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PubMed2001

Do computer simulations of laboratory practicals meet learning needs?

There is a variety of pressures on pharmacology teachers to replace real laboratory practicals with simulations but do they help students achieve the required learning objectives? In this article, the marks obtained by students in a variety of assessments using 'wet' or simulated practicals are analysed. Poorer performance in practical write-ups by students doing 'wet' practicals compared with those doing simulations can be explained by the quality of the data that the students obtain. In examinations, students perform equally well except with questions that are related to the experimental details of 'wet' practicals; students taught using such 'wet' practicals perform better in response to these questions.

Audiovisual Aids↗

PubMed2004

Computer simulation of an adaptive damage-bone remodeling law applied to three unit-bone bars structure.

It is well admitted that the mechanical loading plays an important role in the growth and maintenance of our skeleton, and that microdamage (i.e.: microcracks) occurs naturally when the bone is overloaded during day-to-day activities. It is also argued, from experimental and theoretical viewpoint, that the cells which built and rebuilt the skeleton are sensitive for both strain and microdamage. The recent damage-bone remodeling theory is employed here to study the mechanical response of the three unit-bone bars that simulate bone trabeculae in the form of truss. It is shown that under constant load, such a structure exhibit inhomogeneous strain and it's response to external applied load depends strongly upon the manner in which the microdamage is distributed.

Bone Remodeling↗

PubMed1998

Computer simulation study of synthetic 4-helix bundle that binds halothane.

1. The synthetic peptide H10A24 self-assembles in aqueous solution into a 4-helix bundle, which exhibits saturable binding of halothane. 2. Molecular dynamics simulation techniques have been used to study the vacuum structure of this bundle. 3. The simulation, initiated as four ideal parallel alpha-helices, resulted in a compact bundle, whose secondary structure remains predominantly alpha-helical. 4. The hydrophobic core has no apparent pocket large enough to accomodate halothane.

Algorithms↗

PubMed1999

Computer simulation of trabecular remodeling using a simplified structural model.

A simplified three-dimensional simulation of trabecular bone remodeling has been developed. The model utilizes 441 planar structural units to represent approximately 50 mm3 of initial bone volume with 199 basic multicellular units (BMUs). The simulation takes into account trabecular perforation in the structural model. The cases of male bone remodeling with no menopause and female bone remodeling with menopause are examined from the period of simulated age 25-80 years. Menopause is arbitrarily started at age 45 and extends for 7.5 years. Zero-, first-, and second-order BMU activation responses are employed to examine how the bone would be affected by the method of increase of BMU activation during menopause. At age 80, the female bone remodeling simulation produced a bone volume loss of approximately 49% for all three activation responses. This compared to a 38% bone volume loss for the case of no menopause. For the menopause simulations, an average of about 40% of the total bone loss was due to perforation.

Adult↗

PubMed1986

Computer simulations of cyclic enkephalin analogues.

Molecular dynamics simulations and energy minimization studies of cyclic enkephalin analogues incorporating retro-inverso modifications have been carried out. The dynamic trajectories are analyzed in terms of the relative mobility of the 14-membered rings, conformational transitions among equilibrium states, and hydrogen-bonding patterns. The cyclization of the molecules reduces the motion of the ring structures substantially. Time-correlated conformational transitions resulting in the reorientation of peptide units are observed. Hydrogen bonds form principally C7 structures. Because of the incorporation of retro-inverso residues, C6 and C8 structures are also formed. Starting conformations for energy minimizations were obtained from the molecular dynamics simulations and from a systematic search of the conformational space available to the molecules. Several minimum energy backbone and side-chain conformations were found for each analogue. The effect of retro-inverso residues on hydrogen-bonding patterns and backbone conformations is discussed.

Amino Acid Sequence↗

PubMed2002

Computer simulations of trypanosomal nucleoside hydrolase: determination of the protonation state of the bound transition-state analogue.

Inosine-uridine nucleoside hydrolase (IU-NH) catalyzes the hydrolysis of nucleosides into base and ribose moieties via a ribooxocarbenium ion transition state, which has been characterized using kinetic isotope effects. Protozoan parasites lack de novo purine and pyrimidine biosynthesis and depend on the purine salvage from the host. Vern Schramm and co-workers characterized p-aminophenyliminoribitol (pAPIR) to be a potent inhibitor of IU-NH from Crithidia fasciculata with K(d) of 30 nM. The cyclic amine function of the iminoribitol ring can be either protonated (pAPIRH(+)) or unprotonated (pAPIR). pAPIRH(+) resembles the charge and geometry of the ribooxocarbenium ion transition state and can be looked upon as a transition-state analogue inhibitor; however, it is known that the pAPIR species is initially bound to the enzyme. We have characterized the pAPIRH(+) species as resident of the active site using ab initio calculations and molecular dynamics simulations. This is a novel use of molecular dynamics to investigate the protonation state of the bound ligand to the active site. Nanosecond molecular dynamics simulations reveal a short hydrogen-bonding network between pAPIRH(+)-O2'-Asp14-His241 triad, which is not seen in the crystal structure. Other features discussed are: hydrogen bonding between pAPIRH(+) and Asn168, unusual geometry of the iminoribitol ring, and hydrophobic interactions.

Animals↗

PubMed2000

Computer simulations of the properties of the alpha2, alpha2C, and alpha2D de novo designed helical proteins.

Reduced lattice models of the three de novo designed helical proteins alpha2, alpha2C, and alpha2D were studied. Low temperature stable folds were obtained for all three proteins. In all cases, the lowest energy folds were four-helix bundles. The folding pathway is qualitatively the same for all proteins studied. The energies of various topologies are similar, especially for the alpha2 polypeptide. The simulated crossover from molten globule to native-like behavior is very similar to that seen in experimental studies. Simulations on a reduced protein model reproduce most of the experimental properties of the alpha2, alpha2C, and alpha2D proteins. Stable four-helix bundle structures were obtained, with increasing native-like behavior on-going from alpha2 to alpha2D that mimics experiment.

Amino Acid Sequence↗

PubMed2004

[1D-and 3D- computer simulation for experimental planning and interpretation of pharmacokinetic studies in the inner ear after local drug delivery].

The local delivery of drugs to the cochlea is a promising alternative to systemic treatment of inner ear disorders. Whilst new drugs are being developed for this purpose, it is important to determine the time course and total dose required for the various target regions within the inner ear. Due to the small fluid spaces of the inner ear and the resulting experimental and analytical difficulties, many animal studies have only obtained one sample per animal. This results in limited information about drug time courses at specific locations in the inner ear. We show here how computer models considering general pharmacokinetic principles and inner ear geometry are used for application of the 3R-principle in animal research while avoiding experimental sampling artefacts. This can be achieved by: (1) careful planning and interpretation of experiments to study pharmacokinetics in the inner ear, (2) optimising volume sampling techniques, (3) facilitating the use of advantageous, continuous sampling methods like microdialysis and (4) developing a 3D-model that will permit consideration of the complex geometry of the inner ear when transferring results from one species to another.

Animal Testing Alternatives↗

PubMed1989

Computer simulation of the conformational behavior of cholecystokinin fragments: conformational families of sulfated CCK8.

Display methods, such as principal component analysis, and clustering methods were applied to a sample of cholecystokinin, (sulfated CCK8) conformations obtained from a Monte Carlo simulation. It is shown that six families of conformations can entirely describe the sample. Each family represents a typical conformer. These theoretical models are in agreement with recent experimental results which stress the predominance of folded conformers in aqueous medium.

Computer Simulation↗

PubMed1989

Computer simulation of blood flow in the human arm.

This paper considers a finite element method to characterize blood flow in the human arm arteries. A set of different pressure waveforms, which represent normal and diseased heart pulses, is used for the proximal boundary conditions, and a modified Windkessel model is used for the distal arterial boundary conditions. A comparison of the distal pressure and flow waveforms, for each different proximal pressure, is made to determine whether such waveforms are significantly altered from normal waveforms. The results show that the distal pressure and/or flow waveforms in certain cases are sufficiently different to be possibly used as a diagnostic indicator of an abnormal heart condition. Also considered is the effect of stenosis, change of compliance, and dilatation of the distal beds on the pressure and flow waveforms. A stenosis which has an area reduction of greater than approximately 75% is found to significantly alter both the distal pressure and flow waveforms. Changes in arterial compliance, however, do not strongly influence the waveforms. Dilatation of distal vascular beds is simulated by reducing the lumped resistance of these beds, and this reduction increases mean flow and decreases mean distal pressure, but has little effect on the basic shape of either the pressure or flow waveform.

Aortic Valve Stenosis↗

PubMed1999

Impact of transvenous lead position on active-can ICD defibrillation: a computer simulation study.

Optimizing lead placement in transvenous defibrillation remains central to the clinical aspects of the defibrillation procedure. Studies involving superior vena cava (SVC) return electrodes have found that left ventricular (LV) leads or septal positioning of the right ventricular (RV) lead minimizes the voltage defibrillation threshold (VDFT) in endocardial lead-->SVC defibrillation systems. However, similar studies have not been conducted for active-can configurations. The goal of this study was to determine the optimal lead position to minimize the VDFT for systems incorporating an active can. This study used a high resolution finite element model of a human torso that includes the fiber architecture of the ventricular myocardium to find the role of lead positioning in a transvenous LEAD-->can defibrillation electrode system. It was found that, among single lead systems, posterior positioning of leads in the right ventricle lowers VDFTs appreciably. Furthermore, a septal location of leads resulted in lower VDFTs than free-wall positioning. Increasing the number of leads, and thus the effective lead surface area in the right ventricle also resulted in lower VDFTs. However, the lead configuration that resulted in the lowest VDFTs is a combination of mid-cavity right ventricle lead and a mid-cavity left ventricle lead. The addition of a left ventricular lead resulted in a reduction in the size of the low gradient regions and a change of its location from the left ventricular free wall to the septal wall.

Catheterization, Central Venous↗

PubMed2004

Current- and voltage-clamp recordings and computer simulations of Kenyon cells in the honeybee.

The mushroom body of the insect brain is an important locus for olfactory information processing and associative learning. The present study investigated the biophysical properties of Kenyon cells, which form the mushroom body. Current- and voltage-clamp analyses were performed on cultured Kenyon cells from honeybees. Current-clamp analyses indicated that Kenyon cells did not spike spontaneously in vitro. However, spikes could be elicited by current injection in approximately 85% of the cells. Of the cells that produced spikes during a 1-s depolarizing current pulse, approximately 60% exhibited repetitive spiking, whereas the remaining approximately 40% fired a single spike. Cells that spiked repetitively showed little frequency adaptation. However, spikes consistently became broader and smaller during repetitive activity. Voltage-clamp analyses characterized a fast transient Na+ current (INa), a delayed rectifier K+ current (IK,V), and a fast transient K+ current (IK,A). Using the neurosimulator SNNAP, a Hodgkin-Huxley-type model was developed and used to investigate the roles of the different currents during spiking. The model led to the prediction of a slow transient outward current (IK,ST) that was subsequently identified by reevaluating the voltage-clamp data. Simulations indicated that the primary currents that underlie spiking are INa and IK,V, whereas IK,A and IK,ST primarily determined the responsiveness of the model to stimuli such as constant or oscillatory injections of current.

Algorithms↗

PubMed1989

Computer simulation study of the binding of an antiviral agent to a sensitive and a resistant human rhinovirus.

Molecular dynamics simulations have been used to study the free energy of binding of an antiviral agent to the human rhinovirus HRV-14 and to a mutant in which a valine residue in the antiviral binding pocket is replaced by leucine. The simulations predict that the antiviral should bind to the two viruses with similar affinity, in apparent disagreement with experimental results. Possible origins of this discrepancy are outlined. Of particular importance is the apparent need for methods to systematically sample all significant conformations of the leucine side chain.

Antiviral Agents↗

PubMedDate not supplied

[Research on the factors determining cellular clonogenic capacity following fractional irradiation by the method of computer simulation modelling].

Methods of multifactor dispersion analysis of variance of the results of imitation model tests were used to estimate the factors that influence the clonogenic capacity of cells after fractionated irradiation. The "interval between fractions" and "the share of cells at G0" were the major factors at different ratios between radioresistance and efficiency of repair of resting and proliferating cells.

Animals↗

PubMed1980

A computer simulation model of hospital mergers.

The results of a study and a computer model designed to predict the costs of a potential merger of three hospitals rely on a statistically based cost-prediction model. This model was adapted to reflect several different merger options, and the future costs of the three unmerged hospitals were simulated using a stochastic simulation model.

Computers↗

PubMed1986

Computer simulations of organic reactions in solution.

Quantum and statistical mechanics have been used to determine energy profiles for the SN2 reaction of Cl- + CH3Cl in the gas phase, in aqueous solution, and in liquid DMF. The energy profile in the gas phase has the characteristic double-well form featuring unsymmetrical ion-dipole complexes as minima and a symmetrical transition state. Hydration causes the reaction surface to become almost unimodal and increases the barrier significantly. The reaction profile in DMF is intermediate between those for the gas phase and aqueous solution. The ion-dipole complexes are still free energy minima in DMF. Thus, the reaction in DMF involves initial formation of the complex before the rate-determining step. The computed results are shown to be in good accord with experimental free energies of activation. The same technique has been applied to the addition reaction of OH- + H2C = O in the gas phase and aqueous solution. Ab initio 6-31 + G* calculations indicate that the reaction proceeds essentially without activation in the gas phase. Hydration introduces a substantial energy barrier. The transition state in water has been located at a C-O separation of roughly 2 A. A key finding for both reactions is that the activation barriers induced by hydration result primarily from change in strengths rather than in numbers of solute-water hydrogen bonds along the reaction paths.

Chemical Phenomena↗

PubMed2003

Cardiac near-field morphology during conduction around a microscopic obstacle--a computer simulation study.

In a recent paper, we described the behavior of the cardiac electric near-field, E, parallel to the tissue surface during continuous conduction. We found that the tip of E describes a vector-loop during depolarization with the peak field, E, pointing opposite to the direction of propagation, phiI(m). Experimentally recorded loop morphologies of E, however, frequently showed significant deviations from the theoretically predicted behavior. We hypothesized that this variety of morphologies might be caused by conduction obstacles at a microscopic size scale. This study examines the influence of obstacles on the morphology of vector loops of E and whether the peak of distorted loops remains a reliable indicator for the direction of propagation. We used a computer model of a sheet of cardiac tissue with a central conduction obstacle immersed in an unbounded volume conductor. We studied the loop morphologies of E and the differences between the intracellularly determined direction of propagation, phiI(m), and the direction of E, phiE. Distortions of the vector loop were morphologically similar to those observed experimentally. Differences between phiI(m) and phiE were less than 18 degrees at all observation sites. The obstacle led to deformations of the loop morphology, particularly during the initial and terminal phases, and to a lesser degree near the instant of E. We concluded that E is a reliable indicator of phiI(m).

Animals↗

PubMed2001

Computer simulations aimed at structure prediction of supersecondary motifs in proteins.

It is well established that protein structures are more conserved than protein sequences. One-third of all known protein structures can be classified into ten protein folds, which themselves are composed mainly of alpha-helical hairpin, beta hairpin, and betaalphabeta supersecondary structural elements. In this study, we explore the ability of a recent Monte Carlo-based procedure to generate the 3D structures of eight polypeptides that correspond to units of supersecondary structure and three-stranded antiparallel beta sheet. Starting from extended or misfolded compact conformations, all Monte Carlo simulations show significant success in predicting the native topology using a simplified chain representation and an energy model optimized on other structures. Preliminary results on model peptides from nucleotide binding proteins suggest that this simple protein folding model can help clarify the relation between sequence and topology.

Amino Acid Motifs↗