Beam characterisation studies of the 62 MeV proton therapy beamline at the Clatterbridge Cancer Centre

The Clatterbridge Cancer Centre (CCC) in the United Kingdom is the world’s first hospital proton beam therapy facility, providing treatment for ocular cancers since 1989. A 62 MeV beam of protons is produced by a Scanditronix cyclotron and transported through a passive delivery system. In addition to the long history of clinical use, the facility supports a wide programme of experimental work and as such, an accurate and reliable simulation model of the treatment beamline is highly valuable. However, as the facility has seen several changes to the accelerator and beamline over the years, a comprehensive study of the CCC beam dynamics is needed to firstly examine the beam optics. An extensive analysis was required to overcome facility related constraints to determine fundamental beamline parameters and define an optical lattice written with the Methodical Accelerator Design (MAD-X) and the particle tracking Beam Delivery Simulation (BDSIM) code. An optimised case is presented and simulated results of the optical functions, beam distribution, losses and the transverse rms beam sizes along the beamline are discussed. Corresponding optical and beam information was used in TOPAS to simulate transverse beam profiles and compared to EBT3 film measurements. We provide an overview of the magnetic components, beam transport, cyclotron, beam and treatment related parameters necessary for the development of a present day optical model of the facility. This work represents the first comprehensive study of the CCC facility to date, as a basis to determine input beam parameters to accurately simulate and completely characterise the beamline.     

Magnetic probe measurements of the current sheath on the PF-3 facility

Results are presented from experimental studies of the dynamics of the current sheath (CS) on the PF-3 plasma focus facility. The parameters of the sheath, including the current distribution in it, were measured using absolutely calibrated magnetic probes installed at different positions with respect to the facility axis and the anode surface. The CS dynamics in discharges operating in argon and neon was investigated, and the skin depth in different stages of the discharge was determined. One of the probes was installed at a distance of ≈2 cm from the facility axis, which made it possible to estimate the efficiency of current transfer to the region of pinch formation. Operating modes were obtained in which the current dynamics detected by magnetic probes at different distances from the axis agreed well with the dynamics of the total discharge current until the instant of singularity in the current time derivative. It is shown that shunting breakdowns can lead to the formation of closed current loops. The shunting of the discharge current by the residual plasma is directly related to the efficiency of snowplowing of the working gas by the CS as it propagates from the insulator toward the facility axis.     

Dynamics of the structure of the plasma current sheath in a plasma focus discharge

The study is aimed at investigating the fine structure of the plasma current sheath (PCS) in the PF-3 plasma focus facility. The PCS dynamics in a deuterium discharge was studied. The PCS parameters were measured using absolutely calibrated magnetic probes installed at different positions with respect to the facility axis and the anode surface. A magneto-optical probe recording both the magnetic signal and the PCS optical luminosity was first applied to analyze the PCS structure. This made it possible to spatially resolve the current and shock-wave regions. It is demonstrated that the current distribution is different in different discharge stages. It is shown that the neutron yield is determined by the value of the current compressed toward the axis, rather then the amplitude of the total discharge current.     

Neutron shielding for a new projected proton therapy facility: A Geant4 simulation study

In this work, we used the Monte Carlo-based Geant4 simulation toolkit to calculate the ambient dose equivalents due to the secondary neutron field produced in a new projected proton therapy facility. In particular the facility geometry was modeled in Geant4 based on the CAD design. Proton beams were originated with an energy of 250 MeV in the gantry rooms with different angles with respect to the patient; a fixed 250 MeV proton beam was also modeled. The ambient dose equivalent was calculated in several locations of interest inside and outside the facility, for different scenarios. The simulation results were compared qualitatively to previous work on an existing facility bearing some similarities with the design under study, showing that the ambient dose equivalent ranges obtained are reasonable. The ambient dose equivalents, calculated by means of the Geant4 simulation, were compared to the Australian regulatory limits and showed that the new facility will not pose health risks for the public or staff, with a maximum equivalent dose rate equal to 7.9 mSv/y in the control rooms and maze exit areas and 1.3·10⁻¹ mSv/y close to the walls, outside the facility, under very conservative assumptions. This work represents the first neutron shielding verification analysis of a new projected proton therapy facility and, as such, it may serve as a new source of comparison and validation for the international community, besides confirming the viability of the project from a radioprotection point of view.     

Integration of stochastic simulation with multivariate analysis: Short‐term facility fit prediction

This article describes a decision‐support tool to help pinpoint the potential root causes of sub‐optimal short‐term facility fit issues in biopharmaceutical facilities. This was achieved by creating a tool that integrated stochastic simulation with advanced multivariate statistical analysis. Process fluctuations in product titers in cell culture, step yields, and chromatography eluate volumes were mimicked using Monte Carlo simulation data derived using a stochastic discrete‐event simulation model. The resulting stochastic datasets, with the computed consequences on key metrics such as product mass loss and cost of goods, were examined using advanced multivariate statistical techniques. Principal component analysis combined with clustering algorithms was used to analyze the complex datasets from complete industrial batch processes for biopharmaceuticals. The challenge of visualizing the multidimensional nature of the dataset was addressed using hierarchical and k‐means clustering as well as stacked parallel co‐ordinate plots to help identify process fingerprints and characteristics of clusters leading to sub‐optimal facility fit issues. Industrially‐relevant case studies are presented that focus on technology transfer challenges for therapeutic antibodies moving from early phase to late phase clinical trials. The case study details how sub‐optimal facility fit can be alleviated by allocating alternative product pool tanks. The impact of this operational change is then assessed by reviewing an updated process fingerprint. © 2013 American Institute of Chemical Engineers Biotechnol. Prog., 29: 368–377, 2013     

Study of the dynamics of a plasma current sheath in the KPF-4 Phoenix plasma-focus facility

The engineering characteristics of the KPF-4 Phoenix megajoule Mather-type plasma focus facility constructed at the Sukhumi Physicotechnical Institute are described. Results from preliminary studies of the plasma dynamics at a capacitive-storage energy of up to 700 kJ are discussed. Future experiments in KPF-4 will be oriented at technological applications and will complement the studies carried out in the 2.8-MJ Filippovtype PF-3 plasma focus facility at the Nuclear Fusion Institute of the Russian Research Centre Kurchatov Institute.     

Molecular dynamics of myoglobin at 298 degrees K. Results from a 300-ps computer simulation.

We have carried out a very long (300 ps) molecular dynamics simulation of the protein myoglobin. This trajectory is approximately three times longer than the longest previous molecular dynamics simulation of a protein, and ten times longer than protein simulations of comparable size (1,423 atoms in our model). Here we report results from this long simulation concerning the average structure, the mean square fluctuations of atoms about the average structure, and the nuclear magnetic resonance order parameters for various groups in myoglobin. The results demonstrate that the average coordinates change very slowly during the simulation. The relative atomic mobilities are well described by the simulation. For both the mean square atomic fluctuations and the order parameters, however, there are significant quantitative differences when values calculated using shorter portions of the trajectory are compared with results obtained for the entire 300-ps simulation. The implications of this result for obtaining converged properties from protein molecular dynamics simulations for comparison with experiment are discussed.     

Semi-Markov models for brownian dynamics permeation in biological ion channels

Constructing accurate computational models that explain how ions permeate through a biological ion channel is an important problem in biophysics and drug design. Brownian dynamics simulations are large-scale interacting particle computer simulations for modeling ion channel permeation but can be computationally prohibitive. In this paper, we show the somewhat surprising result that a small-dimensional semi-Markov model can generate events (such as conduction events and dwell times at binding sites in the protein) that are statistically indistinguishable from brownian dynamics computer simulation. This approach enables the use of extrapolation techniques to predict channel conduction when performing the actual brownian dynamics simulation that is computationally intractable. Numerical studies on the simulation of gramicidin A ion channels are presented.     

The Application of the Reaction-Field Method to the Calculation of Dielectric Constants

Abstract

The behaviour of the popular TIP3P water model has been investigated using both molecular dynamics and Monte Carlo simulation procedures. Long-range electrostatic interactions were included through a reaction-field treatment, and the nonbonded interactions were either truncated at the cutoff distance, or smoothly scaled to zero using a switching function. The thermodynamic observables, and in particular the dipole-dipole correlation functions, are found to differ between the two simulation techniques if a rigid nonbonded cutoff is applied. However, use of a switching function gives exact agreement between the simulation methodologies. This difference is ascribed to the effect of energy pumping in the molecular dynamics simulations, and suggests that dielectric constants calculated using this simulation method with the fluctuation procedure in conjunction with a reaction field should be reappraised. Thus the Monte Carlo simulation procedure offers a number of intrinsic advantages over molecular dynamics for the calculation of dielectric constants with a reaction field. The most precise value for the dielectric constant of TIP3P is calculated to be 102 ± 3 at 298 K.     

RNA stability under different combinations of amber force fields and solvation models

The proper matching of force field and solvent is critical to obtain correct result in molecular dynamics simulation of bio-molecules. This problem has been intensively investigated for protein but not for RNA yet. In this paper, we use standard molecular dynamics and replica exchange molecular dynamics to take a series of tests on the RNA stability under different combinations of Amber force field parameters (ff98, ff99 and ff99bsc0) and the general Born implicit solvent models (igb1, igb2 and igb5). It is found that only ff98 and ff99bsc0 with igb1 can keep the native conformations of RNA hairpin and duplex. Our results suggest that ff98 plus igb1 may be reasonable choice for molecular dynamics simulation of RNA dynamics.     

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.     

The essential dynamics of thermolysin: Confirmation of the hinge-bending motion and comparison of simulations in vacuum and water

Comparisons of the crystal structures of thermolysin and the thermolysin-like protease produced by B. cereus have recently led to the hypothesis that neutral proteases undergo a hinge-bending motion. We have investigated this hypothesis by analyzing molecular dynamics simulations of thermolysin in vacuum and water, using the essential dynamics method. This method is able to extract large concerted atomic motions of biological importance from a molecular dynamics trajectory. The analysis of the thermolysin trajectories indeed revealed a large rigid body hinge-bending motion of the Nterminal and C-terminal domains, similar to the motion hypothesized from the crystal structure comparisons. In addition, it appeared that the essential dynamics properties derived from the vacuum simulation were similar to those derived from the solvent simulation. © 1995 Wiley-Liss, Inc.     

A comparison of structural and dynamic properties of different simulation methods applied to SH3.

The dynamic and static properties of molecular dynamics simulations using various methods for treating solvent were compared. The SH3 protein domain was chosen as a test case because of its small size and high surface-to-volume ratio. The simulations were analyzed in structural terms by examining crystal packing, distribution of polar residues, and conservation of secondary structure. In addition, the "essential dynamics" method was applied to compare each of the molecular dynamics trajectories with a full solvent simulation. This method proved to be a powerful tool for the comparison of large concerted atomic motions in SH3. It identified methods of simulation that yielded significantly different dynamic properties compared to the full solvent simulation. Simulating SH3 using the stochastic dynamics algorithm with a vacuum (reduced charge) force field produced properties close to those of the full solvent simulation. The application of a recently described solvation term did not improve the dynamic properties. The large concerted atomic motions in the full solvent simulation as revealed by the essential dynamics method were analyzed for possible biological implications. Two loops, which have been shown to be involved in ligand binding, were seen to move in concert to open and close the ligand-binding site.     

Multiscale modeling and mechanics of filamentous actin cytoskeleton

The adaptive structure and functional changes of the actin cytoskeleton are induced by its mechanical behavior at various temporal and spatial scales. In particular, the mechanical behaviors at different scales play important roles in the mechanical functions of various cells, and these multiscale phenomena require clarification. To establish a milestone toward achieving multiscale modeling and simulation, this paper reviews mathematical analyses and simulation methods applied to the mechanics of the filamentous actin cytoskeleton. The actin cytoskeleton demonstrates characteristic behaviors at every temporal and spatial scale, and mathematical models and simulation methods can be applied to each level of actin cytoskeletal structure ranging from the molecular to the network level. This paper considers studies on mathematical models and simulation methods based on the molecular dynamics, coarse-graining, and continuum dynamics approaches. Every temporal and spatial scale of actin cytoskeletal structure is considered, and it is expected that discrete and continuum dynamics ranging from functional expression at the molecular level to macroscopic functional expression at the whole cell level will be developed and applied to multiscale modeling and simulation.     

On the Approximation of Solvent Effects on the Conformation and Dynamics of Cyclosporin A by Stochastic Dynamics Simulation Techniques

Abstract

The molecular simulation technique of stochastic dynamics (SD) is tested by application to the immunosuppressive drug cyclosporin A (CPA). Two stochastic dynamics simulations are performed, one (SD_CCl4 ) with atomic friction coefficients proportional to the viscosity of the nonpolar solvent CCl₄, and one (SD_H2O) with atomic friction coefficients corresponding to an aqueous solution. The atomic friction coefficients are also taken proportional to an approximate expression for the atomic accessible surface area. The properties of both stochastic dynamics simulations are compared to those of two full molecular dynamics (MD) simulations of cyclosporin A, one in a box with 591 CCl₄ molecules, and one in a box with 632 H₂O molecules.

The properties of cyclosporin A as found in the molecular dynamics simulation in CCl₄ are well reproduced by the SD_CCl4 simulation. This indicates that the neglect of a mean force reresenting the average solvent effects on the solute is justified in the case of nonpolar solvents. For polar solvents, like water, this mean force may not be neglected. The SD_H2O simulation of cyclosporin A clearly fails to reproduce the amount of hydrogen bonding found in the molecular dynamics stimulation of cyclosporin A in water.

A comparison with a molecular dynamics simulation of cyclosporin A in vacuo shows that both the SD_CCl4 and the SD_H2O simulation come closer to the properties of the molecular dynamics simulations in CCl₄ and in H₂O than a molecular dynamics simulation in vacuo.     

Multiple Time Step Brownian Dynamics for Long Time Simulation of Biomolecules

We report a multiple time step algorithm applied to an atomistic Brownian dynamics simulation for simulating the long time scale dynamics of biomolecules. The algorithm was based on the original multiple time step method; a short time step was used to keep faster motions in local equilibrium. When applied to a 28-mer # # ! folded peptide, the simulation gave stable trajectories and the computation time was reduced by a factor of 160 compared to a conventional molecular dynamics simulation using explicit water molecules. We applied it for the folding simulation of a 13-mer ! -helical peptide, giving a successful folding simulation. These results indicate that the Brownian dynamics with the multiple time step algorithm is useful for studies of biomolecular motions by long time simulation.     

Visualization of energetics and conformations from molecular computer simulations

The quantity of data generated from molecular dynamics simulations and energy minimizations of macromolecules is overwhelming. It is an arduous task to extract the relevant and interesting information from the numerous coordinate sets produced. To help solve this problem, the authors have developed a method to aid the visualization of the relevant information from the simulations. This approach combines animation of the results on a high performance graphics device, such as the PS300, with colour-coded atoms based on changes in energy or conformation. The method will be illustrated using as examples: the molecular mechanics minimization of a nonapeptide, the molecular dynamics simulation of the protein myoglobin, including the analysis of the motion of helices during a 300ps trajectory, and changes in sugar puckering that occur during the molecular dynamics simulation of a DNA oligomer. The method is also applicable for analysing energy components and conformational properties of a fixed conformation.     

Optical recording of the compression dynamics of DT-gas-filled pellets in indirect-drive targets

The spatiotemporal dynamics of the compression region of DT-gas filled micropellets was recorded using an optical streak camera in experiments on micropellet implosion in the Iskra-5 high-power laser facility. The experimental data agree with calculations and results of X-ray measurements.     

Discrete simulation of regulatory homo- and heterodimerization in the apoptosis effector phase

MOTIVATION: Quantitative simulation of molecular reaction networks is among the most promising approaches towards an understanding of complex biochemical pathways. Numerous qualitative as well as quantitative data from diverse experimental settings, in particular from genomics and proteomics, have to be contextually linked to convert static data into dynamic functionality. RESULTS: This paper presents the Lattice Molecular Automaton, a Cellular Automaton-based simulation tool, capable of representing complex molecular dynamics at different levels of granularity. A data structure concept represents molecular units, whose dynamics, embedded on a 2D grid, is defined via detailed intermolecular interaction profiles. The data structures hold diverse information as molecular type, potential, as well as kinetic energy states, which allows a precise representation of intracellular reaction networks. The molecular dynamics is performed via local computation of individual molecular states on the lattice, which, in conjunction with discretized space and time, enables excellent scalability of this simulation concept. This paper finally gives Lattice Molecular Automaton simulation results on key elements of apoptosis, the cell death cascade, in particular focusing on the regulatory function of homo- and heterodimerization of members of the Bcl-2 protein family in the apoptosis effector phase. The regulatory proteins Bcl2, Bax, and Bak constitute a diffusion-driven molecular switch with inherent damping of apoptosis induction, thereby controlling the apoptosis reaction cascade under noisy, external apoptosis inducing conditions.