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PubMed1997

Protein superfamily members as targets for computer modeling: the carbohydrate recognition domain of a macrophage lectin.

Members of protein superfamilies display similar folds, but share only limited sequence identity, often 25% or less. Thus, it is not straightforward to apply standard homology modeling methods to construct reliable three-dimensional models of such proteins. A three-dimensional model of the carbohydrate recognition domain of the rat macrophage lectin, a member of the calcium-dependent (C-type) lectin superfamily, has been generated to illustrate how information provided by comparison of X-ray structures and sequence-structure alignments can aid in comparative modeling when primary sequence similarities are low.

Amino Acid Sequence↗
PubMed2003

Computer modeling of the membrane interaction of FYVE domains.

FYVE domains are membrane targeting domains that are found in proteins involved in endosomal trafficking and signal transduction pathways. Most FYVE domains bind specifically to phosphatidylinositol 3-phosphate (PI(3)P), a lipid that resides mainly in endosomal membranes. Though the specific interactions between FYVE domains and the headgroup of PI(3)P have been well characterized, principally through structural studies, the available experimental structures suggest several different models for FYVE/membrane association. Thus, the manner in which FYVE domains adsorb to the membrane surface remains to be elucidated. Towards this end, recent experiments have shown that FYVE domains bind PI(3)P in the context of phospholipid bilayers and that hydrophobic residues on a conserved loop are able to penetrate the membrane interface in a PI(3)P-dependent manner.Here, the finite difference Poisson-Boltzmann (FDPB) method has been used to calculate the energetic interactions of FYVE domains with phospholipid membranes. Based on the computational analysis, it is found that (1) recruitment to membranes is facilitated by non-specific electrostatic interactions that occur between basic residues on the domains and acidic phospholipids in the membrane, (2) the energetic analysis can quantitatively differentiate among the modes of membrane association proposed by the experimentally determined structures, (3) FDPB calculations predict energetically feasible models for the membrane-associated states of FYVE domains, (4) these models are consistent with the observation that conserved hydrophobic residues insert into the membrane interface, and (5) the calculations provide a molecular model for the hydrophobic partitioning: binding of PI(3)P significantly neutralizes positive potential in the region of the hydrophobic residues, which acts as an "electrostatic switch" by reducing the energetic barrier for membrane penetration. Finally, the computational results are extended to FYVE domains of unknown structure through the construction of high quality homology models for human FYVE sequences.

Binding Sites↗
PubMed1988

Experimental DNA-binding and computer modelling studies on an analogue of the anti-tumor drug amsacrine.

The DNA-binding properties of the anti-cancer drug amsacrine and a 9-aminoacridine analogue substituted at the 4 position with a 4-methanesulphonanilido-group, have been examined by means of unwinding, melting and equilibrium binding experiments. These find that the latter compound is at least as effective as a DNA-binder and intercalator as amsacrine itself. Molecular modelling and energetic calculations have confirmed this, and have produced plausible intercalation geometries. These show that there are subtle differences in the low-energy minor groove arrangements adopted by the substituents of the two drugs. Speculation is advanced that these differences may be relevant to the marked differences in cytotoxicity shown by the two compounds.

Amsacrine↗
PubMed2000

A-Tract bending: insights into experimental structures by computational models.

While solution structures of adenine tract (A-tract) oligomers have indicated a unique bend direction equivalent to negative global roll (commonly termed "minor-groove bending"), crystallographic data have not unambiguously characterized the bend direction; nevertheless, many features are shared by all A-tract crystal and solution structures (e.g. propeller twisting, narrow minor grooves, and localized water spines). To examine the origin of bending and to relate findings to the crystallographic and solution data, we analyze molecular dynamics trajectories of two solvated A-tract dodecamers: 1D89, d(CGCGA(6)CG), and 1D98, d(CGCA(6)GCG), using a new general global bending framework for analyzing bent DNA and DNA/protein complexes. It is significant that the crystallographically-based initial structures are converted from dissimilar to similar bend directions equivalent to negative global roll, with the average helical-axis bend ranging from 10.5 degrees to 14.1 degrees. The largest bend occurs as positive roll of 12 degrees on the 5' side of the A-tracts (supporting a junction model) and is reinforced by gradual curvature at each A-tract base-pair (bp) step (supporting a wedge model). The precise magnitude of the bend is subtly sequence dependent (consistent with a curved general sequence model). The conversion to negative global roll only requires small local changes at each bp, accumulated over flexible moieties both outside and inside the A-tract. In contrast, the control sequence 1BNA, d(CGCGA(2)TTCGCG), bends marginally (only 6.9 degrees ) with no preferred direction. The molecular features that stabilize the bend direction in the A-tract dodecamers include propeller twisting of AT base-pairs, puckering differences between A and T deoxyriboses, a narrow minor groove, and a stable water spine (that extends slightly beyond the A-tract, with lifetimes approaching 0.2 ns). The sugar conformations, in particular, are proposed as important factors that support bent DNA. It is significant that all these curvature-stabilizing features are also observed in the crystallographic structures, but yield overall different bending paths, largely due to the effects of sequences outside the A-tract. These results merge structural details reported for A-tract structures by experiment and theory and lead to structural and dynamic insights into sequence-dependent DNA flexibility, as highlighted by the effect of an A-tract variant of a TATA-box element on bending and flexibility required for TBP binding.

Computer Simulation↗
PubMed2005

A predictive study of the mechanical behaviour of coronary stents by computer modelling.

Intravascular stents are small tube-like structures expanded into stenotic arteries to restore blood flow perfusion to the downstream tissues. The stent expansion is an important factor to define the effectiveness of the surgical procedure: it depends on the stent geometry and includes large displacements and deformations, geometric and material non-linearity. Numerical analyses seem appropriate to study such a complex behaviour after a free stent expansion. In this study the finite element method (FEM) was applied to a new generation coronary stent. Results from computations were compared with those from a laboratory experiment in terms of radial expansion and elastic recoil. By means of a scanning electronic microscopy the area of plastic deformation were also detected and compared with those obtained in the numerical simulation. Matching between the different measurements was quite satisfactory even if some discrepancies were present due to the absence of the balloon in the numerical model.

Angioplasty, Balloon, Coronary↗
PubMed2003

A computational model for the adaptation of muscle and tendon length to average muscle length and minimum tendon strain.

This paper hypothesizes that average muscle length and minimum tendon strain govern muscle and tendon length adaptation in all situations. A model has been implemented to test this hypothesis, and simulations have been performed for normal development, bone lengthening, immobilization, and retinacular release experiments in young and adult animals. The simulation results predict that both muscle and tendon lengthen during normal development, with the rate of tendon growth slowing faster than the rate of muscle growth. The results also predict that muscle length increases during bone lengthening in both young and adult animals, while tendon length increases only in young animals. For immobilization in adult animals, the results predict that muscle length increases when the muscle is immobilized in a lengthened position and decreases when the muscle is immobilized in a shortened position with no change in tendon length. For immobilization in young animals, the results predict reduced muscle growth and increased tendon growth regardless of immobilization position. Finally, the simulations predict that retinacular release which increases excursion of the musculotendinous unit leads to increased muscle length with decreased tendon length in young animals and decreased muscle length with no change in tendon length in adult animals. These simulation results are consistent with experimental findings reported in the literature by other investigators. This suggests that average muscle length and minimum tendon strain may represent general principles that govern muscle and tendon length adaptation.

Adaptation, Physiological↗
PubMedDate not supplied

Computer modelling of brain cortex excitation by magnetic field pulses.

In spite of many clinical and experimental applications, the technique of transcranial magnetic stimulation still presents obscure aspects. This especially concerns safety parameters and the exact characterization of the current induced by a single magnetic pulse. The model proposed consists of an equivalent electric network derived by Maxwell's equations and applied to discretized magnetic resonance imaging of a normal subject. This model allows accurate prediction of current distribution, charge per phase and dissipated energy.

Cerebral Cortex↗
PubMed2006

High-resolution computational models of genome binding events.

Direct physical information that describes where transcription factors, nucleosomes, modified histones, RNA polymerase II and other key proteins interact with the genome provides an invaluable mechanistic foundation for understanding complex programs of gene regulation. We present a method, joint binding deconvolution (JBD), which uses additional easily obtainable experimental data about chromatin immunoprecipitation (ChIP) to improve the spatial resolution of the transcription factor binding locations inferred from ChIP followed by DNA microarray hybridization (ChIP-Chip) data. Based on this probabilistic model of binding data, we further pursue improved spatial resolution by using sequence information. We produce positional priors that link ChIP-Chip data to sequence data by guiding motif discovery to inferred protein-DNA binding sites. We present results on the yeast transcription factors Gcn4 and Mig2 to demonstrate JBD's spatial resolution capabilities and show that positional priors allow computational discovery of the Mig2 motif when a standard approach fails.

Base Sequence↗
PubMed2003

Sources of error in noninvasive pulmonary blood flow measurements by partial rebreathing: a computer model study.

BACKGROUND: Partial rebreathing is a noninvasive method for measuring pulmonary blood flow (PBF). This study examines the systematic errors produced by the partial rebreathing technique utilizing a comprehensive mathematical model of the cardiorespiratory system of a healthy, 70-kg adult male. METHODS: The model simulates tidal breathing through a branched respiratory tree and incorporates the effects on carbon dioxide dynamics of lung tissue mass, vascular transport delays, multiple body compartments, and realistic blood-gas dissociation curves. Four studies were performed: (1) errors produced under standard conditions, (2) effects of recirculation, (3) effects of alveolar-proximal airway partial pressure of carbon dioxide (Pco(2)) differences, and (4) effects of rebreathing time. RESULTS: Systematic errors are less than 10% when the simulated PBF is between 3 and 6 l/min. At 2 l/min, PBF is overestimated by approximately 35%. At 14 l/min, PBF is underestimated by approximately 40%. At PBF of greater than 6 l/min, recirculation causes approximately 60% of the systematic error, alveolar-proximal airway differences cause approximately 20%, and alveolar-arterial differences cause approximately 20%. The standard rebreathing time of 50 s is shown to be excessive for PBF of greater than 6 l/min. At PBF of less than 3 l/min, errors are caused by inadequate rebreathing time and alveolar-arterial gradients. CONCLUSIONS: Systematic errors in partial rebreathing cardiac output measurements have multiple causes. Our simulations suggest that errors can be reduced by using a variable rebreathing time, which should be increased at low PBF so that quasi-equilibrium in the alveoli can be achieved and decreased at high PBF to reduce the effects of recirculation.

Adult↗
PubMed2006

Ab initio computational modeling of long loops in G-protein coupled receptors.

A newly developed approach for predicting the structure of segments that connect known elements of secondary structure in proteins has been applied to some of the longer loops in the G-protein coupled receptors (GPCRs) rhodopsin and the dopamine receptor D2R. The algorithm uses Monte Carlo (MC) simulation in a temperature annealing protocol combined with a scaled collective variables (SCV) technique to search conformation space for loop structures that could belong to the native ensemble. Except for rhodopsin, structural information is only available for the transmembrane helices (TMHs), and therefore the usual approach of finding a single conformation of lowest energy has to be abandoned. Instead the MC search aims to find the ensemble located at the absolute minimum free energy, i.e., the native ensemble. It is assumed that structures in the native ensemble can be found by an MC search starting from any conformation in the native funnel. The hypothesis is that native structures are trapped in this part of conformational space because of the high-energy barriers that surround the native funnel. In this work it is shown that the crystal structure of the second extracellular loop (e2) of rhodopsin is a member of this loop's native ensemble. In contrast, the crystal structure of the third intracellular loop is quite different in the different crystal structures that have been reported. Our calculations indicate, that of three crystal structures examined, two show features characteristic of native ensembles while the other one does not. Finally the protocol is used to calculate the structure of the e2 loop in D2R. Here, the crystal structure is not known, but it is shown that several side chains that are involved in interaction with a class of substituted benzamides assume conformations that point into the active site. Thus, they are poised to interact with the incoming ligand.

Amino Acid Sequence↗
PubMed1999

Computational model of the effects of stochastic conditioning on the induction of long-term potentiation and depression.

The long-term potentiation (LTP) or long-term depression (LTD) of synaptic strength are currently considered to be the first microscopic steps leading to learning and memory. The great majority of experiments (both in vitro and in vivo) studying the basic mechanisms of LTP and LTD induction use conditioning protocols in which the presynaptic stimuli are delivered at constant frequencies. This is not, however, what is commonly found in vivo, where a highly irregular spiking activity seems to drive most of the neuronal functions. Thus, some important aspects of the induction characteristics of LTP and LTD expressed in vivo might have been overlooked by the experiments. Using a simple schematic model for a synapse we show here that, in fact, the statistical properties of a presynaptic conditioning signal could change the probability to induce LTP and/or LTD, suggesting a new and faster operating mode for a synapse.

Animals↗
PubMedDate not supplied

[Computer modeling of ESR spectra of the plasma in patients with Down's syndrome].

ESR technique at 77 degrees K was used for studying the blood plasma ESR signals of patients with Down syndrome and of healthy people. It was observed that the first exhibited a tendency towards a decrease of ESR signal with g = 4.3 and increase of the ratio of ceruplasmin (g = 2.05) and transferrin (g = 4.3) ESR signal amplitude. A computer simulation has been carried out by means of special mathematical program of experimental ESR spectra of the blood plasma.

Adolescent↗
PubMed2006

Computational model for early cardiac looping.

Looping is a vital event during early cardiac morphogenesis, as the initially straight heart tube bends and twists into a curved tube, laying out the basic pattern of the future four-chambered heart. Despite intensive study for almost a century, the biophysical mechanisms that drive this process are not well understood. To explore a recently proposed hypothesis for looping, we constructed a finite element model for the embryonic chick heart during the first phase of looping, called c-looping. The model includes the main structures of the early heart (heart tube, omphalomesenteric veins, and dorsal mesocardium), and the analysis features realistic three-dimensional geometry, nonlinear passive and active material properties, and anisotropic growth. As per our earlier hypothesis for c-looping, actin-based morpho-genetic processes (active cell shape change, cytoskeletal contraction, and cell migration) are simulated in specific regions of the model. The model correctly predicts the initial gross morphological shape changes of the heart, as well as distributions of morphogenetic stresses and strains measured in embryonic chick hearts. The model was tested further in studies that perturbed normal cardiac morphogenesis. The model, taken together with the new experimental data, supports our hypothesis for the mechanisms that drive early looping.

Animals↗
PubMed1995

Computer model of the maintenance and selection of genetic heterogeneity in polygamous helminths.

A stochastic simulation model of the transmission and maintenance of genetic heterogeneity in the absence and presence of external selection pressures is presented for polygamous intestinal helminths such as Ascaris. The model assumes that the density distribution of the adult parasites is highly aggregated and that density-dependent effects on fecundity are important. The model gives rise to stable infection rates in the host. Where the parasite population contains genetic heterogeneity, with the exception of stochastic fluctuations which models genetic drift, the ratio of the different alleles remained constant over extended periods of time. This result contrasts with that of an earlier analytical model (Anderson, R.M., May, M.R. & Gutpa S. (1989) Parasitology 99, S59-S79), in which uneven mating probabilities for the different combinations of worm possible in a host was postulated to inevitably lead to fixation of the most abundant allele. New results suggest that in spite of the restricted choice of mating available to a worm in the confines of a host, selection pressure always leads to enrichment of the parasites carrying resistant alleles.

Animals↗
PubMedDate not supplied

Application of computer modelling and lead field theory in developing multiple aimed impedance cardiography measurements.

Conventional impedance cardiography (ICG) methods estimate parameters related to the function of the heart from a single waveform that reflects an integrated combination of complex sources. We have previously developed methods and tools for calculating measurement sensitivity distributions of ICG electrode configurations. In this study, the methods were applied to investigate the prospects of recording multiple aimed ICG waveforms utilizing the 12-lead electrocardiography (ECG) electrode locations. Three anatomically realistic volume conductor models were used: one based on Visible Human Man cryosection data and two on magnetic resonance (MR) images representing end diastolic and end systolic phases of the cardiac cycle. Based on the sensitivity distributions obtained, 236 electrode configurations were selected for preliminary clinical examination on 12 healthy volunteers and 9 valvular patients. The model study suggested that a variety of configurations had clearly enhanced sensitivity to the cardiovascular structures as compared to conventional ICGs. Simulation data and clinical experiments showed logical correspondence supporting the theoretically predicted differences between the configurations. Recorded 12-lead ICG signals had characteristic waveforms and landmarks not coinciding with those of conventional ICG. Furthermore, configurations showing resemblance to invasive data and morphological variations in disease are of interest. The results indicate the applicability of the modelling approach in developing ICG measurement configurations. However, the level of clinical relevance and potential of the 12-lead method remains to be explored in studies employing dynamic modelling and acquisition of invasive reference data.

Adult↗
PubMed1992

Computer modelling of the transmembrane channel formed by a CNBr peptide of diphtheria toxin B fragment.

Diphtheria toxin (DT) forms transmembrane, voltage-dependent channels in a planar lipid bilayer. Channels with similar characteristics were obtained with CB1, a cyanogen bromide peptide of diphtheria toxin B fragment (DTB) (res 340-459). Tryptophan 398 is in interaction with the hydrophobic core of the lipid bilayer. Using the Eisenberg method in association with the Shiffer-Edmunson wheel representation, we have identified two amphipathic alpha-helices within CB1 (res 346-364 and 389-406) that could be involved in the interaction with lipids. Bearing this information in mind, we are providing a model for the structure of the CB1 channel.

Amino Acid Sequence↗
PubMed1985

Effect of left-to-right, mixed left-to-right, and right-to-left shunts on inhalational anesthetic induction in children: a computer model.

We describe a seven-compartment physiologic model of inhalational anesthetic induction with circulatory shunts that was used to simulate inhalational anesthetic induction in children with congenital heart disease. Our conclusions based on this model are that left-to-right (L-R) shunting has little effect on speed of induction; right-to-left (R-L) shunting significantly slows induction of N2O and halothane anesthesia; and adding an L-R shunt to a preexisting R-L shunt will attenuate the slowing of induction caused by the R-L shunt.

Anesthesia, Inhalation↗