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PubMed2002

Slide track analysis of the relative motion between femoral head and acetabular cup in walking and in hip simulators.

Joint simulators are important tools in wear studies of prosthetic joint materials. The type of motion in a joint simulator is crucial with respect to the wear produced. It is widely accepted that only multidirectional motion yields realistic wear for polyethylene acetabular cups. Multidirectionality, however, is a wide concept. The type of multidirectional motion varies considerably between simulators, which may explain the large differences in observed wear rates. At present, little is known about the relationship between the type of multidirectional motion and wear. One illustrative way to compare the motions of various hip simulators is to compute tracks made on the counterface by selected points of the surface of the femoral head and acetabular cup due to the cyclic relative motion. A new computation method, based on Euler angles, was developed, and used to compute slide tracks for the three-axis motion of the hip joint in walking, and for two hip simulators, the HUT-3 and the biaxial rocking motion. The slide track patterns resulting from the gait waveforms were found to be similar to those produced by the HUT-3 simulator. This paper is the first to include a verification of the computed simulator tracks. The tracks were verified in the two simulators using sharp pins, embedded in acetabular cups, engraving distinct grooves onto the femoral heads. The engravings were identical to the computed tracks. The results clearly differed from earlier computations by another research group. This study is intended to start a thorough investigation of the relationship between the type of multidirectional motion and wear.

Acetabulum↗
PubMed2003

Effective use of human simulators in surgical education.

BACKGROUND: We initiated a teaching module utilizing a human simulator midway through 2001-2002 to improve student skills specific to the evaluation of patients in shock during a required clerkship in surgery for fourth-year medical students. We tested the hypothesis that student skills would improve after implementation of this module and identified factors that predicted student performance. MATERIALS AND METHODS: Students (n = 86) chose one of two hospital sites for a clerkship that focuses on the care of acutely ill surgical patients. A case-based lecture focusing on the diagnosis and management of a patient in shock was replaced midway through the academic year by a simulator session with a computerized life-sized mannequin. A standardized clinical final evaluation (OSCE) was used to assess student skills. We evaluated the effect of the simulator session and other factors on student exam performance using univariate and multivariate analysis. RESULTS: The site of the clerkship and the simulator session were significant factors affecting the OSCE score identified by ANOVA, P < 0.05. A stepwise multiple regression analysis testing the effect of simulator module, site, time of year, prior NBME subject exam, and prior OSCE during the third year clerkship identified that the simulator module was the only independent factor that modeled performance on all shock stations, P < 0.01. CONCLUSIONS: In a clerkship that already emphasized faculty facilitated case-based learning, the use of a teaching module employing a human simulator significantly improved test scores. This study supports the efficacy of human simulators to improve student skills related to the management of complex critically ill patients.

Clinical Clerkship↗
PubMed1997

Computer simulation of the enteric neural circuits mediating an ascending reflex: roles of fast and slow excitatory outputs of sensory neurons.

Recent electrophysiological studies of the properties of intestinal reflexes and the neurons that mediate them indicate that the intrinsic sensory neurons may transmit to second order neurons via either fast (30-50 ms duration) or slow (10-60 s duration) excitatory synaptic potentials or both. Which of these possible modes of transmission is involved in the initiation of motility reflexes has not been determined and it is not clear and what the consequences of the different forms of synaptic transmission would be for the properties of the reflex pathways. In the present study, this question has been addressed by the use off a suite of computer programs, Plexus, which was written to simulate the activity of the neurons of the enteric nervous system during intestinal reflexes. The programs construct a simulated enteric nerve circuit based on anatomical and physiological data about the number, functions and interconnections of neurons involved in the control of motility. The membrane potentials of neurons are calculated individually from physiological data about the reversal potentials and membrane conductances for Na+, K+ and Cl-. Synaptic potentials are simulated by changes in specific conductances based on physiological data. The results of each simulation are monitored by recording the membrane potentials of up to 16 separate defined neurons and by recording the summed activity of whole classes of neurons as a function of time and location in the stimulated network. The present series of experiments simulated the behaviour of a network consisting of 18,898 sensory neurons and 3708 ascending interneurons after 75% of the sensory neurons lying in the anal 10 mm of a 30 mm long segment of small intestine were stimulated once. The results were compared with electrophysiological data recorded from myenteric neurons during ascending reflexes evoked either by distension or mechanical stimulation of the mucosa. When transmission from sensory neurons to ascending interneurons was via fast excitatory synaptic potentials, the latencies and durations of the simulated responses were too brief to match the electrophysiologically recorded responses. When transmission from sensory neurons was via slow excitatory synaptic potentials, the latencies were very similar to those recorded physiologically, but the durations of the stimulated responses were much longer than seen in physiological experiments. The latencies and durations of simulated and physiologically recorded responses matched only when the firing of ascending interneurons was limited to the beginning of a slow excitatory synaptic (in this study by limiting the duration of the decrease in K+ conductance). The simulation provided several physiologically testable predictions, indicating that Plexus is an important tool for the investigation of the properties and behaviour of the enteric nervous system.

Computer Simulation↗
PubMed2001

Algorithmic 3D simulation of breast calcifications for digital mammography.

We present a framework for algorithmic three-dimensional simulation of breast calcifications. The simulated calcifications can be viewed from any angle at a higher spatial resolution than currently available for digital mammography, and they can be placed onto a simulated or real mammographic background to provide example cases for computers and radiologists. In order to simulate calcification clusters, we also show how to simulate duct networks and terminal ductal lobular units. We evaluated the model with a double-blind evaluation of 60 cases with four experienced radiologists by mixing 30 cases of simulated calcification clusters on a real or simulated mammographic background with 30 cases of real breast calcification clusters digitized at a spatial resolution of 15 microm from high-resolution radiographs of 5 mm slices of breast specimens. The results indicate that the majority of the 2D projections of the 3D simulated calcifications compare favorably with the radiographic images of real breast calcifications.

Algorithms↗
PubMed1999

Measuring and developing suturing technique with a virtual reality surgical simulator.

BACKGROUND: We have developed an interactive virtual reality (VR) surgical simulator for the training and assessment of suturing technique. The surgical simulator is comprised of surgical tools with force feedback, a 3-dimensional graphics visual display of the simulated surgical field, physics-based computer simulations of the tissues and tools, and software to measure and evaluate the trainee's performance. STUDY DESIGN: This study uses the simulator to measure and compare the skills of 8 experienced vascular surgeons versus 12 medical students when performing a virtual reality suturing task. Eight parameters of the suturing task were measured: total tissue damage, accuracy of needle puncture, peak tissue tearing force, time to complete the task, damage to the surface of the tissue, angular error in needle technique, total distance traveled by the tool tip, and a measure of overall error. Three test conditions (dominant hand, nondominant hand, and 3-dimensional needle guide) were tested. Statistical significance was defined as a univariate two-sided p value < or = 0.05. RESULTS: The surgeons' average performance was significantly better than the students' average performance for three of the measured parameters (total tissue damage, time to complete the task, and total distance traveled by the tool tip) for each of the test conditions. For the test condition most similar to surgery (using the dominant hand to suture) one additional parameter was also significantly different (the measure of overall error). The medical students showed improvements for 6 of the 7 parameters for which the users received feedback during the training process. The surgeons also had significant improvement for 4 of the 7 parameters. The students had a larger improvement than the surgeons for 6 of the parameters, but these differences were not statistically significant. CONCLUSIONS: Data indicate differences between surgeon and nonsurgeon performance and in improvement in performance with training. One possible explanation for the superior performance of the surgeons is that their suturing skills applied well to the simulated suturing task. Additional research is required to confirm or deny the similarity between actual and simulated surgical tasks and the relevance of virtual reality surgical simulation to surgical skill assessment and training.

Computer Simulation↗
PubMed1995

Comparison of MD simulations and NMR experiments for hen lysozyme. Analysis of local fluctuations, cooperative motions, and global changes.

Three 1000 ps molecular dynamics simulations of hen lysozyme have been compared with a range of experimental NMR parameters in order to gain insight into the dynamical properties of the protein and to assess the significance of the motional events observed in the simulations. The simulations, one in vacuum and two in water, were used to estimate interproton distances (for comparison with NOE data), 3JHN alpha and 3J alpha beta coupling constants and 1H-15N order parameters. Comparison of these values with experimental data, particularly NOEs, enabled force field-induced changes to the structure during the simulations to be recognized. It has been shown, however, that these changes can be largely eliminated by slight modifications to the force field. Using a simulation performed in water with this modified force field, it has been found that 1H-15N order parameters calculated for side chain groups in particular correlate well with experimental values and reflect the substantial dependence of these motional properties on the environment, particularly surface exposure, in which the side chain is found. In this case, the simulation then provides models for the motional processes giving rise to the observed experimental data. The results indicate that the order parameter values reflect primarily the number of torsion angles about which rotameric interchange occurs. In addition to local motions, the two different domains of lysozyme have been found to behave differently in the simulations. Possible implications of these differences for the interpretation of unfolding simulations and experimental observations of folding intermediates for lysozyme are discussed.

Animals↗
PubMed1996

A refined model of the thyrotropin-releasing hormone (TRH) receptor binding pocket. Novel mixed mode Monte Carlo/stochastic dynamics simulations of the complex between TRH and TRH receptor.

Previous mutational and computational studies of the thyrotropin-releasing hormone (TRH) receptor identified several residues in its binding pocket [see accompanying paper, Perlman et al. (1996) Biochemistry 35, 7643-7650]. On the basis of the initial model constructed with standard energy minimization techniques, we have conducted 15 mixed mode Monte Carlo/stochastic dynamics (MC-SD) simulations to allow for extended sampling of the conformational states of the ligand and the receptor in the complex. A simulated annealing protocol was adopted in which the complex was cooled from 600 to 310 K in segments of 30 ps of the MC-SD simulations for each change of 100 K. Analysis of the simulation results demonstrated that the mixed mode MC-SD protocol maintained the desired temperature in the constant temperature simulation segments. The elevated temperature and the repeating simulations allowed for adequate sampling of the torsional space of the complex with successful conservation of the general structure and good helicity of the receptor. For the analysis of the interaction between TRH and the binding pocket, TRH was divided into four groups consisting of pyroGlu, His, ProNH2, and the backbone. The pairwise interaction energies of the four separate portions of TRH with the corresponding residues in the receptor provide a physicochemical basis for the understanding of ligand-receptor complexes. The interaction of pyroGlu with Tyr106 shows a bimodal distribution that represents two populations: one with a H-bond and another without it. Asp195 was shown to compete with pyroGlu for the H-bond to Tyr106. Simulations in which Asp195 was interacting with Arg283, thus removing it from the vicinity of Tyr106, resulted in a stable H-bond to pyroGlu. In all simulations His showed a van der Waals attraction to Tyr282 and a weak electrostatic repulsion from Arg 306. The ProNH2 had a strong and frequent H-bonding interaction with Arg306. The backbone carbonyls show a frequent H-bonding interaction with the OH group of Tyr282 and strong, often multiple, interactions with Arg306. Three structures, which maintained these interactions simultaneously, were selected as candidates for ligand-receptor complexes. These show persistent interactions of TRH with Ile 109 and Ile 116 in HX 3 and with Tyr310 and Ser313 in HX 7, which will be tested to refine the structure of the ligand-receptor complex. The superposition of the three structures shows the extent of structural flexibility of the receptor and the ligand in the complex. The backbone of TRH inside the receptor is in an alpha-helical conformation, suggesting that the receptor, through its interaction with the ligand, provides the energy required for the conformational change in the ligand from an extended to the folded form.

Amino Acid Sequence↗
PubMed2006

Insertion and assembly of membrane proteins via simulation.

Interactions of lipids are central to the folding and stability of membrane proteins. Coarse-grained molecular dynamics simulations have been used to reveal the mechanisms of self-assembly of protein/membrane and protein/detergent complexes for representatives of two classes of membrane protein, namely, glycophorin (a simple alpha-helical bundle) and OmpA (a beta-barrel). The accuracy of the coarse-grained simulations is established via comparison with the equivalent atomistic simulations of self-assembly of protein/detergent micelles. The simulation of OmpA/bilayer self-assembly reveals how a folded outer membrane protein can be inserted in a bilayer. The glycophorin/bilayer simulation supports the two-state model of membrane folding, in which transmembrane helix insertion precedes dimer self-assembly within a bilayer. The simulations also suggest that a dynamic equilibrium exists between the glycophorin helix monomer and dimer within a bilayer. The simulated glycophorin helix dimer is remarkably close in structure to that revealed by NMR. Thus, coarse-grained methods may help to define mechanisms of membrane protein (re)folding and will prove suitable for simulation of larger scale dynamic rearrangements of biological membranes.

Bacterial Outer Membrane Proteins↗
PubMed2002

Teaching invasive perinatal procedures: assessment of a high fidelity simulator-based curriculum.

OBJECTIVE: Learning curves pose a difficult problem in the teaching of technical skills: how do you teach procedural skills without compromising patients' health? A simulator-based curriculum has been designed to minimize the risks to patients undergoing amniocentesis by shifting the learning curve away from patients and into the laboratory. This study evaluated the effectiveness of a high-fidelity simulator-based curriculum in improving the performance of amniocentesis by obstetric trainees. DESIGN: Thirty trainees received a course on the practice of amniocentesis. The curriculum consisted of a lecture, a syllabus, and a hands-on training session with the simulator. Pre- and post-training performance were evaluated with two rating scales. Training and performance evaluation were completed using the same simulator. The effectiveness of the simulator-based workshop and the effect of year of training were assessed using a two-way analysis of variance. RESULTS: Performance scores improved from a mean score of 55% to 94% using checklist scoring and from 57% to 88% using global ratings. The two-way analysis of variance revealed a significant effect of training (F1,60 = 43.57; P < 0.001) accounting for 45% of the variance in scores, and a significant effect of experience level (F2,60 = 9.16; P < 0.001) accounting for 25% of the variance in scores. CONCLUSIONS: A comprehensive curriculum based on a high-fidelity simulator was effective at improving skills demonstrated on the simulator. The challenge remains to establish that skills acquired on a simulator are transferable to the clinical setting.

Amniocentesis↗
PubMed2005

Virtual reality colonoscopy simulation: a compulsory practice for the future colonoscopist?

BACKGROUND AND STUDY AIM: As for any manual procedure, the learning curves for medical interventions can have undesirable phases, occurring mostly in the early experience of applying a technique. There have been impressive advances in endoscopic procedures during recent years, and there is an emerging trend that the number of procedures is increasing in parallel with these. In addition, the introduction of screening programs for colorectal cancer will also increase the numbers of procedures needed. Recent developments in medical simulation seem promising with regard to the possibility of "training out" undesirable parts of the learning curve outside the operating room. The aim of this study was to investigate whether the use of the AccuTouch flexible endoscopy simulator improves the early part of the learning curve in colonoscopy training. METHOD: 12 endoscopy trainees, 10 surgeons and two medical gastroenterologists, all with experience in gastroscopy but with no specific colonoscopy experience, were randomly assigned to either simulator training or to a control group. They all received the same theoretical study package and the training group practiced with the AccuTouch colonoscopy simulator until a predefined expert level of performance was reached. All trainees performed their first ten individual colonoscopies described in detail in a separate protocol. RESULTS: Trainees in the simulator-trained group performed significantly better (P=0.0011) and managed to reach the cecum in 52% of their cases (vs. 19% in the control group), and were 4.53 times more likely to succeed compared with the controls. Additionally, there was a significantly shorter procedure time and less patient discomfort in the hands of the simulator-trained group. CONCLUSION: Skills acquired using the AccuTouch simulator transfer well into the clinical colonoscopy environment. The results of this trial clearly support the plan to integrate simulator training into endoscopic education curricula.

Adult↗
PubMed2006

Brownian dynamics simulations with stiff finitely extensible nonlinear elastic-Fraenkel springs as approximations to rods in bead-rod models.

A very stiff finitely extensible nonlinear elastic (FENE)-Fraenkel spring is proposed to replace the rigid rod in the bead-rod model. This allows the adoption of a fast predictor-corrector method so that large time steps can be taken in Brownian dynamics (BD) simulations without over- or understretching the stiff springs. In contrast to the simple bead-rod model, BD simulations with beads and FENE-Fraenkel (FF) springs yield a random-walk configuration at equilibrium. We compare the simulation results of the free-draining bead-FF-spring model with those for the bead-rod model in relaxation, start-up of uniaxial extensional, and simple shear flows, and find that both methods generate nearly identical results. The computational cost per time step for a free-draining BD simulation with the proposed bead-FF-spring model is about twice as high as the traditional bead-rod model with the midpoint algorithm of Liu [J. Chem. Phys. 90, 5826 (1989)]. Nevertheless, computations with the bead-FF-spring model are as efficient as those with the bead-rod model in extensional flow because the former allows larger time steps. Moreover, the Brownian contribution to the stress for the bead-FF-spring model is isotropic and therefore simplifies the calculation of the polymer stresses. In addition, hydrodynamic interaction can more easily be incorporated into the bead-FF-spring model than into the bead-rod model since the metric force arising from the non-Cartesian coordinates used in bead-rod simulations is absent from bead-spring simulations. Finally, with our newly developed bead-FF-spring model, existing computer codes for the bead-spring models can trivially be converted to ones for effective bead-rod simulations merely by replacing the usual FENE or Cohen spring law with a FENE-Fraenkel law, and this convertibility provides a very convenient way to perform multiscale BD simulations.

Algorithms↗
PubMed2007

Convergence and sampling efficiency in replica exchange simulations of peptide folding in explicit solvent.

Replica exchange methods (REMs) are increasingly used to improve sampling in molecular dynamics (MD) simulations of biomolecular systems. However, despite having been shown to be very effective on model systems, the application of REM in complex systems such as for the simulation of protein and peptide folding in explicit solvent has not been objectively tested in detail. Here we present a comparison of conventional MD and temperature replica exchange MD (T-REMD) simulations of a beta-heptapeptide in explicit solvent. This system has previously been shown to undergo reversible folding on the time scales accessible to MD simulation and thus allows a direct one-to-one comparison of efficiency. The primary properties compared are the free energy of folding and the relative populations of different conformers as a function of temperature. It is found that to achieve a similar degree of precision T-REMD simulations starting from a random set of initial configurations were approximately an order of magnitude more computationally efficient than a single 800 ns conventional MD simulation for this system at the lowest temperature investigated (275 K). However, whereas it was found that T-REMD simulations are more than four times more efficient than multiple independent MD simulations at one temperature (300 K) the actual increase in conformation sampling was only twofold. The overall gain in efficiency using REMD resulted primarily from the ordering of different conformational states over temperature, as opposed to a large increase of conformational sampling. It is also shown that in this system exchanges are accepted primarily based on (random) fluctuations within the solvent and are not strongly correlated with the instantaneous peptide conformation raising questions in regard to the efficiency of T-REMD in larger systems.

Computer Simulation↗
PubMed2002

On the simulation of protein folding by short time scale molecular dynamics and distributed computing.

There are proposals to overcome the current incompatibilities between the time scales of protein folding and molecular dynamics simulation by using a large number of short simulations of only tens of nanoseconds (distributed computing). According to the principles of first-order kinetic processes, a sufficiently large number of short simulations will include, de facto, a small number of long time scale events that have proceeded to completion. But protein folding is not an elementary kinetic step: folding has a series of early conformational steps that lead to lag phases at the beginning of the kinetics. The presence of these lag phases can bias short simulations toward selecting minor pathways that have fewer or faster lag steps and so miss the major folding pathways. Attempts to circumvent the lags by using loosely coupled parallel simulations that search for first-order transitions are also problematic because of the difficulty of detecting transitions in molecular dynamics simulations. Nevertheless, the procedure of using parallel independent simulations is perfectly valid and quite feasible once the time scale of simulation proceeds past the lag phases into a single exponential region.

Computer Simulation↗
PubMed2005

Identifying and engineering ion pairs in adenylate kinases. Insights from molecular dynamics simulations of thermophilic and mesophilic homologues.

Molecular dynamics simulations were performed to study thermal stabilization of proteins via electrostatic interactions of ion pairs. Dynamic motions of four ion pairs previously proposed to be important in thermal stability of adenylate kinase from the thermophile Bacillus stearothermophilus were monitored during the simulation. One of the four ion pairs identified in the crystal structure, Lys180-Asp114, was not maintained in close contact suggesting that the ion pair does not contribute to thermal stability. Among the other three ion pairs, the ion pair Arg116-Glu198 was proposed to be the most important for stability. To predict behaviors of the ion pairs when engineered into a mesophilic homologue to increase stability, in silico mutants of adenylate kinase from the mesophile Bacillus subtilis were generated, and their molecular dynamics simulations were carried out. The ion pairs in the mutant simulations displayed similar behaviors to those in the simulation of the thermophilic protein. To validate the results of the simulations experimentally, the same mutants were produced in vitro and their thermal stabilities were measured using differential scanning calorimetry. In agreement with the simulations, the Lys180-Asp114 did not result in any increase in stability by itself or additive effect with other ion pairs, whereas a mutant with the Arg116-Glu198 exhibited the highest stability among the mutants having one of the four ion pairs. These results provide specific knowledge about stability in adenylate kinases and more generally suggest that molecular dynamics simulations can provide valuable information for identifying and engineering ion pairs.

Adenylate Kinase↗
PubMed2006

Applying theory to practice in undergraduate education using high fidelity simulation.

High-fidelity patient simulation allows students to apply their theoretical knowledge of pharmacology and physiology to practice. The purpose of this study was to determine if experiential education using high-fidelity simulation improves undergraduate performance scores on simulation-based and written examinations. After receiving research ethics board approval, students completed a consent form and then answered a ten question multiple-choice quiz to identify their knowledge regarding the management of cardiac arrhythmias. Four simulation scenarios were presented and students worked through each scenario as a team. Faculty facilitated the sessions and feedback was given using students' videotaped performances as a template for discussion. Performance evaluation scores using predetermined checklists and global rating scales were completed. Students then reviewed the American Heart Association guidelines for the management of unstable cardiac arrhythmias. The afternoon session involved repetition of the four case scenarios with the same teams involved but different team leaders. Students then repeated the quiz they received in the morning. Descriptive statistics, paired t-test and repeated measures analysis of variance (ANOVA) were used to analyse results. Two hundred and ninety-nine students completed the study. There was a statistically significant improvement in performance on the pharmacology written test. Simulation team performance also statistically improved and a good correlation between checklist and global rating scores were demonstrated in all but one scenario. Student evaluation of the experience was extremely positive. High-fidelity simulation can be used to allow students to apply theoretical knowledge to practice in a safe and realistic environment. Results of this study indicate that simulation is a valuable learning experience and bridges the gap between theory and practice. Simulation technology has the potential to provide an enriching venue to examine the role of communication and dynamics of novice learners in team environments.

Anesthesiology↗
PubMed2005

Predictive validity of driving-simulator assessments following traumatic brain injury: a preliminary study.

OBJECTIVE: To evaluate whether driving simulator and road test evaluations can predict long-term driving performance, we conducted a prospective study on 11 patients with moderate to severe traumatic brain injury. Sixteen healthy subjects were also tested to provide normative values on the simulator at baseline. METHOD: At their initial evaluation (time-1), subjects' driving skills were measured during a 30-minute simulator trial using an automated 12-measure Simulator Performance Index (SPI), while a trained observer also rated their performance using a Driving Performance Inventory (DPI). In addition, patients were evaluated on the road by a certified driving evaluator. Ten months later (time-2), family members observed patients driving for at least 3 hours over 4 weeks and rated their driving performance using the DPI. RESULTS: At time-1, patients were significantly impaired on automated SPI measures of driving skill, including: speed and steering control, accidents, and vigilance to a divided-attention task. These simulator indices significantly predicted the following aspects of observed driving performance at time-2: handling of automobile controls, regulation of vehicle speed and direction, higher-order judgment and self-control, as well as a trend-level association with car accidents. Automated measures of simulator skill (SPI) were more sensitive and accurate than observational measures of simulator skill (DPI) in predicting actual driving performance. To our surprise, the road test results at time-1 showed no significant relation to driving performance at time-2. CONCLUSION: Simulator-based assessment of patients with brain injuries can provide ecologically valid measures that, in some cases, may be more sensitive than a traditional road test as predictors of long-term driving performance in the community.

Adolescent↗
PubMed1998

Molecular dynamic simulations of environment and sequence dependent DNA conformations: the development of the BMS nucleic acid force field and comparison with experimental results.

Molecular dynamic (MD) simulations using the BMS nucleic acid force field produce environment and sequence dependent DNA conformations that closely mimic experimentally derived structures. The parameters were initially developed to reproduce the potential energy surface, as defined by quantum mechanics, for a set of small molecules that can be used as the building blocks for nucleic acid macromolecules (dimethyl phosphate, cyclopentane, tetrahydrofuran, etc.). Then the dihedral parameters were fine tuned using a series of condensed phase MD simulations of DNA and RNA (in zero added salt, 4M NaCl, and 75% ethanol solutions). In the tuning process the free energy surface for each dihedral was derived from the MD ensemble and fitted to the conformational distributions and populations observed in 87 A- and B-DNA x-ray and 17 B-DNA NMR structures. Over 41 nanoseconds of MD simulations are presented which demonstrate that the force field is capable of producing stable trajectories, in the correct environments, of A-DNA, double stranded A-form RNA, B-DNA, Z-DNA, and a netropsin-DNA complex that closely reproduce the experimentally determined and/or canonical DNA conformations. Frequently the MD averaged structure is closer to the experimentally determined structure than to the canonical DNA conformation. MD simulations of A- to B- and B- to A-DNA transitions are also shown. A-DNA simulations in a low salt environment cleanly convert into the B-DNA conformation and converge into the RMS space sampled by a low salt simulation of the same sequence starting from B-DNA. In MD simulations using the BMS force field the B-form of d(GGGCCC)2 in a 75% ethanol solution converts into the A-form. Using the same methodology, parameters, and conditions the A-form of d(AAATTT)2 correctly converts into the B-DNA conformation. These studies demonstrate that the force field is capable of reproducing both environment and sequence dependent DNA structures. The 41 nanoseconds (nsec) of MD simulations presented in this paper paint a global picture which suggests that the DNA structures observed in low salt solutions are largely due to the favorable internal energy brought about by the nearly uniform screening of the DNA electrostatics. While the conformations sampled in high salt or mixed solvent environments occur from selective and asymmetric screening of the phosphate groups and DNA grooves, respectively, brought about by sequence induced ion and solvent packing.

Adenine↗
PubMed2006

Validation of a Monte Carlo simulation of the Philips Allegro/GEMINI PET systems using GATE.

A newly developed simulation toolkit, GATE (Geant4 Application for Tomographic Emission), was used to develop a Monte Carlo simulation of a fully three-dimensional (3D) clinical PET scanner. The Philips Allegro/GEMINI PET systems were simulated in order to (a) allow a detailed study of the parameters affecting the system's performance under various imaging conditions, (b) study the optimization and quantitative accuracy of emission acquisition protocols for dynamic and static imaging, and (c) further validate the potential of GATE for the simulation of clinical PET systems. A model of the detection system and its geometry was developed. The accuracy of the developed detection model was tested through the comparison of simulated and measured results obtained with the Allegro/GEMINI systems for a number of NEMA NU2-2001 performance protocols including spatial resolution, sensitivity and scatter fraction. In addition, an approximate model of the system's dead time at the level of detected single events and coincidences was developed in an attempt to simulate the count rate related performance characteristics of the scanner. The developed dead-time model was assessed under different imaging conditions using the count rate loss and noise equivalent count rates performance protocols of standard and modified NEMA NU2-2001 (whole body imaging conditions) and NEMA NU2-1994 (brain imaging conditions) comparing simulated with experimental measurements obtained with the Allegro/GEMINI PET systems. Finally, a reconstructed image quality protocol was used to assess the overall performance of the developed model. An agreement of <3% was obtained in scatter fraction, with a difference between 4% and 10% in the true and random coincidence count rates respectively, throughout a range of activity concentrations and under various imaging conditions, resulting in <8% differences between simulated and measured noise equivalent count rates performance. Finally, the image quality validation study revealed a good agreement in signal-to-noise ratio and contrast recovery coefficients for a number of different volume spheres and two different (clinical level based) tumour-to-background ratios. In conclusion, these results support the accurate modelling of the Philips Allegro/GEMINI PET systems using GATE in combination with a dead-time model for the signal flow description, which leads to an agreement of <10% in coincidence count rates under different imaging conditions and clinically relevant activity concentration levels.

Computer Simulation↗