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PubMed1995

Computer simulation of the directional displacement of rod-shaped, arc-shaped, and circular objects in an array of obstacles, representing a simple model for the gel electrophoresis of small DNA.

The gel electrophoresis of DNA of identical length but various static conformations was simulated using a two-dimensional model of the movement of rod-shaped, arc-shaped, and circular objects through random arrays of disk-shaped obstacles. At low obstacle density, the displacement rate of these objects decreases from the rod-shaped to the circular to the arc-shaped objects. At high obstacle densities, the displacement rate of circular objects approaches zero. The alignment of the arc-shaped objects along the axis of the directional movement of the objects were retarded in their movement by collisions with the obstacles; the number of collisions of the former, in view of their greater ability to align, was less than that of the latter. Circular objects were exclusively retarded by collisions, while the arc-shaped objects exhibited an additional retarding mechanism, viz. the suspension ("hanging") on the obstacles. When the rigid objects were made flexible, their displacement increased. The increase was most pronounced with the circular objects, allowing them to penetrate at obstacle densities from which the rigid objects were excluded.

Computer Simulation↗

PubMed1996

Comparison and assessment of blood gas related quantities including base excess, the gas exchange indices, and temperature corrected pH/PO2/PCO2, as defined in approved NCCLS standard C12-A, using a computer simulation of input variables.

Blood gases and related quantities reported to clinicians have, since the earliest days, included both directly measured as well as calculated or estimated quantities. Some developed as substitutes for quantities that were or are difficult to measure routinely, others to explain relationships between older, difficult to measure quantities and newly measureable quantities, and still others attempt to better understand the physiology of the acid-base process. The net result is a plethora of acid-base and related quantities that may be reported by different blood gas systems. In an attempt to address the issue of which quantities have stood the test of usefulness over time, and further, to examine the optimum algorithm for use in quantification, the NCCLS has developed, through its consensus process, a recommended set of quantities and their quantifying algorithms. We have studied these quantities and compared them with some other recognized approaches and present our analysis in this report. The major conclusion is that among those quantities recommended, the NCCLS algorithms present the most sensible overall approach and that we would recommend their use as described so that the quantities can be most effectively applied clinically, without differences in final values occurring due solely simple algorithm differences.

Acid-Base Equilibrium↗

PubMed2005

Computer simulations of successful defibrillation in decoupled and non-uniform cardiac tissue.

AIM: The aim of the present study is to investigate the origin and effect of virtual electrode polarization in uniform, decoupled and non-uniform cardiac tissue during field stimulation. METHODS: A discrete bidomain model with active membrane behaviour was used to simulate normal cardiac tissue as well as cardiac tissue that is decoupled due to fibrosis and gap junction remodelling. Various uniform and non-uniform electric fields were applied to the external domain of uniform, decoupled and non-uniform resting cardiac tissue as well as cardiac tissue in which spiral waves were induced. RESULTS: Field stimulation applied on non-uniform tissue results in more virtual electrodes compared with uniform tissue. The spiral waves were terminated in decoupled tissue, but not in uniform, homogeneous tissue. By gradually increasing local differences in intracellular conductivities, the amount and spread of virtual electrodes increased and the spiral waves were terminated. CONCLUSION: Fast depolarization of the tissue after field stimulation may be explained by intracellular decoupling and spatial heterogeneity present in normal and pathological cardiac tissue. We demonstrated that termination of spiral waves by means of field stimulation can be achieved when the tissue is modelled as a non-uniform, anisotropic bidomain with active membrane behaviour.

Anisotropy↗

PubMed2005

Computer simulation study of pattern transfer in AB diblock copolymer film adsorbed on a heterogeneous surface.

In this work we investigate how a pattern imposed in a copolymer film at a certain distance from the surface propagates through the film onto an adsorbing heterogeneous surface. We bias the copolymer film to adopt a specified target pattern and then use simulation to design a surface pattern that helps the adsorbed film to maintain that target pattern. We examine the effect of varying the copolymer chain length, the size of the target pattern, and the distance from the surface where the target pattern is applied, z', on the extent of pattern transfer. For each chain length, target pattern, and z' we compare the energy of the system when a pattern is applied in the bulk to the energy when no pattern is applied in order to understand why a certain pattern size is transferred to the surface with higher fidelity than the others. At constant chain length, pattern transfer is best when the pattern size brings the energy of the system close to the energy when no pattern is applied. At constant pattern size, pattern transfer is best in the systems with longer chains. This is because longer chains are more likely to adsorb as brushes and loops which then helps transfer the pattern through the adsorbed film down to the surface.

Adsorption↗

PubMed2001

Evaluation of methods for detecting recombination from DNA sequences: computer simulations.

Recombination is a key evolutionary process that shapes the architecture of genomes and the genetic structure of populations. Although many statistical methods are available for the detection of recombination from DNA sequences, their absolute and relative performance is still unknown. Here we evaluated the performance of 14 different recombination detection algorithms. We used the coalescent with recombination to simulate DNA sequences with different levels of recombination, genetic diversity, and rate variation among sites. Recombination detection methods were applied to these data sets, and whether they detected or not recombination was recorded. Different recombination methods showed distinct performance depending on the amount of recombination, genetic diversity, and rate variation among sites. The model of nucleotide substitution under which the data were generated did not seem to have a significant effect. Most methods increase power with more sequence divergence. In general, recombination detection methods seem to capture the presence of recombination, but they are not very powerful. Methods that use substitution patterns or incompatibility among sites were more powerful than methods based on phylogenetic incongruence. Most methods do not seem to infer more false positives than expected by chance. Especially depending on the amount of diversity in the data, different methods could be used to attain maximum power while minimizing false positives. Results shown here will provide some guidance in the selection of the most appropriate method/s for the analysis of the particular data at hand.

Computer Simulation↗

PubMed2004

Structure, dynamics and interaction with kinase targets: computer simulations of calmodulin.

Calmodulin (CaM) is a small protein involved in calcium signaling; among the targets of CaM are a number of kinases, including myosin light chain kinases (MLCK), various CaM-dependent kinases and phosphorylase kinase. We present results of molecular dynamics (MD) simulations of 4-ns length for calmodulin in its three functional forms: calcium-free, calcium-loaded, and in complex with both calcium and a target peptide, a fragment of the smooth muscle MLCK. The simulations included explicit water under realistic conditions of constant temperature and pressure, the presence of counterions and Ewald summation of electrostatic forces. Our simulation results present a more complete description of calmodulin structure, dynamics and interactions in solution than previously available. The results agree with a wide range of experimental data, including X-ray, nuclear magnetic resonance (NMR), fluorescence, cross-linking, mutagenesis and thermodynamics. Additionally, we are able to draw interesting conclusions about microscopic properties related to the protein's biological activity. First, in accord with fluorescence data, we find that calcium-free and calcium-loaded calmodulin exhibit significant structural flexibility. Our simulations indicate that these motions may be described as rigid-body translations and rotations of the N- and C-terminal domains occurring on a nanosecond time scale. Our second conclusion deals with the standard model of calmodulin action, which is that calcium binding leads to solvent exposure of hydrophobic patches in the two globular domains, which thus become ready to interact with the target. Surprisingly, the simulation results are inconsistent with the activation model when the standard definitions of the hydrophobic patches are used, based on hydrophobic clefts found in the X-ray structure of calcium-loaded calmodulin. We find that both experimental and simulation results are consistent with the activation model after a redefinition of the hydrophobic patches as those residues which are actually involved in peptide binding in the experimental structure of the calmodulin-peptide complex. The third conclusion is that the calmodulin-peptide interactions in the complex are very strong and are dominated by hydrophobic effects. Using quasi-harmonic entropy calculations, we find that these strong interactions induce a significant conformational strain in the protein and peptide. This destabilizing entropic contribution leads to a moderate overall binding free energy in the complex. Our results provide interesting insights into calmodulin binding to its kinase targets. The flexibility of the protein may explain the fact that CaM is able to bind many different targets. The large loss of conformational entropy upon CaM:peptide binding cancels the entropy gain due to hydrophobic interactions. This explains why the observed entropic contribution to the binding free energy is small and positive, and not large and negative as expected for a complex with such extensive hydrophobic contacts.

Animals↗

PubMed2002

High-resolution computer simulation of the dynamics of isoelectric focusing using carrier ampholytes: the post-separation stabilizing phase revisited.

A dynamic electrophoresis simulator that accepts 150 components and voltage gradients employed in the laboratory was used to provide a detailed description of the stabilizing phase in isoelectric focusing under conditions that were hitherto inaccessible. High-resolution focusing data are presented for pH gradients spanning 7 units (pH 3-10 and pH 4-11 with 20 carrier ampholytes/pH unit) and 3.5 units (pH 7-10.5 and pH 5-8.5 with 40 carrier ampholytes/pH unit). Stabilizing phase behavior for configurations (i) with the focusing column ends only permeable to OH(-) and H(+) at cathode and anode, respectively, and (ii) with the focusing column being sandwiched between NaOH (catholyte) and phosphoric acid (anolyte) are described. Simulation data reveal the stabilizing phase to be diffusion-controlled and characterized by changes that progress from the column ends towards neutrality (i.e., towards the center in case of pH gradients bracketing neutrality). Transient states are characterized by moving concentration valleys of carrier ampholytes that significantly alter the distributions of pH and conductivity. Nonlinear pH gradients are produced. The magnitude of the changes occuring is dependent on the span of the pH gradient. Gradients that encompass greater extremes of pH show more pronounced stabilizing phases. For all systems subjected to a constant 300 V/cm, the initial separation and subsequent stabilization require less than 10 min and more than 7000 min, respectively. The presence of electrolytes at the column ends disrupts the stabilizing phase, with the degree of disruption dependent on the concentrations of the acid and base employed as electrode solutions. The data not only indicate that a true steady state is never attained in the average laboratory experiment, they also suggest that a true steady state in absence of immobilized pH gradients cannot be achieved experimentally at all.

Buffers↗

PubMed2006

Computational simulations of vocal fold vibration: Bernoulli versus Navier-Stokes.

The use of the mechanical energy (ME) equation for fluid flow, an extension of the Bernoulli equation, to predict the aerodynamic loading on a two-dimensional finite element vocal fold model is examined. Three steady, one-dimensional ME flow models, incorporating different methods of flow separation point prediction, were compared. For two models, determination of the flow separation point was based on fixed ratios of the glottal area at separation to the minimum glottal area; for the third model, the separation point determination was based on fluid mechanics boundary layer theory. Results of flow rate, separation point, and intraglottal pressure distribution were compared with those of an unsteady, two-dimensional, finite element Navier-Stokes model. Cases were considered with a rigid glottal profile as well as with a vibrating vocal fold. For small glottal widths, the three ME flow models yielded good predictions of flow rate and intraglottal pressure distribution, but poor predictions of separation location. For larger orifice widths, the ME models were poor predictors of flow rate and intraglottal pressure, but they satisfactorily predicted separation location. For the vibrating vocal fold case, all models resulted in similar predictions of mean intraglottal pressure, maximum orifice area, and vibration frequency, but vastly different predictions of separation location and maximum flow rate.

Binomial Distribution↗

PubMed1992

Unidirectional block in cardiac fibers: effects of discontinuities in coupling resistance and spatial changes in resting membrane potential in a computer simulation study.

The mechanisms for conduction and unidirectional block (UDB) in cardiac tissue under spatial changes in cell-to-cell coupling resistivity (Ri) and resting potential (Vrest) were studied. Cable theory was used to simulate the cardiac fiber, and the Beeler and Reuter model, or a modified model based on the Ebihara-Johnson formulation was used to describe the ionic currents. The effects of discontinuities in Ri as would result from collagenous or fibrotic tissue on propagation characteristics were studied. We were especially interested in the effects on propagation characteristics of discontinuities in Ri in the border zone between normal and ischemic tissue. We found that conduction block is more likely to occur when an abrupt decrease in Ri is encountered as compared to an abrupt increase in Ri. Discontinuities in Ri were found to cause changes in propagation characteristics, changing regions of bidirectional block to UDB or bidirectional propagation. Spatial changes in Vrest were also studied. We found that when Vrest alone was altered, block was not likely to occur, while discontinuities in Ri superimposed with Vrest gradients increased the likelihood of block. We also found that Ri discontinuities located in the border zone between normal and ischemic tissue can create exit block or propagation of a parasystolic focus.

Action Potentials↗

PubMedDate not supplied

A conformational comparison of two stereoisomeric cyclic dermorphin analogues employing NMR and computer simulations.

In a continuation of our program to study the structure-activity relationship of peptide opiates, we report the conformational analysis of two cyclic tetrapeptides related to dermorphin--Tyr-c[D-Orn-Phe-Asp]-NH2 and Tyr-c[D-Asp-Phe-Orn]-NH2. These analogues have similar binding properties marked by a high selectivity for the mu-opioid receptors because of a drastic decrease in the affinity for the delta-opioid receptor. The conformational preferences of these analogues of dermorphin determined from proton nmr, molecular dynamics, and energy minimizations are quite similar. The constraint of the 13-membered ring formed from cyclization is quite evident from the conformational analysis. The constrained ring system acts as a template maintaining the relative orientation of the exocyclic tyrosine and side chain of phenylalanine. Two intramolecular hydrogen bonds measured for the D-Orn analogue in DMSO were disrupted upon the addition of water. For the D-Asp analogue, two intramolecular hydrogen bonds were found stable in DMSO and water. The global conformations of the two peptides determined from nuclear Overhauser effects did not change with the solvent titration. The difference in the hydrogen bonding within the 13-membered ring may account for the slight differences observed in the efficacy of the analogues at the mu-opioid receptors.

Amino Acid Sequence↗

PubMed1987

A theory of follicle selection: II. Computer simulation of estradiol administration in the primate.

A theory of follicle selection (Lacker, 1981) is tested in the primate by simulating the effects of estradiol administration at different times, strengths, and durations during the follicular phase of the menstrual cycle (Clark et al., 1981; Zeleznik, 1981; Dierschke et al., 1985). The theory can account for the observed atretogenic effects of circulating estradiol on follicle development including full, partial, and delayed atresia of the dominant follicle (Dierschke et al., 1985) and can explain why similar estradiol doses achieve different qualitative effects when given at different times during the cycle. The theory predicts that recovery from early atresia may be possible, and it can also account for the loss of control in the number of maturing follicles that has been observed when estradiol antibodies are given in the midfollicular phase (Zeleznik et al., 1985). These results support the hypothesis that the selection mechanism in the primate is a consequence of feedback involving an essentially equipotent follicle population interacting through circulating estradiol and pituitary gonadotropins. A quantitative test of the theory awaits experimental identification of the maturation surfaces that are predicted by it. An experimental design for this purpose is proposed.

Animals↗

PubMed1997

Computer simulation of the effects of alterations in blood flows and body composition on thiopental pharmacokinetics in humans.

BACKGROUND: Understanding the influence of physiological variables on thiopental pharmacokinetics would enhance the scientific basis for the clinical usage of this anesthetic. METHODS: A physiological pharmacokinetic model for thiopental previously developed in rats was scaled to humans by substituting human values for tissue blood flows, tissue masses, and elimination clearance in place of respective rat values. The model was validated with published serum concentration data from 64 subjects. The model was simulated after intravenous thiopental administration, 250 mg, over 1 min, to predict arterial plasma concentrations under conditions of different cardiac outputs, degrees of obesity, gender, or age. RESULTS: The human pharmacokinetic model is characterized by a steady state volume of distribution of 2.2 l/kg, an elimination clearance of 0.22 l/min, and a terminal half-life of 9 h. Measured thiopental concentrations are predicted with an accuracy of 6 +/- 37% (SD). Greater peak arterial concentrations are predicted in subjects with a low versus a high cardiac output (3.1 and 9.4 l/min), and in subjects who are lean versus obese (56 and 135 kg). Acutely, obesity influences concentrations because it affects cardiac output. Prolonged changes are due to differences in fat mass. Changes with gender and age are relatively minor. CONCLUSIONS: The physiological pharmacokinetic model developed in rats predicts thiopental pharmacokinetics in humans. Differences in basal cardiac output may explain much of the variability in early thiopental disposition between subjects.

Adult↗

PubMed2006

Investigation of the catalytic mechanism of farnesyl pyrophosphate synthase by computer simulation.

Farnesyl pyrophosphate synthase (FPPS) catalyses the formation of a key cellular intermediate in isoprenoid metabolic pathways, farnesyl pyrophosphate, by the sequential head-to-tail condensation of two molecules of isopentenyl diphosphate (IPP) with dimethylallyl diphosphate (DMAPP). Recently, FPPS has been shown to represent an important target for the treatment of parasitic diseases such as Chagas disease and African trypanosomiasis. Bisphosphonates, pyrophosphate analogues in which the oxygen bridge between the two phosphorus atoms has been replaced by a carbon substituted with different side chains, are able to inhibit the FPPS enzyme. Moreover, nitrogen-containing bisphosphonates have been proposed as carbocation transition state analogues of FPPS. On the basis of structural and kinetic data, different catalytic mechanisms have been proposed for FPPS. By analyzing different reaction coordinates we propose that the reaction occurs in one step through a carbocationic transition state and the subsequent transfer of a hydrogen atom from IPP to the pyrophosphate moiety of DMAPP. Moreover, we have analyzed the role of the active site amino acids on the activation barrier and the reaction mechanism. The structure of the active site is well conserved in the isoprenyl diphosphate synthase family; thus, our results are relevant for the understanding of this important class of enzymes and for the design of more potent and specific inhibitors for the treatment of parasitic diseases.

Amino Acids↗

PubMed1989

Comparison of computer simulations of the F-type and L-type non-oxidative hexose monophosphate shunts with 31P-NMR experimental data from human erythrocytes.

Mathematical modelling was used to predict the behaviour of the two most favoured schemes for the operation of the non-oxidative hexose monophosphate shunt (HMS), the F-type and the L-type pathways. The models simulate the time courses of sugar-phosphate concentrations when various substrates are metabolized via each pathway. A 31P-NMR technique, with which to observe time courses of concentrations of sugar phosphates in a human red cell lysate, was developed. The accuracy of each hypothesised scheme was then evaluated by comparing predicted with observed data. The results were more consistent with time courses of sugar-phosphate levels predicted by the F-type (classical) pathway than those predicted by the L-type model. However, the accumulation of sedoheptulose 1,7-bisphosphate when a haemolysate was incubated with ribose 5-phosphated showed that the F-type pathway is not a complete description of the system of reactions. Transaldolase was demonstrated to be essential for the normal metabolism of sugar phosphates by haemolysates. The effects of the heat-inactivation of transaldolase on the metabolism of sugar phosphates were accurately predicted by the F-type model. The relevance of attempting to describe the reaction of the non-oxidative HMS as a distinct 'pathway' or 'cycle' is discussed.

Computer Simulation↗

PubMed2005

Identification of essentially derived varieties with molecular markers: an approach based on statistical test theory and computer simulations.

Genetic similarities (GS) based on molecular markers have been proposed as a tool for identification of essentially derived varieties (EDVs). Nevertheless, scientifically reliable criteria for discrimination of EDVs and independently derived varieties with GS estimates are scanty, and implementation into practical breeding has not yet taken place. Our objectives were to (1) assess the influence of chromosome number and length, marker density, and distribution, as well as the degree of polymorphism between the parental inbreds on the distribution of GS between parental inbreds and their progenies [GS(P1,O)] derived from F2 and different backcross populations and (2) evaluate these factors with regard to the power for distinguishing F2- versus BC1- and BC1- versus BC2-derived lines with molecular markers. We developed an approach based on statistical test theory for the identification of EDVs with molecular markers. Standard deviations and overlaps of distributions of GS(P1,O) of F2-, BC1-, and BC2-derived lines were smaller with (1) increasing chromosome number and length, (2) increasing marker density, and (3) uniformly instead of randomly distributed markers, approaching a lower boundary determined by the genetic parameters. The degree of polymorphism between the parental inbreds influenced the power only if the remaining number of polymorphic markers was low. Furthermore, suggestions are made for (1) determining the number of markers required to ascertain a given power and (2) EDV identification procedures.

Computer Simulation↗

PubMed2001

Potential seasonal ecological challenge of heat strain among Australian Aboriginal people practicing traditional subsistence methods: a computer simulation.

It has been largely accepted that Australian Aboriginal people practicing hunting and gathering traditionally underused their objective economic possibilities by working short hours relative to nonhunter-gatherer populations. However, the possibility that their subsistence quest might have been limited by potential heat strain has not been considered for Australian hunter-gatherers. In this article the influence of work and heat load on the potential for heat strain among adult male Australian Aboriginal people is modelled. The possibility that the short working day of Arnhem Land adults reported in the literature might reflect ecologically limited work scheduling by way of potential heat strain is examined. Three climatic regions of the North of Western Australia and the Northern Territory were identified, using data available from the Australian Bureau of Meteorology. Data from the months of January, April, July, and October were used with the United States Army Heat Strain Model, along with assumptions with respect to work load and time scheduling. Predictive modelling indicates that a late start to the working day could carry considerable risks of potential heat strain during the summer, when humidity and maximum daily temperature are highest for all three climatic regions, but especially in the tropical coastal region. While extended work times may have been needed to acquire adequate food under traditional conditions, work output could have been limited by potential heat strain under some conditions likely to have prevailed.

Adaptation, Physiological↗

PubMed1996

Pulsed-field-trapping electrophoresis: a computer simulation study.

Experimental investigations have shown that adding a large, globular and neutral protein (such as streptavidin) at one end of the DNA fragments to be separated by gel electrophoresis strongly affects the dynamics of these molecules, leading to what is known as trapping electrophoresis (TE). In TE, the velocity decreases much more rapidly with DNA molecular size than under normal gel electrophoresis conditions, suggesting that TE may be used to increase the power of separation of polyacrylamide gel electrophoresis. Unfortunately, the bands are broader and fewer readable bands can fit on a single gel slab. Our previous theoretical study of TE also predicted the existence of long-lasting anomalous regimes where one cannot define a velocity or a diffusion constant. These secondary effects of trapping are related to the very broad distribution of detrapping times (the time needed to exit a trap). In order to increase the usefulness of TE, it has been suggested that pulsed fields may help the molecules exit traps more rapidly. In this article, we present a detailed numerical study of pulsed field TE. We conclude that simple pulsed fields alone may not be enough to increase the sequencing power of polyacrylamide TE because the rate of band broadening cannot be controlled. We also report the existence of anomalous regimes in the presence of pulsed fields, a factor that has been previously neglected in analytical models. Other approaches are also proposed.

Bacterial Proteins↗

PubMed2006

Branching patterns and drainage territories of the middle hepatic vein in computer-simulated right living-donor hepatectomies.

Full right hepatic grafts are most frequently used for adult-to-adult living donor liver transplantation (LDLT). One of the major problems is venous drainage of segments 5 and 8. Thus, this study was designed to provide information on venous drainage of right liver lobes for operation-planning. Fifty-six CT data sets from routine clinical imaging were evaluated retrospectively using a liver operation-planning system. We defined and analyzed venous drainage segments and the impact of anatomic variations of the middle hepatic vein (MHV) on venous outflow from segments 5 and 8. MHV variations led to significant shifts of segment 5 drainage between the middle and right hepatic vein. In cases with the most frequent MHV branching pattern (n = 33), a virtual hepatectomy closely right to the MHV intersected drainage vessels that provided drainage for 30% of the potential graft, not taking into account potential veno-venous shunts. In individuals with inferior MHV branches that extend far into segments 5 and 6 (n = 10), the overall graft volume at risk of impaired venous drainage increased by 5% (p < 0.001). If this is confirmed in clinical trials and correlated with intraoperative findings, the use of liver operation-planning systems would be beneficial to improve overall outcome after right lobe LDLT.

Computer Simulation↗