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PubMedDate not supplied

A computer simulation of the food effect: transient changes in hepatic blood flow and Michaelis-Menten parameters as mediators of hepatic first pass metabolism and bioavailability of propranolol.

A physiological model of propranolol disposition was designed to help explain the large increase in AUC seen when the drug is administered with food. The mass balance equation for the liver compartment used Michaelis-Menten terms to describe hepatic metabolism. Previously published pharmacokinetic and physiological parameters were used throughout. The three parameters, Qh, Kmt, and Vmax, were varied for different durations and by a factor of two to increase AUC. The parameter variations were patterned after the changes in splanchnic blood flow following a high protein meal. The model exhibits saturation kinetics for most of the absorption phase after a simulated single oral dose of 1 mg kg-1, during which hepatic extraction is decreased. As the dose is decreased, the degree of saturation lessens. Using an input rate representative of regular release, changes to Qh caused little change in AUC. While the model was moderately sensitive to Kmt changes, large increases in AUC were seen after Vmax was altered. The sensitivity of the system to Kmt and Vmax changes became greater as the duration of the changes was increased. The AUC was most sensitive to Vmax variation, leading to the conclusion that mechanisms involving this parameter should be explored further. Reducing the input rate to mimic sustained release decreased the AUC for a given dose as well as the sensitivity of AUC to changes in Kmt and Vmax.

Animals↗

PubMed2000

[3-dimensional movement analysis after internal fixation of pelvic ring fractures. A computer simulation].

Several studies exist describing the biomechanical behavior of several external or internal fixation techniques of the posterior and anterior pelvic ring. Recently, the traditional models using isolated anatomical sections or fixed pelvic ring specimens for evaluation of linear or two-dimensional data have been replaced by three-dimensional measurement systems and simulations of muscle forces. These studies have contributed important information to the understanding of the biomechanics of the intact and injured pelvic ring, however, a consequent movement analysis is still missing. In the present study, 3-D data acquired during several series of testing implants for stabilization of the posterior pelvic ring (sacrum: sacral bars, sacral plates, transiliosacral lag screws; Sl joint: anterior plates, transiliosacral lag screws), using a complete pelvic ring model with single leg stance and static abductor muscle simulation, were converted into a commercially available 3-D animation package. By use of simple graphical representation of anatomical elements of the posterior pelvic ring, reproducible and reliable movement patterns for different types of stabilization could be identified, which demonstrated potential "weakness" of the fixation before failure occurred. These movements were analyzed by "replay functions" and were comparable to observations during the original experiment. The following movements were observed. Sacral fracture, transforaminal: (1) rotation of the transiliosacral lag screws around its axis, even with a second screw into S1; (2) Sacral bars: shearing with compression of the cranial-posterior fracture zone; (3) Sacral plates: minimal translation in the proximal fracture zone and distraction in the distal fracture line, effectively compensated by an additional plate at the S3 level. Sl joint disruption: (1) anterior plating (two plates), minimal translation in the plane of the Sl joint; (2) transiliosacral lag screws, rotational movement around the axis of the screws with only minimal movement at the S1 level. The provided information confirmed the observations and allowed a more detailed and comfortable examination of movement patterns. A better understanding of potential "failure zones" might be useful to optimize the dimensions, design, and the positioning of implants for the pelvic girdle. For further studies, more complex computer models including finite element technology might be useful to add accessory information and could result in a decreased need of living specimen testing.

Biomechanical Phenomena↗

PubMedDate not supplied

Assessment of response/error relationship and imprecision profile in immunoassay using computer simulation procedures.

Simulation procedures were applied to assess the response/error relationship (RER) and the imprecision profile (IP) for two model assays, a T4 RIA and a TSH IFMA both using duplicate samples. In order to define the reference functions, the mean data obtained in 10 successive experiments for dose/response curve (DR), RER and IP were employed. The following conclusions emerged from the study: (a) run sizes of ca. 100 duplicates can acceptably describe within-assay IPs, irrespective of the data distribution through the dose range; (b) the contribution of DR fitting error to the total variability of estimate can be disregarded in the case of small series but not for the larger ones; (c) the variability components related to the response error can be efficiently controlled by applying criteria based on RER parameters.

Computer Simulation↗

PubMed2005

Computer-simulated bone architecture in a simple bone-remodeling model based on a reaction-diffusion system.

Bone is a complex system with functions including those of adaptation and repair. To understand how bone cells can create a structure adapted to the mechanical environment, we propose a simple bone remodeling model based on a reaction-diffusion system influenced by mechanical stress. Two-dimensional bone models were created and subjected to mechanical loads. The conventional finite element method (FEM) was used to calculate stress distribution. A stress-reactive reaction-diffusion model was constructed and used to simulate bone remodeling under mechanical loads. When an external mechanical stress was applied, stimulated bone formation and subsequent activation of bone resorption produced an efficient adaptation of the internal shape of the model bone to a given stress, and demonstrated major structures of trabecular bone seen in the human femoral neck. The degree of adaptation could be controlled by modulating the diffusion constants of hypothetical local factors. We also tried to demonstrate the deformation of bone structure during osteoporosis by the modulation of a parameter affecting the balance between formation and resorption. This simple model gives us an insight into how bone cells can create an architecture adapted to environmental stress, and will serve as a useful tool to understand both physiological and pathological states of bone based on structural information.

Bone Remodeling↗

PubMed2005

Computer simulation of forward wave propagation in soft tissue.

A method for simulating forward wavefront propagation in heterogeneous tissue is discussed. The intended application of this method is for the study of aberration produced when performing ultrasound imaging through a layer of soft tissue. A one-way wave equation that permits smooth variation in all acoustically important variables is derived. This equation also describes tissue exhibiting nonlinear elasticity and arbitrary frequency-dependent relaxation. A numerical solution to this equation is found by means of operator splitting and propagation along the spatial depth coordinate. The numerical solution is accurate when compared to analytical solutions for special cases, and when compared to numerical solutions of the full wave equation by other methods. The presented implementation provides a fast numerical method for studying the impact of aberration in medical ultrasound imaging through soft tissue--both on the transmitted beam and the nonlinearly generated harmonic beam.

Animals↗

PubMed1989

Errors in microsphere determination of cardiac output: a computer simulation in fetal sheep.

Through use of a compartmental model, we simulated the measurement of cardiac output and distribution by means of radioactively labeled microspheres in fetal lambs with weights between 0.5 and 3 kg. A systematic error in measured cardiac output caused by artifactual changes in blood volume caused by the injection and withdrawal of fluids during the procedure was less than 5% for fetal weights greater than or equal to 1 kg but increased for fetal weights less than 1 kg and when hypovolemia was simulated at all fetal weights. Sensitivity analysis disclosed no significant effect of changes in vascular resistance. We examined the effects of recirculation of microspheres and found no significant increase in error in the measured value of cardiac output due to 20% recirculation of all spheres entering a single isolated organ system; however, errors between 7 and 14% were observed with simulations of 20% recirculation in more than one compartment simultaneously. Recirculation also introduced significant errors in the measured distribution of cardiac output in certain cases. The effect on the measured cardiac output of a temporary change in the true cardiac output was dampened by the artifactual blood volume changes mentioned above and the fact that the measurement is a time-weighted average. We also evaluated four different experimental designs. We conclude that the microsphere technique provides a remarkably reliable means of quantifying cardiac output and individual organ flow in the fetus. The nonrandom errors inherent in the procedure examined in this study are of the order of 10%, which is likely to be less than the moment-to-moment variation in the true cardiac output.

Algorithms↗

PubMed1998

Computer simulations of carbon monoxide photodissociation in myoglobin: structural interpretation of the B states.

The early diffusion processes of a photodissociated ligand (carbon monoxide) in sperm whale myoglobin and its Phe29 mutant are studied computationally. An explicit solvent model is employed in which the protein is embedded in a box of at least 2300 water molecules. Electrostatic interactions are accounted for by using the particle mesh Ewald. Two hundred seventy molecular dynamics trajectories are computed for 10 ps. Different models of solvation and the ligand, and their influence on the diffusion are examined. The two B states of the CO are identified as "docking" sites in the heme pocket. The sites have a similar angle with respect to the heme normal, but differ in the orientation in the plane. The computational detection of the B states is stable under a reasonable variation of simulation conditions. However, in some trajectories only one of the states is observed. It is therefore necessary to use extensive simulation data to probe these states. Comparison to diffraction experiments and spectroscopy is performed. The shape of the experimental infrared spectra is computed. The overall linewidth is in an agreement with experiment. The contributions to the linewidth (van der Waals and electrostatic interactions) are discussed.

Animals↗

PubMed1992

Binding of an antiviral agent to a sensitive and a resistant human rhinovirus. Computer simulation studies with sampling of amino acid side-chain conformations. II. Calculation of free-energy differences by thermodynamic integration.

Thermodynamic-cycle perturbation theory and molecular dynamics simulations were used to calculate the difference in the free energy of binding of the antiviral compound WIN53338 to the wild-type human rhinovirus 14 and to a drug-resistant mutant of the virus in which valine 188 of the viral protein 1 is mutated to leucine. Because of the difficulty of achieving adequate sampling of all of the rotational isomers of amino acid side-chains in molecular dynamics simulations, an explicit treatment of the effects of the existence of multiple rotational isomers of residue 188 on the calculated free energies was used. The rotamers of residue 188 were first mapped by steric and energetic techniques as described in the accompanying article. Thermodynamic integration was then carried out during simulations of the virus, both with and without the antiviral compound bound, by mutating residue 188 while restraining its side-chain to one conformation. The contributions of the other rotamers of residue 188 to the free-energy changes for this mutation were then added to those calculated by thermodynamic integration as correction factors. Binding of WIN53338 to the wild-type virus was calculated to be favored over binding to the mutant virus by 1.7(+/- 3.0) kcal/mol. This is consistent with experimental data which, if differences in activity are assumed to be due to differences in binding, indicate that the binding affinity of WIN53338 for the wild-type virus is at least 0.15 to 1.7 kcal/mol greater than for the mutant virus. Thermodynamic integration was also performed in the conventional manner without restraints and was found to give less accurate results.

Antiviral Agents↗

PubMed2002

On the Debye-Waller factor of hexagonal ice: a computer simulation study.

We investigate by molecular dynamics (MD) simulations the temperature dependence of the Debye-Waller (DW) factor of hexagonal ice with 25 different proton-disordered configurations. Each initial configuration is composed of 288 water molecules with no net dipole moment. The intermolecular interaction of water is described by TIP4P potential. Each production run of the simulation is 15 ns or longer. We observe a change in slope of the DW factor around 200 K, which cannot be explained within the framework of either classical or quantum harmonic approximation. Configurations generated by MD simulations are subjected to the steepest descent energy minimization. Analysis of the local energy minimum structures reveals that water molecules above 200 K jump to other lattice sites via some local energy minimum structures which contain some water molecules sitting on the locations other than the lattice sites. As time evolves, these defect molecules move back and forth to the lattice sites yielding defect-free structures. Those motions are responsible for the unusual increase in the DW factor at high temperatures. In making a transition from an energy-minimum structure to another one, a small number of water molecules are involved in a highly cooperative fashion. The larger DW factor at higher temperature arises from jump-like motions of water molecules among these locally stable configurations which may or may not be a family of the proton-disordered ice forms satisfying the "ice rule".

Computer Simulation↗

PubMed2006

Similarities and differences in interaction of K+ and Na+ with condensed ordered DNA. A molecular dynamics computer simulation study.

Four 20 ns molecular dynamics simulations have been performed with two counterions, K+ or Na+, at two water contents, 15 or 20 H2O per nucleotide. A hexagonal simulation cell comprised of three identical DNA decamers [d(5'-ATGCAGTCAG) x d(5'-TGACTGCATC)] with periodic boundary condition along the DNA helix was used. The simulation setup mimics the DNA state in oriented DNA fibers or in crystals of DNA oligomers. Variation of counterion nature and water content do not alter averaged DNA structure. K+ and Na+ binding to DNA are different. K+ binds to the electronegative sites of DNA bases in the major and the minor grooves, while Na+ interacts preferentially with the phosphate groups. Increase of water causes a shift of both K+ and Na+ from the first hydration shell of O1P/O2P and of the DNA bases in the minor groove with lesser influence for the cation binding to the bases in the major groove. Mobility of both water and cations in the K-DNA systems is faster than in the Na-DNA systems: Na+ organizes and immobilizes water structure around itself and near DNA while for K+ water is less organized and more dynamic.

Base Pairing↗

PubMed1997

Computer simulations of prebiotic evolution.

This paper is a review of our previous work on the field of possible ways of prebiotic evolution. We propose an algorithm providing sequences of model proteins with rapid folding into a given native conformation. Thermodynamical analysis shows that the increase in speed is matched by an increase in stability: the evolved sequences are much more stable in their native conformation than the initial random sequence. We discuss a possible origin of the first biopolymers, having stable unique structure. We suggest that at the prebiotic stage of evolution, long organic polymers had to be compact in order to avoid hydrolysis and had to be soluble and thus must not be exceedingly hydrophobic. We present an algorithm that generates such sequences of model proteins. The evolved sequences turn out to have a stable unique structure, into which they quickly fold. This result illustrates the idea that the unique three-dimensional native structure of first biopolymers could have evolved as a side effect of a nonspecific physico-chemical factors acting at the prebiotic stage of evolution.

Algorithms↗

PubMed2005

Biaxial nematics: computer simulation studies of a generic rod-disc dimer model.

One possible route to the elusive biaxial nematic phase is through rod-disc dimers in which the rod and disc mesogenic units are linked via a flexible spacer. We have developed a continuous generic model of such rod-disc dimers in which neighbouring like groups tend to align parallel to each other while unlike groups tend to be orthogonal. A torsional potential controls the relative orientations of the groups within a single dimer; depending on the strength of the torsional potential, the groups may be orthogonal or parallel in the conformational ground state. Monte Carlo simulations show that a rigid rod-disc dimer is most likely to form a biaxial nematic phase if the anisotropies of the two groups are the same. Introduction of flexibility is found to have little effect on the qualitative behaviour of the dimer as the relative anisotropy of the two mesogenic groups is changed. However, when the torsional potential strongly favours the alignment of the rod and disc within a single molecule with their symmetry axes parallel there is a dramatic change. The system then exhibits a strong hysteresis in the molecular shape and biaxiality and the biaxial nematic-isotropic transition becomes strongly first order, in marked contrast to the second-order character usually found for this transition. This first-order transition is observed to occur for a range of relative anisotropies of the two groups rather than at a single point.

Anisotropy↗

PubMed2005

Behaviour of small solutes and large drugs in a lipid bilayer from computer simulations.

To reach their biological target, drugs have to cross cell membranes, and understanding passive membrane permeation is therefore crucial for rational drug design. Molecular dynamics simulations offer a powerful way of studying permeation at the single molecule level. Starting from a computer model proven to be able to reproduce the physical properties of a biological membrane, the behaviour of small solutes and large drugs in a lipid bilayer has been studied. Analysis of dihedral angles shows that a few nano seconds are sufficient for the simulations to converge towards common values for those angles, even if the starting structures belong to different conformations. Results clearly show that, despite their difference in size, small solutes and large drugs tend to lie parallel to the bilayer normal and that, when moving from water solution into biomembranes, permeants lose degrees of freedom. This explains the experimental observation that partitioning and permeation are highly affected by entropic effects and are size-dependent. Tilted orientations, however, occur when they make possible the formation of hydrogen bonds. This helps to understand the reason why hydrogen bonding possibilities are an important parameter in cruder approaches which predict drug absorption after administration. Interestingly, hydration is found to occur even in the membrane core, which is usually considered an almost hydrophobic region. Simulations suggest the possibility for highly polar compounds like acetic acid to cross biological membranes while hydrated. These simulations prove useful for drug design in rationalising experimental observations and predicting solute behaviour in biomembranes.

Adrenergic beta-Antagonists↗

PubMed2005

Absolute and relative entropies from computer simulation with applications to ligand binding.

A comparison between two related methods, Schlitter's formula and quasiharmonic analysis, for calculating absolute entropies from the covariance matrix of atomic fluctuations using molecular dynamics (MD) simulations is presented. Calculations for a set of organic compounds in the gas phase are compared to the corresponding statistical thermodynamics results for translational and rotational entropies and to experimental data for vibrational entropies. Encouraging agreement is obtained for translational entropies, but for the rotational contribution, both methods fail to reproduce the theoretically calculated values. Absolute and relative vibrational entropies are found to be better reproduced using quasiharmonic analysis compared to Schlitter's formula. For rotational entropies, we propose a method based on the variances in Euler angles, which gives good agreement with theory. Alternative methods for estimating translational entropies based on principal root mean-square (rms) fluctuations of the center of mass are also presented, and these reproduce theoretically calculated values well. These methodologies are applied to the binding of benzene to T4-lysozyme, where close agreement with the literature is obtained for translational and rotational entropies.

Bacteriophage T4↗

PubMed2004

The effects of changing bone and muscle size on limb inertial properties and limb dynamics: a computer simulation.

The magnitude and distribution of bone and muscle mass within limbs affect limb inertial properties, maximum movement speed and the energy required to maintain submaximal movements. Musculoskeletal modeling and movement simulations were used to determine how changes in bone and muscle cross-sectional area (and thus mass) affect human thigh and shank inertial properties, the maximum speed of unloaded single-leg cycling and the energy required to sustain submaximal single-leg cycling. Depending on initial conditions, shank moments of inertia increased 61-72 kg cm2 per kg added bone and 72-100 kg cm2 per kg added muscle. Thigh moments of inertia increased 46-63 kg cm2 per kg bone and 180-225 kg cm2 per kg muscle. Maximum unloaded cycling velocity increased with increased muscle mass (approximately 2.2-2.9 rpm/kg muscle), but decreased with increased cortical bone mass (approximately 2.0-2.8 rpm/kg bone). The internal work associated with unloaded submaximal cycling increased with increased muscle mass (approximately 0.42-0.48 J/kg muscle) and bone mass (approximately 0.18-0.22 J/kg bone).

Acceleration↗

PubMed2004

A proficient enzyme: insights on the mechanism of orotidine monophosphate decarboxylase from computer simulations.

Decarboxylation of orotidine 5'-monophosphate (Omp) to uridine 5'-monophosphate by orotidine 5'-monophosphate decarboxylase (ODCase) is currently the object of vivid debate. Here, we clarify its enzymatic activity with long time scale classical molecular dynamics and hybrid ab initio Car-Parrinello/molecular mechanics simulations. The lack of structural (experimental) information on the ground state of ODCase/Omp complex is overcome by a careful construction of the model and the analysis of three different strains of the enzyme. We find that the ODCase/substrate complex is characterized by a very stable charged network Omp-Lys-Asp-Lys-Asp, which is incompatible with the previously proposed direct decarboxylation driven by a ground-state destabilization. A direct decarboxylation induced by a transition-state electrostatic stabilization is consistent with our findings. The calculated activation free energy for the direct decarboxylation with the formation of a C6 carboanionic intermediate yields an overall rate enhancement by the enzyme (k(cat)/k(wat) = 3.5 x 10(16)) in agreement with experiments (k(cat)/k(wat) = 1.7 x 10(17)). The decarboxylation is accompanied by the movement of a fully conserved lysine residue toward the developing negative charge at the C6 position.

Computer Simulation↗

PubMed2001

A computer simulation model of mass media interventions directed at tobacco use.

OBJECTIVES: The goal of this study was to develop a simulation model to examine the effects of tobacco control mass media interventions on smoking rates and smoking-attributable deaths. METHODS: The model projects the number of smokers and smoking-related deaths. Based on empirical and theoretical research, the effects of media interventions, varying in magnitude and duration, directed at all smokers and directed specifically at youth under age 18 are modeled. RESULTS: The model predicts that sustained media interventions of sufficient magnitude and duration directed at all smokers have the potential to substantially reduce the number of smokers and premature deaths, with the effects growing over time. For the same expenditures, youth interventions would appear to have smaller and more delayed effects. CONCLUSIONS: Media interventions, particularly those targeted at the general population and of sufficient scale and duration, have the ability to substantially reduce smoking rates and save lives, but their effects are likely to depend on how they are implemented.

Adolescent↗

PubMed1987

Conformational analysis of the cholecystokinin C-terminal octapeptide: a nuclear magnetic resonance and computer-simulation approach.

The C-terminal octapeptide portion of cholecystokinin (CCK8) has well-defined biological properties which include action as a neurotransmitter and induction of gall-bladder contraction and pancreatic enzyme secretion. Many analogues of CCK8 have been prepared and tested for potency, making this an ideal model system in which to initiate evaluation of structure-function relationships. The present study uses high-resolution proton nuclear magnetic resonance (NMR) spectroscopy and energy minimization techniques to evaluate the solution (DMSO) and in vacuo conformation(s) of CCK8. The NMR results provide amide and C alpha H alpha chemical shift temperature dependencies and all phi dihedral angles and chi 1 rotamer populations. The energy minimization data located deep potential energy wells, for which all torsion angles are reported. Collectively, the data support models for CCK8 where the structures are characterized by a high degree of folding. These conformations are characterized by sharp turns, possibly stabilized by hydrogen-bonds. Taken together with pharmacologic data and somewhat similar folded structures implied from fragments of CCK8, it is suggested that both electrostatic and steric effects are needed for full biological potency.

Computer Simulation↗