experimental evidence gained from studies of embryos in which neurulation has been perturbed. The results indicate that alteration of one of the properties of non-neural tissue can delay or inhibit neurulation, supporting the idea, gained from observation of embryos bearing genes which predispose to NTD, that the tissue underlying the neuroepithelium may contribute to the elevation of the neural folds. The results also show that reduction of the contractile properties of a small proportion of the neuroepithelial cell population may have a profound effect on overall tissue profiling. The results suggest that the elevation of the neural folds, and hence successful neurulation, may be vulnerable to relatively minor deficiencies in cell properties.

Animals↗
PubMed1991

Cardiac electrophysiological experiments in numero, Part I: Concepts and strategies of mathematical and computer models.

This article is the first of three articles that review mathematical and computer models of the heart and describe their construction, development, research potential, and clinical utility. This article explains the methodological principles of mathematical and computer simulation of biomedical systems. The strategies of model construction, testing, and application are presented; the advantages and limitations of computer simulation studies are explained, and the basic value of computer simulation for cardiological research and practice is discussed.

Cardiac Pacing, Artificial↗
PubMed1979

Metabolism of totally ischemic excised dog heart. I. Construction of a computer model.

Construction and fit to the experimental data of a computer model of glycolysis, the Krebs cycle, and related metabolism in an ischemic dog heart preparation, involving 122 metabolites, 65 enzymes, and 406 chemical reactions, is described. The experimental preparation simulated is a dog heart excised from the body, placed in a beaker of Tyrode's solution, and sampled for 100 min; the model required only moderate modification from models representing perfused rat hearts, and little modification from a model of another ischemic dog heart preparation. Common underlying mechanisms for the ischemia are indicated, although this preparation appears to evolve more slowly with time, perhpas owing to heavy sedation and diffusion-limited transport. Lactate is, at first, exported and then accumulates intracellularly; pH falls, but not as much in the mitochondria as the cytoplasm; redox couples go reduced, but with counterintuitive time courses; calcium phosphate is calculated to precipitate, as often observed in cardiac ischemia.

Adenine Nucleotides↗