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PubMed1991

Computer simulation and analysis of the reaction pathway of triosephosphate isomerase.

A theoretical approach designed for chemical reactions in the condensed phase is used to determine the energy along the reaction path of the enzyme triosephosphate isomerase. The calculations address the role of the enzyme in lowering the barrier to reaction and provide a decomposition into specific residue contributions. The results suggest that, although Lys-12 is most important, many other residues within 16 A of the substrate contribute and that histidine-95 as the imidazole/imidazolate pair could act as an acid/base catalyst.

Amino Acid Sequence↗

PubMed2006

Multiscale modeling of protein transport in silicon membrane nanochannels. Part 1. Derivation of molecular parameters from computer simulations.

We report in this account our efforts in the development of a novel multiscale simulation tool for integrated nanosystem design, analysis and optimization based on a three-tiered modeling approach consisting of (i) molecular models, (ii) atomistic molecular dynamics simulations, and (iii) dynamical models of protein transport at the continuum scale. In this work we used molecular simulations for the analysis of lysozyme adsorption on a pure silicon surface. The molecular modeling procedures adopted allowed (a) to elucidate the specific mechanisms of interaction between the biopolymer and the silicon surface, and (b) to derive molecular energetic and structural parameters to be employed in the formulation of a mathematical model of diffusion through silicon-based nanochannel membranes, thus filling the existing gap between the nano--and the macroscale.

Adsorption↗

PubMed1997

A computer simulation model for the spread of nosocomial infections caused by multidrug-resistant pathogens.

A Monte Carlo simulation model was developed for the spread of antibiotic-resistant bacteria in hospital units. The model allows for the representation of every patient and staff member. Staff-patient interactions, staff handwashing compliance, admission of colonized patients, and antibiotic use are included in the model. The simulation model provides colonization curves for patients and staff and offers the possibility of simulating different kinds of hospital units. Simulation of the spread of an antibiotic-resistant pathogen in an intensive care unit was performed. We studied the impact of handwashing compliance on colonization. The importance of handwashing in preventing colonization and the influence of admission of colonized patients in perpetuating an epidemic were confirmed by the model. The model offers a new approach to modeling the spread of nosocomial pathogens in hospital units. It allows one to study the impact of infection control measures and represents a valuable educational tool for staff.

Algorithms↗

PubMed2003

Heterogeneous synaptic covering and differential charge transfer sensitivity among the dendrites of a reconstructed abducens motor neurone: correlations between electron microscopic and computer simulation data.

Ultrastructural studies on the synaptology of dendritic arborizations of motoneurones have been problematic because dendrites are very thin in relation to their great length, and most of the studies on this topic have therefore dealt with only small parts of the dendritic tree. Here we compared the ultrastructural characteristics of the axon terminals distributed along the various dendrites of a single motoneurone. For this purpose, the light microscopic 3D reconstruction of the dendritic arborization of an intracellularly labelled abducens motoneurone was combined with an electron microscopic analysis of its synaptic contacts. Dendritic profiles were randomly sampled along the various dendrites and the axon terminals they received were classified on the basis of their ultrastructural features and their GABA-immunoreactivity. It emerged that the various dendrites differed according to the type and local arrangement of their synaptic inputs. Our second aim was to incorporate the morphological data obtained into a model giving the charge transfer effectiveness T(x) of the dendritic sites. The sensitivity S(x) of T(x) to changes in the membrane resistivity (Rm) simulating various levels of tonic synaptic activity was calculated. It turned out that both the proximal and distal regions of the dendritic arborization have a dense synaptic covering and a weak sensitivity to changes in the Rm, whereas the intermediate dendrites have a sparse synaptic covering and a high sensitivity to changes in tonic synaptic activity. This pattern of organisation might mediate the "gating" of a population of synapses covering some dendritic regions in a state-dependent fashion.

Abducens Nerve↗

PubMed1995

Computer simulation of nerve growth cone filopodial dynamics for visualization and analysis.

The neuronal growth cone plays a fundamental role in nerve development and regeneration. A sensory-motile structure, it determines the path of axonal extension through its interactions with the extracellular environment, ultimately directing the formation of functional connections in the nervous system. Though several mechanisms of interaction have been proposed, these have been difficult to describe quantitatively due to the complexity of growth cone behavior, as manifested in the randomly and rapidly changing shape of the growth cone. The application of mathematical techniques to model growth cone shape and motility in terms of underlying processes represents a promising approach with untapped potential for helping to unravel this complexity while revealing new insights into axonal pathfinding events. This paper presents a simulation model for filopodial dynamics, a primary feature of the motile growth cone. The model produces realizations of dynamic filopodial structure on representative growth cones for a given set of model parameters, which include the rates of filopodial initiation, extension, and retraction, filopodial length at maximum extension, and angular orientation. These parameters are based on recent experimental characterization of filopodial dynamics [Buettner et al., 1994: Dev. Biol. 163:407-422]. The mathematical relationship between the model parameters and average filopodial number and length per growth cone is described, and the contribution of individual parameters to overall filopodial morphology is illustrated both visually and numerically. In addition, the model is used to simulate filopodial encounter with a target for various conditions of filopodial dynamics. The result is characterized in terms of a mean encounter time for a population of growth cones and provides an indication of the effect of individual parameters of filopodial dynamics on the encounter process. Future experimental testing will be required to develop the model further. However, in its current form, the model enables a first approximation analysis of many hypothesis of growth cone migration and pathfinding and offers insight into the the underlying mechanisms of nerve growth and regeneration.

Cell Size↗

PubMed2005

Perinatal maturation of the respiratory rhythm generator in mammals: from experimental results to computational simulation.

The survival of neonatal mammals requires a correct function of the respiratory rhythm generator (RRG), and therefore, the processes that control its prenatal maturation are of vital importance. In humans, lambs and rodents, foetal breathing movements (FBMs) occur early during gestation, are episodic, sensitive to bioamines, central hypoxia and inputs from CNS upper structures, and evolve with developmental age. In vitro, the foetal rodent RRG studied in preparations where the upper CNS structures are lacking continuously produces a rhythmic command, which is sensitive to hypoxia and bioaminergic inputs. The rhythm is slow with variable periods 4 days before birth. It becomes faster 2 days before birth, similar to the postnatal rhythm. Compelling evidence suggests that a region of the RRG called the preBötzinger complex (PBC) contains respiratory pacemaker neurones which play a primary role in perinatal rhythmogenesis. Although the RRG functions during early gestation, no pacemakers are found in the putative PBC area and its electrical stimulation and lesion do not affect the early foetal rhythm. To know whether the early foetal and perinatal rhythms originate from either pacemaker neurones or network connection properties, and to know which maturational processes might explain the appearance of PBC pacemakers and the rhythm increase during perinatal development, we computationally modelled maturing RRG. Our model shows that both network noise and persistent sodium conductance are crucial for rhythmogenesis and that a slight increase in the persistent sodium conductance can solve the pacemaker versus network dilemma in a noisy network.

Animals↗

PubMed2003

Computer simulations of membrane protein folding: structure and dynamics.

A lattice model of membrane proteins with a composite energy function is proposed to study their folding dynamics and native structures using Monte Carlo simulations. This model successfully predicts the seven helix bundle structure of sensory rhodopsin I by practicing a three-stage folding. Folding dynamics of a transmembrane segment into a helix is further investigated by varying the cooperativity in the formation of alpha helices for both random folding and assisted folding. The chain length dependence of the folding time of a hydrophobic segment to a helical state is studied for both free and anchored chains. An unusual length dependence in the folding time of anchored chains is observed.

Algorithms↗

PubMed1989

Computer simulation of the hydrostatic skeleton. The physical equivalent, mathematics and application to worm-like forms.

The functional principles of a hydrostatic skeleton were combined to obtain a physical model which includes geometry, number and length-tension relationships of the elastic elements in the body wall, internal volume and internal pressure. The model skeleton with pre-set internal volume assumes a certain shape and develops a specific internal pressure in order to minimize the potential energy stored in the elastic elements. This shape is calculated as equilibrium state by using finite element methods and optimization techniques. This model is flexible enough to accommodate different geometries and length-tension-relationships of the elastic elements. Presently, the model is implemented with linear length-tension relationships and certain geometrical restrictions, such as uniform width over the entire animal, and rectangular cross sections; the general case is outlined. First simulations with the "unit-worm" yield stable solutions, i.e. stable shapes for all combinations of parameters tested so far. They define the conditions for bringing all muscles to an optimal operating point. We detected a pressure maximum with increasing volume, assessed the contribution of circular muscles to bending, and determined the shapes of animals with different muscle activations in each body half (Chapman-matrix). We summarize our results by the volume rule and stabilization rule, two simple concepts which predict changes in shape as the result of muscle activation.

Animals↗

PubMed2006

Full configuration interaction computer simulation study of the thermodynamic and kinetic stability of hydrated dielectrons.

The hydrated electron is a unique solvent-supported state comprised of an excess electron that is confined to a cavity by the surrounding water. Theoretical studies have suggested that two-electron solvent-supported states also can be formed; in particular, simulations indicate that two excess electrons could pair up and occupy a single cavity, forming a so-called hydrated dielectron. Although hydrated dielectrons have not been observed directly by experiment, their existence has been posited to explain the lack of an ionic strength effect in hydrated electron bimolecular annihilation [Schmidt, K. H.; Bartels, D. M. Chem. Phys. 1995, 190, 145]. To determine whether dielectrons may be created in the laboratory, we use thermodynamic integration (TI), combined with mixed quantum/classical molecular dynamics simulation, to examine the thermodynamic stability of hydrated electrons and dielectrons. For the dielectron calculations, we solve the two-electron quantum problem using full configuration interaction. Our results suggest that hydrated dielectrons are thermodynamically unstable relative to separated (single) hydrated electrons, although we also show that increasing the pressure could drive the equilibrium toward the formation of dielectrons. Because the simulations suggest that hydrated dielectrons are kinetically stable, we also examine a scenario for creating metstable, nonequilibrium populations of dielectrons, which involves the capture of a newly injected electron by a preexisting, equilibrated hydrated electron. These calculations, which allow for the full nonadiabatic relaxation of the injected electron, show that hydrated electrons may indeed act as trapping sites for unequilibrated electrons, so that capture may be a viable mechanism for creating dielectrons. We suggest possible experimental procedures to create such nonequilibrium hydrated dielectrons using either pulse radiolysis or ultrafast spectroscopic techniques.

Computer Simulation↗

PubMed2005

Computer simulation of explicit proton translocation in cytochrome c oxidase: the D-pathway.

Proton translocation in the D-pathway of cytochrome c oxidase has been studied by a combination of classical molecular dynamics and the multistate empirical valence bond methodology. This approach allows for explicit Grotthuss proton hopping between water molecules. According to mutagenesis experiments, the role of proton donor/acceptor along the D-pathway is carried by the highly conserved residue Glu-242. The present multistate empirical valence bond simulations indicate that the protonation/deprotonation state of Glu-242 is strongly coupled to the distance of proton propagation in the D-pathway. The proton was seen to travel the full length of the D-pathway when Glu-242 was deprotonated; however, it was trapped halfway along the path when Glu-242 was protonated. Further investigation in terms of both proton dynamical properties and free energy calculations for the pathway of proton transport provides evidence for a two-step proton transport mechanism in the D-pathway.

Animals↗

PubMed1993

A computer simulation of the non-Newtonian blood flow at the aortic bifurcation.

A two-dimensional numerical model was developed to determine the effect of the non-Newtonian behavior of blood on a pulsatile flow at the aortic bifurcation. The blood rheology was described by a weak-form Casson equation. The successive-over-relaxation (SOR) method was used to solve both the vorticity and Poisson equations numerically. It was disclosed that the non-Newtonian property of blood did not drastically change the flow patterns, but caused an appreciable increase in the shear stresses and a slightly higher resistance to both flow separations and the phase shifts between flow layers.

Aorta, Abdominal↗

PubMed1993

The use of an enzyme single fiber reactor in the study of leukemic cell proliferation: in vitro experiments and computer simulation.

This paper describes the use of an immobilized enzyme reactor in the study of the in vitro effects of lysine deprivation on leukemic blood. L-lysine alpha-oxidase is immobilized in a single hollow fiber reactor to remove lysine from the blood of sheep infected by BLV. The treatment relies on the higher sensitivity of leukemic cells to nutrient depletion than that of normal cells. A population balance model is used to describe the changes in the leukocyte proliferative capacity after treatment. Additionally, preliminary data from in vitro tests with human blood demonstrate the potential of L-lysine alpha-oxidase and the enzymatic reactor in treating leukemia.

Amino Acid Oxidoreductases↗

PubMed2002

Bundles consisting of extended transmembrane segments of Vpu from HIV-1: computer simulations and conductance measurements.

Part of the genome of the human immunodeficiency virus type 1 (HIV-1) encodes for a short membrane protein Vpu, which has a length of 81 amino acids. It has two functional roles: (i) to downregulate CD4 and (ii) to support particle release. These roles are attributed to two distinct domains of the peptide, the cytoplasmic and transmembrane (TM) domains, respectively. It has been suggested that the enhanced particle release function is linked to the ion channel activity of Vpu, with a slight preference for cations over anions. To allow ion flux across the membrane Vpu would be required to assemble in homooligomers to form functional water-filled pores. In this study molecular dynamics simulations are used to address the role of particular amino acids in 4, 5, and 6 TM helix bundle structures. The helices (Vpu(6-33)) are extended to include hydrophilic residues such as Glu, Tyr, and Arg (EYR motif). Our simulations indicate that this motif destabilizes the bundles at their C-terminal ends. The arginines point into the pore to form a positive charged ring that could act as a putative selectivity filter. The helices of the bundles adopt slightly higher average tilt angles with decreasing number of helices. We also suggest that the helices are kinked. Conductance measurements on a peptide (Vpu(1-32)) reconstituted into lipid membranes show that the peptide forms ion channels with several conductance levels.

Amino Acid Sequence↗

PubMed2002

Computer simulation of 57Fe bleomycin auger effects in DNA.

The antibiotic bleomycin binds to the DNA and induces double strand breaks (DSBs). To increase the cleavages. 57Fe is used to form a complex suitable for Mössbauer effect. The de-excitation of the resonant excited 57Fe nucleus releases Auger electrons and X rays. The goal of this work is to evaluate the increase in yield of DSBs due to the 57Fe, using Monte Carlo simulation methods. Particles spectra and the yields of single strand breaks (SSBs) and DSBs were calculated by considering direct events on DNA and reaction of all radical species generated in the radiolysis of its environment. The Auger spectrum shows a large number of electrons with energies below 100 eV, mainly responsible for direct damage, while another group around 600-700 eV is responsible for indirect damage effects. Bleomycin receives about one fourth of the energy deposited in DNA and an average of 0.65 DSB per de-excitation is observed.

Antibiotics, Antineoplastic↗

PubMed2004

High-resolution computer simulation of the dynamics of isoelectric focusing of proteins.

A dynamic electrophoresis simulator that accepts 150 components and voltage gradients employed in the laboratory was used to provide a detailed description of the focusing process of proteins under conditions that were hitherto inaccessible. High-resolution focusing data of four hemoglobin variants in a convection-free medium are presented for pH 3-10 and pH 5-8 gradients formed with 20 and 40 carrier ampholytes/pH unit, respectively. With 300 V/cm, focusing is shown to occur within 5-10 min, whereas at 600 V/cm separation is predicted to be complete between 2.5 and 5 min. The time interval required for focusing of proteins is demonstrated to be dependent on the input protein charge data and, however less, on the properties of the carrier ampholytes. The simulation data reveal that the number of transient protein boundaries migrating from the two ends of the column towards the focusing positions is equal to the number of sample components. Each protein is being focused via the well-known double-peak approach to equilibrium, a process that is also characteristic for focusing of the carrier ampholytes. The predicted focusing dynamics for the hemoglobin variants in pH 3-10 and pH 5-8 gradients are shown to qualitatively agree well with experimental data obtained by whole-column optical imaging.

Computer Simulation↗

PubMed2002

Direct observation of the folding and unfolding of a beta-hairpin in explicit water through computer simulation.

The cooperative folding and unfolding of a beta-hairpin structure are observed in explicit water at native folding conditions through self-guided molecular dynamics simulation. The folded structure agrees excellently with the NMR NOE data. After going through a fully hydrated state, the peptide folds into a beta-hairpin structure in a highly cooperative process. During the folding process it is observed that side chain interaction occurs first, while intrapeptide hydrogen bonds only form at the final stage. On the contrary, the unfolding process starts with the breaking of interstrand hydrogen bonds. Energetic analysis indicates that the driving force of the folding is the intrapeptide interaction, while the solvent interaction opposes the folding.

Amino Acid Sequence↗

PubMed2001

Experimental and computational simulation of total hip arthroplasty dislocation.

Other than fatal pulmonary embolism and deep infection, dislocation following total hip replacement remains probably the most vexing complication to patient and surgeon. Subluxation and dislocation are complex, poorly understood phenomena. Many important questions in this area unfortunately do not lend themselves well to clinical or registry study. Appropriate realistic laboratory models have been lacking. This article synthesizes new work undertaken independently by two groups of biomechanical investigators using very different, but complimentary, methodologies to study the mechanisms of dislocation, and especially the influence of specific design and surgical variables.

Arthroplasty, Replacement, Hip↗

PubMed1990

The dynamics of HIV spread: a computer simulation model.

Mathematical modeling of the AIDS pandemic has been limited by the difficulty of satisfactorily representing the marked behavioral heterogeneity that characterizes the various populations at risk. We propose an approach which models the spread of infection as a discrete-event simulation using SIMSCRIPT, a powerful simulation language. The program developed provides sufficient flexibility to adequately represent and study a wide range of risk-group dynamics. Using this tool we have verified the May-Anderson prediction relating contact rate heterogeneity to the rate of HIV spread. We have also been able to assess the sensitivity of the model to the particular choice of distribution for contact rates, disease stage durations, and intercontact intervals. It is thought that this approach will permit the empirical testing of hypotheses which do not lend themselves to a purely mathematical treatment.

Acquired Immunodeficiency Syndrome↗