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PubMed2005

Using computer simulation to assist in the robustness analysis of an ion-exchange chromatography step.

This paper presents a methodology to gain process knowledge and assist in the robustness analysis of an ion-exchange step in a protein purification process using a model-based approach. Factorial experimental design is common practice in industry today to obtain robustness characterization of unit operations with respect to variations in process parameters. This work aims at providing a better insight into what process variations affect quality and to further reduce the experimental work to the regions of process variation that are of most interest. This methodology also greatly increases the ability to predict process performance and promotes process understanding. The model calibration part of the methodology involves three consecutive steps to calibrate a steric mass action (SMA) ion-exchange chromatography model. Firstly, a number of gradient elution experiments are performed. Secondly, experimental breakthrough curves have to be generated for the proteins if the adsorption capacity of the medium for each component is not known. Thirdly, a multi-component loading experiment is performed to calibrate the multi-component effects that cannot be determined from the single-component experiments. The separation process studied in this work is the separation of polyclonal IgG from a mixture containing IgG, myoglobin and BSA. The calibrated model is used to simulate six process variations in a full factorial experiment. The results of the simulations provide information about the importance of the different process variations and the simulations are also used to determine the crucial points for the process parameter variations. The methodology can be used to assist in the robustness analysis normally performed in the pharmaceutical industry today as it is able to predict the impact on process performance resulting from variations in salt concentration, column load, protein concentration and flow rate.

Chromatography, Gel↗

PubMed1987

Complexity and significance in computer simulations of physiological systems.

Complexity in a theoretical model may or may not be associated with a high level of arbitrariness, depending on how the model is constructed. In this paper I use examples from cardiac electrophysiology to illustrate two techniques for maintaining significance in complex simulations. First, the approaches of analysis and synthesis are compared as methods of constructing models of complex systems. When a model is constructed by synthesis of known principles, facts, and subunits, it may have any degree of complexity without losing significance; the same is not true for analysis models. Significance can also be maintained by assembling a limited model to test a specific hypothesis of mechanism.

Adenosine Triphosphate↗

PubMedDate not supplied

[Stability analysis of various forms of fusion of the lumbar vertebrae using a computer simulation model].

To analyze mechanical properties of a lumbar functional unit a mathematical simulation model was developed. Using this model in different lumbar fusions immediate postoperative and secondary stability was analysed. Stability of different interbody and posterior fusions was compared looking at different techniques of operation an instrumentation. The calculation showed best results in the combination of posterolateral fusion with interspinal distraction or transpedicular screw instrumentation. These showed well-balanced load carrying properties primarily and high secondary stability.

Computer Simulation↗

PubMed1996

Computer simulation of the triosephosphate isomerase catalyzed reaction.

A major challenge for theoretical simulation methods is the calculation of enzymic reaction rates directly from the three-dimensional protein structure together with some idea of the chemical reaction mechanism. Here, we report the evaluation of a complete free energy profile for all the elementary steps of the triosephosphate isomerase catalyzed reaction using such an approach. The results are compatible with available experimental data and also suggest which of the possible reaction intermediates is kinetically observable. In addition to previously identified catalytic residues, the simulations show that a crystallographically observed active site water molecule plays an important role during catalysis and an intersubunit interaction that could explain the low activity of the monomeric enzyme is also observed. The calculations clearly demonstrate the important catalytic effects associated with stabilization of charged high energy intermediates and reduction of reorganization energy, which are likely to be general principles of enzyme catalyzed charge transfer and separation reactions.

Catalysis↗

PubMed1992

Computer simulation of linkage and heterogeneity in tuberous sclerosis: a critical evaluation of the collaborative family data.

The existence of locus heterogeneity for a genetic disease may complicate linkage studies considerably, especially when very few large families with the disease are available. In this situation a modest collection of families is unlikely to be sufficient for successful localisation of one or more disease genes. Recently, eight research groups working on tuberous sclerosis (TSC) brought together linkage data pertaining to the candidate chromosomes 9, 11, and 12 for a large group of families. In a series of simulation studies we determined the probability of detecting linkage and linkage heterogeneity in this set of families. On average TSC families are very small; in most cases there are fewer than two informative meioses. The size distribution of chromosome 9 linked families was similar to that of non-linked families. This indicates that a dramatic difference in the clinical severity of major genetic forms of TSC is unlikely. The results of our simulation studies show that this set of families can generate highly significant evidence for linkage and heterogeneity. When two TSC genes are equally common, the strongest evidence for linkage and heterogeneity could be obtained using a method based on the incorporation of multiple candidate regions in a single analysis, with an average lod score of 24.27.

Chromosome Mapping↗

PubMed1993

[Evaluation of serum enzyme levels considering biological half lives of enzymes--alteration of lactate dehydrogenase isoenzyme pattern due to computer simulation].

The rapid clearance of certain releasing enzymes from blood stream may modify their usefulness as markers of disease. Serum LD isoenzyme patterns are often quite different from those in the affected tissues. Such differences result from differences in the biological half lives of the individual isoenzyme. In order to reveal such phenomena, we applied the one-compartment model to simulate the time dependent changes in the serum LD isoenzyme patterns as a most simple model. When we simulated leukemic cells as an affected origin, LD isoenzyme patterns obtained at a stage of clinical deterioration or active stage, were characterized by a high proportion of LD-2, LD-3 and LD-4, and resembled those of the original leukemic cells. In general, strong similarities in alterations of LD isoenzyme patterns were obtained between the clinical observed time course and simulated time course. These changes in LD isoenzyme patterns are practically observed in the cases of leukemia, lymphoma, and so on. If the original organs are identical, then it is change of disease stage that is responsible for modification of variable LD isoenzyme patterns. Such phenomena must therefore be noted--in doing so, we shall be able to estimate the origin of enzyme release, disease stage, and prognosis.

Computer Simulation↗

PubMed1991

Theory of ocular dominance column formation. Mathematical basis and computer simulation.

A general theory previously proposed by the author which describes synaptic stabilization on the basis of three basic assumptions is employed for the understanding of ocular dominance column formation. A reduced mathematical model is constructed based on the thermodynamics in the Ising spin variables representing the afferent synaptic connection distribution. The results of Monte Carlo simulations on the segregation of ipsilateral and contralateral synaptic terminals in the input layer of the primary visual cortex suggest the existence of phase transition phenomena. Three types of ocular dominance column patterns--stripe, blob, and uniform--are visualized according to the values of the correlation strength and the degree of imbalance in activity between the left and right retinas. The theory presented here successfully explains how ocular dominance columns are developed.

Animals↗

PubMed2004

Elastic scattering and light transport in three-dimensional collagen gel constructs: a mathematical model and computer simulation approach.

A mathematical modeling approach for elastic scattering and light propagation is presented, which can be used to obtain the scattering coefficient, the index of refraction, and the distribution of the collagen fibrils in a gel. Collagen fibrils can be realistically represented by small cylindrical particles. The analysis of the scattering of light by such particles provides the scattering coefficient. Light transport in multilayered tissues has been modeled and the collagen fibrils scattering coefficient has been considered as main input parameters. Assuming that a gel is composed of fibrils with the same diameter, it is possible to obtain all the input parameters of the model and, therefore, a simulated spectrum. This can be repeated for several diameters. Considering a gel composed of fibrils with different diameters, it is possible to obtain a best-fitting simulated spectrum as a weighted sum (least-square-error based) of the spectra corresponding to several fibril diameters, and, therefore, obtain an estimate of the percentages of fibrils of each diameter in the gel. Moreover, the scattering coefficient and refractive index, which are also provided by the model, are relevant parameters as they relate to tissue properties in their own right.

Algorithms↗

PubMed1999

Computer simulations of the dynamics of human choriogonadotropin and its alpha subunit.

Human choriogonadotropin (hCG) belongs to a family of heterodimeric glycoprotein hormones involved in reproduction. Over 75 ns of molecular dynamics simulations of this heterodimer and the free alpha subunit were performed and validated by experimental information to arrive at a qualitative dynamical description of these molecules. A number of 5-ns simulations at 400 degrees K describe a sufficiently stable heterodimer structure, whereas the free alpha subunit shows the experimentally observed partial unfolding. From the main collective fluctuations of the free alpha subunit, it can be derived that residues alpha35-55 form a domain that is highly flexible with respect to the other domain, which contains all five disulfide bonds. The apparent loss of secondary structure in the region alpha33-58 may very well be induced by this. Dynamic domains can also be determined from the hCG heterodimer simulations. The most important collective mode of motion shows that the flexibility of the alpha subunit is reduced by concerted rotation with both the long loop and the determinant loop of the beta subunit. The motion of the free alpha subunit does not differ significantly from the motion it has in the hCG heterodimer, but the amplitudes along the most important eigenvectors are larger.

Carbohydrates↗

PubMed1990

Computer simulation of the mechanically-assisted failing canine circulation.

A model of the cardiovascular system is presented. The model includes representations of the left and right ventricles, a nonlinear multielement model of the aorta and its main branches, and lumped models of the systemic veins and the pulmonary circulation. A simulation of the intra-aortic balloon pump and representations of physiological compensatory mechanisms are also incorporated in the model. Parameters of the left ventricular model were set to simulate either the normal or failing canine circulation. Pressure and flow waveforms throughout the circulation as well as ventricular pressure and volume were calculated for the normal, failing, and assisted failing circulation. Cardiac oxygen supply and consumption were calculated from the model. They were used as direct indices of cardiac energy supply and utilization to assess the effects of cardiac assistance.

Animals↗

PubMed2006

Computer simulation of wild-type and mutant human cardiac Na+ current.

Long QT syndrome (LQTS) and Brugada syndrome (BrS) are inherited diseases predisposing to ventricular arrhythmias and sudden death. Genetic studies linked LQTS and BrS to mutations in genes encoding for cardiac ion channels. Recently, two novel missense mutations at the same codon in the gene encoding the cardiac Na+ channel (SCN5A) have been identified: Y1795C (causing the LQTS phenotype) and Y1795H (causing the BrS phenotype). Functional studies in HEK293 cells showed that both mutations alter the inactivation of Na+ current and cause a sustained Na+ current upon depolarisation. In this paper, a nine state Markov model was used to simulate the Na+ current in wild-type Na+ cardiac channel and the current alterations observed in Y1795C and Y1795H mutant channels. The model includes three distinct closed states, a conducting open state and five inactivation states (one fast-, two intermediate- and two closed-inactivation). Transition rates between these states were identified on the basis of previously published voltage-clamp experiments. The model was able to reproduce the experimental Na+ current in mutant channels just by altering the assignment of model parameters with respect to wild-type case. Parameter assignment was validated by performing action potential clamp experiments and comparing experimental and simulated I(Na) current. The Markov model was subsequently introduced in the Luo-Rudy model of ventricular myocyte to investigate "in silico" the consequences on the ventricular cell action potential of the two mutations. Coherently with their phenotypes, the Y1795C mutation prolongs the action potential, while the Y1795H mutation causes only negligible changes in action potential morphology.

Action Potentials↗

PubMed2002

Temperature dependence of protein dynamics: computer simulation analysis of neutron scattering properties.

The temperature dependence of the internal dynamics of an isolated protein, bovine pancreatic trypsin inhibitor, is examined using normal mode analysis and molecular dynamics (MD) simulation. It is found that the protein exhibits marked anharmonic dynamics at temperatures of approximately 100-120 K, as evidenced by departure of the MD-derived average mean square displacement from that of the harmonic model. This activation of anharmonic dynamics is at lower temperatures than previously detected in proteins and is found in the absence of solvent molecules. The simulation data are also used to investigate neutron scattering properties. The effects are determined of instrumental energy resolution and of approximations commonly used to extract mean square displacement data from elastic scattering experiments. Both the presence of a distribution of mean square displacements in the protein and the use of the Gaussian approximation to the dynamic structure factor lead to quantified underestimation of the mean square displacement obtained.

Biophysical Phenomena↗

PubMed2000

Computer simulations of glycolytic enzyme interactions with F-actin.

Muscle actin and fructose-1,6-bisphosphate aldolase (aldolase) were chemically crosslinked to produce an 80 kDa product representing one subunit of aldolase linked to one subunit of actin. Hydroxylamine digestion of the crosslinked product resulted in two 40.5 kDa fragments, one that was aldolase linked to the 12 N-terminal residues of actin. Brownian dynamics simulations of muscle aldolase and GAPDH with F-actin (muscle, yeast, and various mutants) estimated the association free energy. Mutations of residues 1-4 of muscle actin to Ala individually or two in combination of the first four residues reduced the estimated binding free energy. Simulations showed that muscle aldolase binds with the same affinity to the yeast actin as to the double mutated muscle actin; these mutations make the N-terminal of muscle actin identical to yeast, supporting the conclusion that the actin N-terminus participates in binding. Because the depth of free energy wells for yeast and the double mutants is less than for native rabbit actin, the simulations support experimental findings that muscle aldolase and GAPDH have a higher affinity for muscle actin than for yeast actin. Furthermore, Brownian dynamics revealed that the lower affinity of yeast actin for aldolase and GAPDH compared to muscle actin, was directly related to the acidic residues at the N-terminus of actin.

Actins↗

PubMed2006

Parameter determination for a computer simulation model of a diver and a springboard.

This study used kinematic data on springboard diving performances to estimate viscoelastic parameters of a planar model of a springboard and diver with wobbling masses in the trunk, thigh, and calf segments and spring dampers acting at the heel, ball, and toe of the foot segment. A subject-specific angle-driven eight-segment model was used with an optimization algorithm to determine viscoelastic parameter values by matching simulations to four diving performances. Using the parameters determined from the matching of a single dive in a simulation of another dive resulted in up to 31% difference between simulation and performance, indicating the danger of using too small a set of kinematic data. However, using four dives in a combined matching process to obtain a common set of parameters resulted in a mean difference of 8.6%. Because these four dives included very different rotational requirements, it is anticipated that the combined parameter set can be used with other dives from these two groups.

Acceleration↗

PubMed2004

Computer simulation of the influence of cellular adhesion on the morphology of the interface between tissues of proliferating and quiescent cells.

We investigate the influence of cellular adhesion on the morphology of the interface between a tissue of proliferating and quiescent cells using the cellular Potts model. We show that a decrease in surface tension changes the morphology of the interface and that only for negative surface tensions cell detachment from the proliferative tissue occurs suggesting that this might be a necessary condition for metastatization in malignant neoplasies.

Algorithms↗

PubMed2006

Interconverting conformations of variants of the human amyloidogenic protein beta2-microglobulin quantitatively characterized by dynamic capillary electrophoresis and computer simulation.

Capillary electrophoretic separation profiles of cleaved variants of beta2-microglobulin (beta2m) reflect the conformational equilibria existing in solutions of these proteins. The characterization of these equilibria is of interest since beta2m is responsible for amyloid formation in dialysis-related amyloidosis and thus is able to attain alternative conformations that lead to irreversible aggregation and precipitation. In this study, we quantitate the increased conformational instability of cleaved beta2m by extracting rate constants and activation energies by simulating the experimental data using a unified theory for dynamic chromatography and dynamic electrophoresis. The results are correlated with the outcome of independent experiments based on mass spectrometric measurement of H/D exchange. This study illustrates that dynamic capillary electrophoresis is suitable for the investigation of the interconversion of protein conformations of amyloidogenic molecules and is not only restricted to ideal model compounds.

Amyloid↗

PubMed1994

Evaluation of the performance of controlled release dosage forms of ticlopidine using in vitro intestinal permeability and computer simulations.

Prototype controlled release formulations of ticlopidine hydrochloride were developed, but when administered to humans, these formulations significantly reduced the bioavailability of intact drug in plasma. In order to examine the intestinal permeability characteristics and gastrointestinal metabolism of 14C-ticlopidine, we employed an in vitro diffusion cell system to directly measure the permeation of ticlopidine across various segments of monkey and rabbit intestine. High pressure liquid chromatography was used to determine the amount of intact ticlopidine on both the mucosal and serosal sides of the intestinal tissue. Simulations based upon the known pharmacokinetics of ticlopidine were conducted using STELLA, a modeling program, to provide insight as to the nature of the decreased bioavailability of these ticlopidine CR dosage forms. These simulations indicate that the absorption of intact ticlopidine is a non-linear phenomena, with inordinately large increases in absorbed intact drug with increases in dose. Conversely, decreases in drug available for immediate absorption, as with the controlled release dosage forms, lead to non-linear decreases in bioavailability. Such a finding is very consistent with the extensive first-pass metabolism suggested from the tissue permeability studies.

Animals↗

PubMed2005

Structure and dynamics of phospholamban in solution and in membrane bilayer: computer simulations.

We have performed molecular dynamics simulations of phospholamban (PLB), a 52-residue integral membrane protein that inhibits calcium ATPase in the cardiac sarcoplasmic reticulum. We present a microscopic description of the structure and dynamics of PLB in solution and membrane environments, based on 10 ns molecular dynamics simulations of PLB in lipid bilayer and 5 ns simulations in methanol and water, and a water-soluble model of PLB in water. Throughout the simulations, PLB retains its "L"shape, with two well-defined helical domains at the N- and C-termini. In the simulations of PLB in methanol and water, the helices were almost perpendicular, with average interhelix angles of 54 +/- 13 degrees and 63 +/-15 degrees , respectively. In the lipid bilayer trajectory, both the interhelix angle and its fluctuations were larger, with an average of 130 +/- 19 degrees and with the transmembrane C-terminal approximately perpendicular to the bilayer plane. The internal dynamics of phospholamban is characterized by large amplitude collective motions of the two helical domains: hinge bending, twisting of both N- and C-terminal helices, and flexing of the C-terminal helix. The central linker of PLB is highly flexible, due mostly to elastic deformations of this region. The simulation results are in good agreement with NMR data on PLB secondary structure and helix orientations in solution, micelles, and lipid bilayers, as well as fluorescence measurements of interdomain distances. Our most interesting findings involve the details of the PLB dynamics, which are difficult to obtain by experimental approaches. Two kinds of motions of the helical domains found in the simulations can clearly have functional roles. The population of conformations with relatively open interdomain angles, as well as large fluctuations of this coordinate in the bilayer, allows the N-terminal helix to come into contact with the PLB binding site on the calcium ATPase, while the presence of twisting motions around its axis enables the helix to orient the correct face to the binding site.

1,2-Dipalmitoylphosphatidylcholine↗