Engineering of electron transfer properties of metallo-proteins

The results of site-directed mutagenesis experiments on azurins and cytochrome c-550, aimed at modifying the redox properties of the metal centres, are presented and discussed. Applications in the design of bioelectronic devices are briefly discussed.     

A dynamic simulation model of tissue growth and cell patterning

The distributions of cells in tissues of experimental chimaeras and mosaics can serve as tests of mechanisms and rules by which single cells organize themselves into complex, multicellular structures during embryogenesis. We have devised a dynamic, computer simulation model of tissue growth and cell patterning which is directly applicable to the analysis of chimaeras and mosaics. In the model, schematized cells possess a small behavioral repertoire and simple rules for the carrying out of these behaviors. Populations of such cells evolve tissue patterns in real-time that are very similar to those seen in experimental animals. In particular, we have modeled the major pattern features seen in amphibian and mammalian eye chimaeras and mosaics. We have demonstrated that cell mixing can be a passive concomitant of interstitial cell division, a result which alleviates the need to postulate active cell mixing in such mammalian systems. We expect this approach to be a valuable addition to methods of pattern analysis in development.     

Model-based simulation of dynamic magnetic resonance imaging signals

This paper presents a model-based method to efficiently simulate dynamic magnetic resonance imaging signals. Using an analytical spatiotemporal object model, the method can approximate time-varying k-space signals such as those from objects in motion and/or during dynamic contrast enhancement. Both rigid-body and non-rigid-body motions can be simulated using the proposed method. In addition, it can simulate data with arbitrary data sampling order and/or non-uniform k-space trajectory. A set of simulated images were compared with real data acquired from a rat model on a 4.7 T scanner to verify the model. The efficient simulation method is expected to be useful for rapid testing of various imaging and image analysis algorithms such as image reconstruction, image registration, motion compensation, and kinetic parameter mapping.     

应用地理信息系统模拟森林景观动态的研究

根据地理信息系统的结构,通过数据文件的转换,把它与森林动态模型有机地结合起来,可实现对森林景观动态的模拟和预测。这种模拟方法的数据输入灵活,运行速度快,尤其是它可以获得一些以各种图表的形式输出的模拟结果。本文用文字和框图详细描述了地理信息系统的组成与结构,及森林动态模型的选择与运行方式,并以长白山森林景观为例,叙述了这种模拟方法的整个过程。     

Analysis of Delta-Notch interaction by molecular modeling and molecular dynamic simulation studies

Notch is a single-pass transmembrane receptor protein. Delta (member of the DSL protein family), a Notch ligand, is also single-pass transmembrane protein that can interact with Notch to form the Delta-Notch complex. It has been demonstrated that of the 36 Epidermal Growth Factor (EGF) repeats of Notch, 11th and 12th are sufficient to mediate interactions with Delta. Crystal structure of mammalian Notch1 extracellular ligand binding domain shows the presence of 11th and 12th EGF-like repeats. Here a portion of the Drosophila Delta protein, known to interact with Notch extracellular domain, has been modeled using homology modeling. The structure of the Delta-Notch complex was subsequently modeled by protein-docking method using GRAMM. Molecular dynamic simulations of the modeled structures were performed. The probable structures for Delta-Notch complex have been proposed based on interaction energy parameter and planarity studies.     

Mammalian cell culture synchronization under physiological conditions and population dynamic simulation

The overall behavior of cell cultures is determined by the actions and regulations of all cells and their interaction in a mixed population. However, the dynamics caused by diversity and heterogeneity within cultures is often neglected in the study of cell culture processes. Usually, a bulk behavior is assumed, although heterogeneity prevails in most cases. It is, however, not valid to conclude from the bulk behavior to the single cell behavior. Instead, it is necessary to include the behavior and kinetics of subpopulations and their interactions into models in order to elucidate the dynamic effects occurring in typical cell cultures. Heterogeneity in cell cultures is largely caused by the progress of the cell cycle. Cell cycle-dependent dynamics resulting for example in variable transfection efficiencies or expression bistability have recently attracted attention. In order to elucidate cell cycle-dependent regulations in cell cultures, it is desirable to synchronize a culture with minimal perturbation, which is possible with different yield and quality using physical methods, but not possible for frequently used chemical, or whole-culture methods. Then, the culture is cultivated again under physiological conditions and subpopulation-resolved analysis and modeling approaches are applied. This should allow to account for the variable contributions of subpopulations to the whole behavior and also for obtaining hereto unaccessible dynamic information of cellular regulation. In this short review, we summarize techniques and key issues to be considered for successful synchronization, cultivation, and modeling in order to achieve the goal of better understanding cell culture at a population level.     

Role of reflex gain and reflex delay in spinal stability--a dynamic simulation

The goal of this study was to investigate the role of reflex and reflex time delay in muscle recruitment and spinal stability. A dynamic biomechanical model of the musculoskeletal spine with reflex response was implemented to investigate the relationship between reflex gain, co-contraction, and stability in the spine. The first aim of the study was to investigate how reflex gain affected co-contraction predicted in the model. It was found that reflexes allowed the model to stabilize with less antagonistic co-contraction and hence lower metabolic power than when limited to intrinsic stiffness alone. In fact, without reflexes there was no feasible recruitment pattern that could maintain spinal stability when the torso was loaded with 200N external load. Reflex delay is manifest in the paraspinal muscles and represents the time from a perturbation to the onset of reflex activation. The second aim of the study was to investigate the relationship between reflex delay and the maximum tolerable reflex gain. The maximum acceptable upper bound on reflex gain decreased logarithmically with reflex delay. Thus, increased reflex delay and reduced reflex gain requires greater antagonistic co-contraction to maintain spinal stability. Results of this study may help understanding of how patients with retarded reflex delay utilize reflex for stability, and may explain why some patients preferentially recruit more intrinsic stiffness than healthy subjects.     

Stochastic P systems and the simulation of biochemical processes with dynamic compartments

We introduce a sequential rewriting strategy for P systems based on Gillespie's stochastic simulation algorithm, and show that the resulting formalism of stochastic P systems makes it possible to simulate biochemical processes in dynamically changing, nested compartments. Stochastic P systems have been implemented using the spatially explicit programming language MGS. Implementation examples include models of the Lotka-Volterra auto-catalytic system, and the life cycle of the Semliki Forest virus.     

Hybrid dynamic/static method for large-scale simulation of metabolism

Background  

Many computer studies have employed either dynamic simulation or metabolic flux analysis (MFA) to predict the behaviour of biochemical pathways. Dynamic simulation determines the time evolution of pathway properties in response to environmental changes, whereas MFA provides only a snapshot of pathway properties within a particular set of environmental conditions. However, owing to the large amount of kinetic data required for dynamic simulation, MFA, which requires less information, has been used to manipulate large-scale pathways to determine metabolic outcomes.     

Molecular dynamic simulation study of cholesterol and conjugated double bonds in lipid bilayers

Conjugated linoleic acids (CLA) are found naturally in dairy products. Two isomers of CLA, that differ only in the location of cis and trans double bonds, are found to have distinct and different biological effects. The cis 9 trans 11 (C9T11) isomer is believed to have anti-carcinogenic effects, while the trans 10 cis 12 (T10C12) isomer is believed to be associated with anti-obesity effects. In this paper we extend earlier molecular dynamics (MD) simulations of pure CLA–phosphatidylcholine bilayers to investigate the comparative effects of cholesterol on bilayers composed of the two respective isomers. Simulations of phosphatidylcholine lipid bilayers in which the sn-2 chains contained one of the two isomers of CLA were performed in which, for each isomer, the simulated bilayers contained 10% and 30% cholesterol (Chol). From MD trajectories we calculate and compare structural properties of the bilayers, including areas per molecule, thickness of bilayers, tilt angle of cholesterols, order parameter profiles, and one and two-dimensional radial distribution function (RDF), as functions of Chol concentration. While the structural effect of cholesterol is approximately the same for both isomers, we find differences at an atomistic level in order parameter profiles and in two-dimensional radial distribution functions.     

A platform for dynamic simulation and control of movement based on OpenSim and MATLAB

Numerical simulations play an important role in solving complex engineering problems and have the potential to revolutionize medical decision making and treatment strategies. In this paper, we combine the rapid model-based design, control systems and powerful numerical method strengths of MATLAB/Simulink with the simulation and human movement dynamics strengths of OpenSim by developing a new interface between the two software tools. OpenSim is integrated with Simulink using the MATLAB S-function mechanism, and the interface is demonstrated using both open-loop and closed-loop control systems. While the open-loop system uses MATLAB/Simulink to separately reproduce the OpenSim Forward Dynamics Tool, the closed-loop system adds the unique feature of feedback control to OpenSim, which is necessary for most human movement simulations. An arm model example was successfully used in both open-loop and closed-loop cases. For the open-loop case, the simulation reproduced results from the OpenSim Forward Dynamics Tool with root mean square (RMS) differences of 0.03° for the shoulder elevation angle and 0.06° for the elbow flexion angle. MATLAB's variable step-size integrator reduced the time required to generate the forward dynamic simulation from 7.1s (OpenSim) to 2.9s (MATLAB). For the closed-loop case, a proportional-integral-derivative controller was used to successfully balance a pole on model's hand despite random force disturbances on the pole. The new interface presented here not only integrates the OpenSim and MATLAB/Simulink software tools, but also will allow neuroscientists, physiologists, biomechanists, and physical therapists to adapt and generate new solutions as treatments for musculoskeletal conditions.     

Design of a minimal protein oligomerization domain by a structural approach

Because of the simplicity and regularity of the alpha-helical coiled coil relative to other structural motifs, it can be conveniently used to clarify the molecular interactions responsible for protein folding and stability. Here we describe the de novo design and characterization of a two heptad-repeat peptide stabilized by a complex network of inter- and intrahelical salt bridges. Circular dichroism spectroscopy and analytical ultracentrifugation show that this peptide is highly alpha-helical and 100% dimeric tinder physiological buffer conditions. Interestingly, the peptide was shown to switch its oligomerization state from a dimer to a trimer upon increasing ionic strength. The correctness of the rational design principles used here is supported by details of the atomic structure of the peptide deduced from X-ray crystallography. The structure of the peptide shows that it is not a molten globule but assumes a unique, native-like conformation. This de novo peptide thus represents an attractive model system for the design of a molecular recognition system.     

Terrestrial nitrogen cycle simulation with a dynamic global vegetation model

A global scale Dynamic Nitrogen scheme (DyN) has been developed and incorporated into the Lund–Posdam–Jena (LPJ) dynamic global vegetation model (DGVM). The DyN is a comprehensive process‐based model of the cycling of N through and within terrestrial ecosystems, with fully interactive coupling to vegetation and C dynamics. The model represents the uptake, allocation and turnover of N in plants, and soil N transformations including mineralization, N₂ fixation, nitrification and denitrification, NH₃ volatilization, N leaching, and N₂, N₂O and NO production and emission. Modelled global patterns of site‐scale nitrogen fluxes and reservoirs are highly correlated to observations reported from different biomes. The simulation of site‐scale net primary production and soil carbon content was improved relative to the original LPJ, which lacked an interactive N cycle, especially in the temporal and boreal regions. Annual N uptake by global natural vegetation was simulated as 1.084 Pg N yr⁻¹, with lowest values <1 g N m⁻² yr⁻¹ (polar desert) and highest values in the range 24–36.5 g N m⁻² yr⁻¹ (tropical forests). Simulated global patterns of annual N uptake are consistent with previous model results by Melillo et al. The model estimates global total nitrogen storage potentials in vegetation (5.3 Pg N), litter (4.6 Pg N) and soil (≥67 Pg as organic N and 0.94 Pg as inorganic N). Simulated global patterns of soil N storage are consistent with the analysis by Post et al. although total simulated N storage is less. Deserts were simulated to store 460 Tg N (up to 0.262 kg N m⁻²) as NO₃⁻, contributing 80% of the global total NO₃⁻ inventory of 580 Tg N. This model result is in agreement with the findings of a large NO₃⁻ pool beneath deserts. Globally, inorganic soil N is a small reservoir, comprising only 1.6% of the global soil N content to 1.5 m soil depth, but the ratio has a very high spatial variability and in hot desert regions, inorganic NO₃⁻ is estimated to be the dominant form of stored N in the soil.     

Interactions of GFAP with ceftriaxone and phenytoin: SRCD and molecular docking and dynamic simulation

BackgroundGFAP is the major intermediate filament protein in mature astrocytes. Its increased expression and aggregation was firstly associated to Alexander's disease, and successively in different neurological diseases including scrapie, Alzheimer's and Creutzfeld–Jacob diseases. Recently, ceftriaxone a multi-potent β-lactam antibiotic able to overcome the blood–brain barrier, successfully eliminated the cellular toxic effects of misfolded mutated GFAP, similarly to phenytoin sodium, in a cellular model of Alexander's disease and inhibited α-synuclein aggregation protecting PC12 cells from the exposure to 6-hydroxydopamine.MethodsIn this study, synchrotron radiation circular dichroism spectroscopy has been used to obtain structural information about the GFAP-ceftriaxone (phenytoin) interactions, while computational methods allowed the identification of the relevant putative binding site of either ceftriaxone or phenytoin on the dimer structure of GFAP, permitting to rationalize the spectroscopic experimental results.ResultsWe found that GFAP exhibited enhanced stability upon the addition of two equivalents of each ligands with ceftriaxone imparting a more spontaneous interactions and a more ordered complex system than phenytoin.ConclusionsSRCD data and MD models indicate a stronger protective effect of ceftriaxone in neurological disorders characterized by an increased production and polymerization of GFAP.General significanceThis result, in addition to our previous works in which we documented that ceftriaxone interacts with α-synuclein inhibiting its pathological aggregation and that a cyclical treatment with this molecule in a patient with adult-onset Alexander's disease halted, and partly reversed, the progression of neurodegeneration, suggests the possibility of a chaperone-like effect of ceftriaxone on protein involved in specific neurodegenerative diseases.     

Molecular simulation study of structural and dynamic properties of mixed DPPC/DPPE bilayers

Molecular dynamics simulations have been used to study structural and dynamic properties of fully hydrated mixed 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine (DPPE) bilayers at 0, 25, 50, 75, and 100 mol % DPPE. Simulations were performed for 50 ns at 350 K and 1 bar for the liquid-crystalline state of the mixtures. Results show that the average area per headgroup reduces from 0.65 +/- 0.01 nm(2) in pure DPPC to 0.52 +/- 0.01 nm(2) in pure DPPE systems. The lipid tails become more ordered with increasing DPPE concentration, resulting in a slight increase in membrane thickness (3.43 +/- 0.01 nm in pure DPPC to 4.00 +/- 0.01 nm in pure DPPE). The calculated area per headgroup and order parameter for pure DPPE deviates significantly from available experimental measurements, suggesting that the force field employed requires further refinement. In-depth analysis of the hydrogen-bond distribution in DPPE molecules shows that the amine groups strongly interact with the phosphate and carbonyl groups through inter/intramolecular hydrogen bonds. This yields a bilayer structure with DPPE headgroups preferentially located near the lipid phosphate and ester oxygens. It is observed that increasing DPPE concentrations causes competitive hydrogen bonding between the amine groups (hydrogen-donor) and the phosphate/carbonyl groups or water (hydrogen-acceptor). Due to the increasing number of hydrogen-donors from DPPE molecules with increasing concentration, DPPE becomes more hydrated. Trajectory analysis shows that DPPE molecules in the lipid mixtures move laterally and randomly around the membrane surface and the movement becomes more localized with increasing DPPE concentrations. For the conditions and simulation time considered, no aggregation or phase separation was observed between DPPC and DPPE.     

Analysis and simulation of dynamic response behavior of Scots pine trees to wind loading

This paper presents an empirical approach for the decomposition, simulation, and reconstruction of wind-induced stem displacement of plantation-grown Scots pine trees. Results from singular spectrum analysis (SSA) allow a low-dimensional characterization of the complex and complicated tree motion patterns in response to non-destructive wind excitation. Since motion of the sample trees was dominated by sway in the first mode, the application of SSA on time series of sample trees’ stem displacement yielded characteristic and distinguishable non-oscillatory trend components, quasi-oscillatory sway, and noise, of which only the non-oscillatory components were correlated directly with wind characteristics. Although sway in the range of the dominant damped fundamental frequency dominated the measured stem displacement signals, it was almost decoupled from near-surface airflow. The ability to discriminate SSA-components is demonstrated based on correlation and spectral analysis. These SSA-components, as well as wind speed measured in the canopy space of the Scots pine forest, were used to train neural networks, which could then reasonably simulate tree response to wind excitation.     

Insilico modeling and molecular dynamic simulation of claudin-1 point mutations in HCV infection

Claudin-1 (CLDN1) in association with envelope glycoprotein (CD81) mediates the fusion of HCV into the cytosol. Recent studies have indicated that point mutations in CLDN1 are important for the entry of hepatitis C virus (HCV). To validate these findings, we employed a computational platform to investigate the structural effect of two point mutations (I32M and E48K). Initially, three-dimensional co-ordinates for CLDN1 receptor sequence were generated. Then, three mutant models were built using the point mutation including a double mutant (I32M/E48K) model from the native model structure. Finally, all the four model structures including the native and three mutant models were subjected to molecular dynamics (MD) simulation for a period of 25?ns to appreciate their dynamic behavior. The MD trajectory files were analyzed using cluster and principal component method. The analysis suggested that either of the single mutation has negligible effect on the overall structure of CLDN1 compared to the double mutant form. However, the double mutant model of CLDN1 shows significant negative impact through the impairment of H-bonds and the simultaneous increase in solvent accessible surface area. Our simulation results are visibly consistent with the experimental report suggesting that the CLDN1 receptor distortion is prominent due to the double mutation with large surface accessibility. This increase in accessible surface area due to the coexistence of double mutation may be presumed as one of the key factor that results in permissive action of HCV attachment and infection.     

WebCell: a web-based environment for kinetic modeling and dynamic simulation of cellular networks

SUMMARY: WebCell is a web-based environment for managing quantitative and qualitative information on cellular networks and for interactively exploring their steady-state and dynamic behaviors in response to systemic perturbations. It is designed as a user-friendly web interface, allowing users to efficiently construct, visualize, analyze and store reaction network models, thereby facilitating kinetic modeling and in silico simulation of biological systems of interest. A collected model library is also available to provide comprehensive implications for cellular dynamics of the published models.