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At least 1,657 records · Page 92Linked to original sources

PubMed1988

Transmembrane flux and receptor desensitization measured with membrane vesicles. Homogeneity of vesicles investigated by computer simulation.

The use of membrane vesicles to make quantitative studies of transmembrane transport and exchange processes involves an assumption of homogeneity of the membrane vesicles. In studies of 86Rb+ exchange mediated by acetylcholine receptor from the electric organ of Electrophorus electricus and of 36Cl- exchange mediated by GABA receptor from rat brain, measurements of ion exchange and receptor desensitization precisely followed first order kinetics in support of this assumption. In other measurements a biphasic decay of receptor activity was seen. To elucidate the molecular properties of receptors from such measurements it is important to appreciate what the requirements of vesicle monodispersity are for meaningful results and what the effect of vesicle heterogeneity would be. The experiments were simulated with single vesicle populations with variable defined size distributions as well as with mixtures of different populations of vesicles. The properties of the receptors and their density in the membrane could be varied. Different receptors could be present on the same or different membrane vesicles. The simulated measurements were not very sensitive to size dispersity. A very broad size distribution of a single vesicle population was necessary to give rise to detectable deviations from first order kinetics or errors in the determined kinetic constants. Errors could become significant with mixtures of different vesicle populations, where the dispersity in initial ion exchange rate constant, proportional to the receptor concentration per internal volume, became large. In this case the apparent rate of receptor desensitization would diverge in opposite directions from the input value when measured by two different methods, suggesting an experimental test for such kinetic heterogeneity. A biphasic decrease of receptor activity could not be attributed to vesicle heterogeneity and must be due to desensitization processes with different rates. Significant errors would not arise from the size dispersity apparent in subpopulations of vesicles seen by imaging techniques in membrane preparations.

Animals↗

PubMed2004

Computer simulation of the KvAP voltage-gated potassium channel: steered molecular dynamics of the voltage sensor.

The recent crystal structures of the voltage-gated potassium channel KvAP and its isolated voltage-sensing 'paddle' (composed of segments S1-S4) challenge existing models of voltage gating and raise a number of questions about the structure of the physiologically relevant state. We investigate a possible gating mechanism based on the crystal structures in a 10 ns steered molecular dynamics simulation of KvAP in a membrane-mimetic octane layer. The structure of the full KvAP protein has been modified by restraining the S2-S4 domain to the conformation of the isolated high-resolution paddle structure. After an initial relaxation, the paddle tips are pulled through the membrane from the intracellular to the extracellular side, corresponding to a putative change from closed to open. We describe the effect of this large-scale motion on the central pore domain, which remains largely unchanged, on the protein hydrogen-bonding network and on solvent. We analyze the motion of the S3b-S4 portion of the protein and propose a possible coupling mechanism between the paddle motion and the opening of the channel. Interactions between the arginine residues in S4, solvent and chloride ions are likely to play a role in the gating charge.

Amino Acid Sequence↗

PubMed2002

Computer simulation studies on significance of lipid polar head orientation.

Models of lipid bilayer were extended and dipole structure of polar head in lipid molecules was included. As a result a wavy structure, resembling experimentally observed 'ripple phase', was obtained. The discussion on significance of interactions between dipoles that constitute polar part of the model membrane is presented. Assumptions of the model are closer to the real conditions and reflect the real phenomena much better. Dependence of the model system behaviour on dielectric permeability, ionic strength, and temperature was studied. An influence of reduced number of freedom degrees in the dipole system on the membrane properties was also considered. It was proved that if dielectric permeability of membrane polar part is significantly smaller than water dielectric permeability then the membrane model does not have to take into account changeability of dipole tilt towards membrane surface. This assumption becomes more significant for dielectric permeability epsilon approaching epsilon = 80. Packing degree of hydrocarbon chains in hydrophobic part of the membrane is also responsible for the angle value between dipoles and the membrane surface. The model results are compared to experimental results obtained by means of fluorescence probe fluorescein-PE.

Cell Membrane↗

PubMed1995

Electrostatics of hemoglobins from measurements of the electric dichroism and computer simulations.

Hemoglobins from normal human cells, from sickle cells, and from horse were investigated by electrooptical methods in their oxy and deoxy forms. The reduced linear dichroism measured as a function of the electric field strength demonstrates the existence of permanent dipole moments in the range of 250-400 Debye units. The reduced limiting dichroism is relatively small (< or = 0.1); it is negative for hemoglobin from sickle cells and positive for the hemoglobins from normal human cells and from horse. The dichroism decay time constants are in the range from about 55 to 90 ns. Calculations of the electrooptical data from available crystal structures are given according to models of various complexity, including Monte Carlo simulations of proton fluctuations with energies evaluated by a finite difference Poisson-Boltzmann procedure. The experimental dipole moments are shown to be consistent with the results of the calculations. In the case of human deoxyhemoglobin, the root mean square dipole is higher than the mean dipole by a factor of about 4.5, indicating a particularly large relative contribution due to proton fluctuations. The ratio of the root mean square dipole to the mean dipole is much smaller (approximately 1.1 to approximately 1.5) for the other hemoglobin molecules. The calculations demonstrate that the dichroism decay time constants are not simply determined by the size/shape of the proteins, but are strongly influenced by the orientation of the dipole vector with respect to the axis of maximal absorbance. The comparison of experimental and calculated electrooptical data provides a useful test for the accuracy of electrostatic calculations and/or for the equivalence of structures in crystals and in solutions.

Animals↗

PubMed1995

Computer simulations of signal transduction mechanism in alpha 1B-adrenergic and m3-muscarinic receptors.

Molecular dynamics simulations of the hamster alpha 1B-adrenergic and the rat m3-muscarinic seven-helix bundle receptor models have been carried out. The free, agonist-bound and antagonist-bound forms have been considered. Moreover, three mutant forms of the m3-muscarinic receptor (N507-->A, N507-->D and N507-->S) have also been simulated; among these, the N507-->S mutant shows a constitutive activity. A comparative structural/dynamics analysis has been performed to elucidate (i) the perturbations induced by the functionally different ligands upon binding to their target receptor, (ii) the features of the three single-point mutants with respect to the receptor wild type and (iii) the properties shared by the agonist-bound forms of the alpha 1B-adrenergic receptor and the m3-muscarinic receptor and by the constitutively active mutant N507-->S. The consistency obtained between the structural rearrangement of the transmembrane seven-helix bundle models considered, and the experimental pharmacological efficacies of the ligands and of the mutants, constitute an important validation of the 3-D models obtained and allow the inference of the mechanism of ligand- or mutation-induced receptor activation at the molecular level.

Adrenergic alpha-Agonists↗

PubMed1992

Time trends of smoking cessation: a micro-population computer simulation model.

The Micro-population model of Risk-group Dynamics (MRD) approaches smoking behavior at the level of the individual and integrates physiological and social factors to describe the evolution of behavior change in the population. MRD is innovative in several ways: (1) the model describes mathematically the interactions among these behavioral factors; (2) the model accounts for both the variability of these factors among different persons and the universality of basic rules describing these factors in all individuals; and (3) the model can be applied to various types of populations and a wide range of intervention strategies. MRD combines the physiological, psychological and social determinants into a hazard function for relapse to smoking. This hazard function is then organized into a three term expression incorporating: a baseline hazard characteristic to each individual, a decreasing term for the diminishing aspect of the initial hazard and an effect of external interventions. The model gives promising results when applied to the Multiple Risk Factors Intervention Trial (MRFIT) data using the assumptions of a Weibull distribution for the baseline hazard, a negative exponential for the decrease in the initial hazard and a constant intensity for the external intervention.

Algorithms↗

PubMed1995

Effects of barriers on propagation of action potentials in two-dimensional cardiac tissue. A computer simulation study.

A two-dimensional anisotropic model of cardiac ventricular muscle was used to study the effects of discontinuities (barriers), such as dead cells or high-resistance areas, on longitudinal plane-wave propagation. Problems in propagation appear when long barriers become thicker and their spacing closer. Short barriers with large widths and small spacing also cause propagation disturbances and significant delays in their vicinity. If the plane wave front propagates through the barriers, the velocity returns to near normal within one-length constant away from the end of the barrier region. For a funnel-like structure, an opening of 13 cells should exist for longitudinal plane wave propagation. For smaller openings, the ratio of openings required for propagation to occur when traveling from a narrow to a wider area of tissue is proportional to the anisotropy ratio, which can cause unidirectional block. Tortuosity, created by spatial distribution of dead cell barriers, can facilitate propagation by changing the effective impedance the wave front sees, and can create multiple local delays, which may result in discrepancies when measuring propagation velocity.

Action Potentials↗

PubMedDate not supplied

Localized current field hyperthermia in carcinoma of the cervix: 3-D computer simulation of SAR distribution.

Software was developed for the 3D simulation of SAR distribution for a 500 kHz localized current field hyperthermia system to be used in patients with carcinoma of the cervix. This hyperthermia system was specifically designed for use with a modified Fletcher-Suit intracavitary applicator. It consists of software modules for data input, tetrahedral grid generation and a numerical calculation of SAR distribution using an adaptive, multilevel finite element code. The AVS (Advanced Visual System, Inc.) system was used for the visual presentation of the results. A quasi-static approach was employed for the determination of SAR distribution. Results of the performed numerical tests were presented and they showed an important, clinically relevant ability to obtain a selective power deposition. This selective power deposition depended on the applicator geometry, i.e. the distance between the components of a Fletcher-Suit applicator and their relative position and the use of different modes of excitation.

Brachytherapy↗

PubMed1992

Computer simulation of the blood-brain barrier: a model including two membranes, blood flow, facilitated and non-facilitated diffusion.

A mathematical model of blood-brain barrier (BBB) transport was developed to assist in experimental design and data analysis. The model includes the luminal and antiluminal endothelial cell membranes, each with separate transport systems. Substrate movement between 3 compartments can be calculated: the capillary lumen, the endothelial cell cytoplasm, and the brain parenchyma. Blood flow, substrate concentration and competition in each compartment, concentration gradients along the capillary, and non-steady-state conditions are considered. The utility of the model is demonstrated by predicting: (1) complex concentration profiles along the length of the capillary lumen under different circumstances, (2) the permeability-surface area products along the capillary lumen, (3) the time course of events during brain-uptake index (BUI) experiments, (4) the accuracy of the BUI in measuring glucose transport over a range of endogenous glucose concentrations, (5) the influence of 2 membranes in series with different kinetic constants, and (6) a comparison of kinetic constants expected from high-flow infusion and BUI experiments.

Blood-Brain Barrier↗

PubMed2005

Folding pathways for initiator and effector procaspases from computer simulations.

The folding pathways of procaspases 3, 7, and 8 have been studied using a Go-like Hamiltonian and molecular dynamics simulations coupled with a parallel tempering scheme. The folding pathways and the overall structures of procaspases 3 and 7 are similar, and are characterized by monomeric as well as dimeric folding intermediates in agreement with the available structural and thermochemical data. The folding pathway of procaspase 8, on the other hand, is characterized by a larger population of monomers and partially folded dimer intermediates, and only a relatively small population of folded dimer species. The most stable structure predicted for procaspase 8 is a dimer, in which the position of the linker is remarkably different from the one observed in procaspases 3 and 7, leading to the fact that all the contacts that stabilize the active site are essentially formed. This novel and unexpected structure provides a rationale for the observed activity of the procaspase 8 dimer, and thus could be highly relevant for the initiation of FAS-mediated apoptosis.

Caspase 3↗

PubMed1997

Rectal paracetamol dosing regimens: determination by computer simulation.

A pharmacokinetic dynamic simulation model was used to predict rectal paracetamol dosing schedules which would maintain steady state plasma concentrations of 10-20 mg.l-1. These plasma concentrations of paracetamol are known to reduce fever. The conventional dosing schedule of 15 mg.kg-1 four hourly was unsatisfactory. Steady state concentrations of 8-12 mg.l-1 were only reached after 16 h. A loading dose of 50 mg.kg-1 followed by 30 mg.kg-1 six hourly achieved plasma concentrations of 9-18 mg.l-1. Paracetamol is a mild analgesic. A higher plasma paracetamol concentration of 25 mg.l-1 is known to give satisfactory analgesia to 60% of children after tonsillectomy. This concentration can be reached after a loading dose of 70 mg.kg-1 and a maintenance dose of 50 mg.kg-1 8 hourly. Doses above 150 mg.kg-1.day-1 have been reported to cause reversible liver toxicity after 2-8 days and should not be sustained.

Acetaminophen↗

PubMed1993

Cytoskeleton and motility: an immunohistological and computer simulation analysis of melanocytic skin tumors.

Tumor cell motility and tumor cell proliferation are supposed to be essential for tumor invasion. The cytoskeleton, which consists of different components, is considered to be important for maintaining cell shape and facilitating cell movement. Numerous data are available about tumor cell motility in vitro, but the behavior of tumor cells in vivo is as yet poorly understood. In the present study, estimates of tumor cell motility and proliferation were statistically derived from morphological tumor patterns in human melanocytic skin tumors, and their relationship to expression of certain cytoskeletal components was evaluated. Overexpression of vimentin within tumor cells correlated with low actual tumor cell motility and proliferation, indicating a structurally stabilizing function of these filaments. An overexpression of actin was found within tumor cells of high motility and proliferation, suggesting the contribution of cytocontractile elements to active tumor cell locomotion in situ. Concerning the cytoskeleton of the stromal cells, expression of actin, myosin and tubulin correlated with a high number of motile tumor cells and high mitotic counts. Thus increased tumor cell motility seems to be associated with cytoskeletal changes not only of the tumor cells themselves but also of the surrounding stromal cells.

Cell Division↗

PubMed1992

Computer simulation of occupant neck response to airbag deployment in frontal impacts.

A mathematical simulation was performed to study the potential of head and neck injury to an unbelted driver restrained by an airbag. The baseline study represented a 50th percentile male dummy driving in a compact car with the steering wheel perpendicular to the floor. The vehicle was moving at 48 km/hour at the time of impact. Model predictions were compared with sled test results. The data agreed reasonably well. A parametric study was performed to study the effect of changing the steering wheel angle and the size of the airbag. It was found that when the standard 20 degrees angle steering wheel was used, neck joint torques were decreased by 22 percent while the resultant head acceleration increased 41 percent from the base line study. When the vertical dimension of the airbag was reduced by 10 percent, neck joint torques were increased by 14 percent, while head acceleration showed a slight decrease of 9 percent.

Acceleration↗

PubMed2001

Effect of clean indoor air laws on smokers: the clean air module of the SimSmoke computer simulation model.

OBJECTIVES: To develop a simulation model to examine the effects of clean indoor air laws on prevalence rates and smoking attributable deaths. METHODS: Based on empirical and theoretical research, the effects of clean air laws are modelled by type of law. The model considers clean air laws at the state levels between 1993 and 2000, and projects the number of smokers and smoking attributable deaths in the USA under different scenarios from 2000 onward. RESULTS: The model predicts that comprehensive clean air laws have the potential to reduce substantially the number of smokers and smoking attributable deaths, and these effects are predicted to grow over time. The predicted impact of new worksite laws are reduced when previously implemented private and public worksite restrictions are taken into account. CONCLUSIONS: Clean indoor air laws have the ability to reduce smoking rates substantially and save lives, but their impact is likely to depend on their comprehensiveness and prior private worksite restrictions in place.

Adult↗

PubMed1996

Relationship between infrared spectra and isomorphous substitution in smectites: a computer simulation study.

Smectites, members of the 2:1 layer silicate family, share the common feature that two tetrahedral sheets sandwich a sheet of octahedrally coordinated metal ion. The diversity of the members of the 2:1 layer silicates occurs because of their capacity for isomorphous substitution of various cations in the octahedral or tetrahedral sheets. Substitution of a divalent metal ion (such as Mg2+) for the trivalent Al3+ or a trivalent metal ion (such as Al3+) for the tetravalent silicon results in a net negative charge, which then undergoes interaction with positive ions (the exchangeable cations) to form an interlayer hydrated phase. Local density functional (LDF) calculations were employed to model isomorphous substitution of Al3+ by Na+, K+, Mg2+, Fe2+, and Fe3+ in the octahedral layer of a dioctahedral smectite clay such as montmorillonite. The energies of the isomorphous substitution were then compared with the experimental observation. The ordering for successful substitution is Al3+ > Fe3+ > Mg2+ > Fe2+ > Na+ < K+. This ordering is consistent with experimental observation. The vibrational frequencies for the isomorphous substituted systems were calculated by LDF calculation and were compared with the experimental IR results. The results match very well with experiment. This understanding will help in successful prediction of the catalytic activity of smectite clays.

Aluminum Silicates↗

PubMed2002

Circulatory effects of internal jugular vein compression: a computer simulation study.

The effects of compression of the internal jugular veins and the inferior vena cava are simulated using an equivalent electronic circuit, which included simulation of cardiocirculatory phenomena and special features of the cerebral circulation. Compression of the inferior vena cava resulted in a profound decrease in cardiac output (from 4.5 to 1.51min(-1)) and arterial pressure (from 140/85 to 50/35 mmHg). Compression of the internal jugular veins resulted in a negligible decrease in cardiac output and arterial pressure, with a cerebral blood flow that was slightly decreased. Cerebral capillary and internal jugular pressures were considerably increased, leading to obstruction of cerebral veins and increased pressure (from 9 to 22 mmHg) and volume (from 120 to 145 ml) of the cerebrospinal fluid (CSF). Increased cerebral capsule compliance resulted in decreased CSF pressure (from 9 to 8.5 mmHg), but CSF volume increased (from 120 to 190 ml). A small increase in brain volume (from 1,000 ml to 1,060 ml, 6% volume increase) was compensated for by an equal decrease in the volume of CSF. When brain volume was above 1,080 ml, the absorption of CSF was reduced, and its pressure increased.

Cerebrovascular Circulation↗

PubMed2003

Quantitative assessment of cerebral autoregulation from transcranial Doppler pulsatility: a computer simulation study.

Transcranial Doppler (TCD) ultrasonography is largely used today to achieve non-invasive assessment of cerebral autoregulation and cerebrovascular reactivity in neurosurgical patients. Recent experimental and clinical studies suggest that not only the pattern of mean velocity, but also velocity pulse amplitude alterations during changes in cerebral perfusion pressure (CPP) contain information on autoregulation status. The aim of this work is to investigate the relationship between cerebral autoregulation and TCD pulsatility by means of a comprehensive mathematical model of intracranial dynamics and cerebrovascular regulation. Simulation results, performed using different values of the most important clinical parameters of the model (autoregulation strength, cerebrospinal fluid (CSF) outflow resistance and intracranial elastance coefficient) show that velocity pulse amplitude increases with a reduction in CPP in patients with intact autoregulation, whereas changes in velocity pulsatility are modest in patients with weak autoregulation. Finally, velocity pulse amplitude decreases during a CPP reduction in patients with impaired autoregulation. Moreover, the relationship between the velocity pulse amplitude changes and autoregulation strength is almost linear in a wide range of CPP values, and is scarcely affected by changes in CSF circulation and intracranial elasticity. Starting from these results, we suggest a new quantitative index to assess autoregulation strength, i.e. G(aut)% = (s-b)/a, where G(aut)% is autoregulation strength (100% means intact autoregulation, 0% means impaired autoregulation), a approximately -0.03; b approximately 1.5 and s is the slope of the relationship ' percentage changes of velocity pulse amplitude to arterial pressure pulse amplitude vs. CPP changes'.

Adaptation, Physiological↗

PubMed2006

Water properties inside nanoscopic hydrophobic pocket studied by computer simulations.

The structure and dynamics of water in the vicinity of the hemispherical hydrophobic pocket of 8 A radius were examined via molecular dynamics simulations in NVT ensemble. Density, hydrogen bonding properties, and residence times of water molecules were projected on two-dimensional planes providing a spatial description of water behavior. We found that the average water density is significantly depleted relative to bulk value. A detailed analysis of pocket occupancy revealed fluctuations between states of completely empty pocket and a pocket filled with a bulklike fluid, which seem to result from collective behavior of water molecules. Free energy differences accompanying these fluctuations are rather small, suggesting that the given pocket radius is close to the critical one for transition between gas and liquid phases in the considered system. We show that the situation is different in the case of a simple Lennard-Jones fluid. These results indicate that changing the surface curvature from flat to concave may lead to qualitative difference in water behavior in its vicinity. We think that our studies may also put some light on binding site desolvation process which is necessary to understand to make correct predictions of binding energies.

Computer Simulation↗