Inherent speedup limitations in multiple time step/particle mesh Ewald algorithms

Multiple time step (MTS) algorithms present an effective integration approach to reduce the computational cost of dynamics simulations. By using force splitting to allow larger time steps for the more slowly varying force components, computational savings can be realized. The Particle-Mesh-Ewald (PME) method has been independently devised to provide an effective and efficient treatment of the long-range electrostatics interactions. Here we examine the performance of a combined MTS/PME algorithm previously developed for AMBER on a large polymerase beta/DNA complex containing 40,673 atoms. Our goal is to carefully combine the robust features of the Langevin/MTS (LN) methodology implemented in CHARMM-which uses position rather than velocity Verlet with stochasticity to make possible outer time steps of 150 fs-with the PME formulation. The developed MTS/PME integrator removes fast terms from the reciprocal-space Ewald component by using switch functions. We analyze the advantages and limitations of the resulting scheme by comparing performance to the single time step leapfrog Verlet integrator currently used in AMBER by evaluating different time-step protocols using three assessors for accuracy, speedup, and stability, all applied to long (i.e., nanosecond) simulations to ensure proper energy conservation. We also examine the performance of the algorithm on a parallel, distributed shared-memory computer (SGI Origin 2000 with 8 300-MHz R12000 processors). Good energy conservation and stability behavior can be demonstrated, for Newtonian protocols with outer time steps of up to 8 fs and Langevin protocols with outer time steps of up to 16 fs. Still, we emphasize the inherent limitations imposed by the incorporation of MTS methods into the PME formulation that may not be widely appreciated. Namely, the limiting factor on the largest outer time-step size, and hence speedup, is an intramolecular cancellation error inherent to PME. This error stems from the excluded-nonbonded correction term contained in the reciprocal-space component. This cancellation error varies in time and introduces artificial frequencies to the governing dynamics motion. Unfortunately, we find that this numerical PME error cannot be easily eliminated by refining the PME parameters (grid resolution and/or order of interpolating polynomial). We suggest that methods other than PME for fast electrostatics may allow users to reap the full advantages from MTS algorithms.     

迁移时间归一化法改善毛细管电泳表征中药大黄的重现性

探讨了迁移时间归一化法改善中药毛细管电泳分析迁移时间重现性的原理,并将其应用于实际样品的分析。迁移时间归一化法认为,在相同的操作电压、缓冲液组成和温度条件下,多次电泳实验中迁移时间产生差别的主要原因是多次电泳实验中电渗流产生了差异。迁移时间归一化法就是通过选择电泳谱图中的一个或两个峰作为标记峰,将各次电泳实验的迁移时间都归一到第一次电泳实验中的迁移时间。比较多次电泳实验中迁移时间(t)的相对标准偏差(RSD)、经单峰归一化处理的迁移时间(t′)的RSD、经双峰归一化处理的迁移时间(t″)的RSD、迁移时间比(t/tistd,istd代表所选择的标记物)的RSD,发现RSD(t″)相似文献   

Isolation of tomato pectin methylesterase and polygalacturonase on monolithic columns

An improved cation-exchange chromatographic procedure on Convective Interaction Media (CIM, BIA Separations, Ljubljana, Slovenia) short monolithic methacrylate disk columns was used for the isolation of salt-independent pectin methylesterase (PME; EC 3.1.1.11) isoform and endo-polygalacturonase PG1 (PG, EC 3.2.1.15) from ripe tomato fruit extract after studying the chromatographic conditions including type of disk, binding buffer, pH, eluent composition and different gradients. Between 10 and 20 microg of proteins gave reliable chromatograms. Both carboxymethyl (CM) and sulfonyl (SO3) disks were equally suitable for the fractionation of tomato extract using the new gradient, but only CM disk was appropriate for further purification of the PME and PG fractions, and provided fast and sharp separation of proteins. The isolation of pure PG1 could be achieved only by addition of 20% of acetonitrile to the mobile phase. About 200 microg of proteins were loaded at one chromatographic run at the fractionation and purification. Determination of the molecular weights of the separated proteins showed that dimer of salt-independent PME isoform was formed in concentrated solutions of the enzyme but dissociated upon dilution of the solution. From 6 kg of fresh tomato flesh, 28 mg of purified salt-independent PME, 12.5mg of purified and active PG1 and 4 mg of PG2 fraction contaminated with salt-dependent PME isoform were obtained by means of semi-preparative chromatography on CIM disks.     

Symplectic molecular dynamics simulations on specially designed parallel computers

We have developed a computer program for molecular dynamics (MD) simulation that implements the Split Integration Symplectic Method (SISM) and is designed to run on specialized parallel computers. The MD integration is performed by the SISM, which analytically treats high-frequency vibrational motion and thus enables the use of longer simulation time steps. The low-frequency motion is treated numerically on specially designed parallel computers, which decreases the computational time of each simulation time step. The combination of these approaches means that less time is required and fewer steps are needed and so enables fast MD simulations. We study the computational performance of MD simulation of molecular systems on specialized computers and provide a comparison to standard personal computers. The combination of the SISM with two specialized parallel computers is an effective way to increase the speed of MD simulations up to 16-fold over a single PC processor.     

Optimization of parameters for molecular dynamics simulation using smooth particle-mesh Ewald in GROMACS 4.5

Based on our critique of requirements for performing an efficient molecular dynamics simulation with the particle-mesh Ewald (PME) implementation in GROMACS 4.5, we present a computational tool to enable the discovery of parameters that produce a given accuracy in the PME approximation of the full electrostatics. Calculations on two parallel computers with different processor and communication structures showed that a given accuracy can be attained over a range of parameter space, and that the attributes of the hardware and simulation system control which parameter sets are optimal. This information can be used to find the fastest available PME parameter sets that achieve a given accuracy. We hope that this tool will stimulate future work to assess the impact of the quality of the PME approximation on simulation outcomes, particularly with regard to the trade-off between cost and scientific reliability in biomolecular applications.     

An evaluation of exogenous application of protoporphyrin IX and its dimethyl ester as a photodynamic diagnostic agent in poorly differentiated human nasopharyngeal carcinoma

5-Aminolevulinic acid and its esterified analogues have been under much investigation to enhance the endogenous production of protoporphyrin IX (PpIX) in tumor cells. However, in this work, we studied the in vitro and in vivo efficacy of exogenously administered PpIX and its esterified analogue, PpIX dimethyl ester (PME), in poorly differentiated human nasopharyngeal carcinoma (NPC/CNE-2) as a photodynamic diagnostic (PDD) agent. NPC/CNE-2 at its earliest time, 1 h after incubation with PME in in vitro studies, has exhibited 64% (P <0.01) higher tumor to normal cell (T/N) fluorescence ratio than with PpIX. In an in vivo mouse xenograft model, comparable photosensitizer concentration in tumor after intravenous administration was observed at 1-3 h time points, but at 9 h, PME had 31% (P=0.05) greater concentration in tumor compared with PpIX. In addition, by constituting PME and PpIX in different topical gel composites, of which, PME gel composition of 8:2 Plasdone and Gantrez resulted in the highest T/N ratio at 6 h after application (34%; P <0.05) in comparison with other gel composites. Evaluation of PME and PpIX constituted in the delivery vehicles investigated showed comparable selectivity for tumor at 1-3 h, thus neither photosensitizer is more efficient than the other for PDD at the early time points; however, beyond 6 h, PME had higher selectivity for tumor compared with PpIX. Thus, further investigation is warranted to improve the drug delivery vehicle for greater tumor selectivity at a shorter incubation time.     

Fast and spectrally accurate Ewald summation for 2-periodic electrostatic systems

A new method for Ewald summation in planar/slablike geometry, i.e., systems where periodicity applies in two dimensions and the last dimension is "free" (2P), is presented. We employ a spectral representation in terms of both Fourier series and integrals. This allows us to concisely derive both the 2P Ewald sum and a fast particle mesh Ewald (PME)-type method suitable for large-scale computations. The primary results are: (i) close and illuminating connections between the 2P problem and the standard Ewald sum and associated fast methods for full periodicity; (ii) a fast, O(N log N), and spectrally accurate PME-type method for the 2P k-space Ewald sum that uses vastly less memory than traditional PME methods; (iii) errors that decouple, such that parameter selection is simplified. We give analytical and numerical results to support this.     

A new hierarchical parallelization scheme: generalized distributed data interface (GDDI), and an application to the fragment molecular orbital method (FMO)

A two-level hierarchical scheme, generalized distributed data interface (GDDI), implemented into GAMESS is presented. Parallelization is accomplished first at the upper level by assigning computational tasks to groups. Then each group does parallelization at the lower level, by dividing its task into smaller work loads. The types of computations that can be used with this scheme are limited to those for which nearly independent tasks and subtasks can be assigned. Typical examples implemented, tested, and analyzed in this work are numeric derivatives and the fragment molecular orbital method (FMO) that is used to compute large molecules quantum mechanically by dividing them into fragments. Numeric derivatives can be used for algorithms based on them, such as geometry optimizations, saddle-point searches, frequency analyses, etc. This new hierarchical scheme is found to be a flexible tool easily utilizing network topology and delivering excellent performance even on slow networks. In one of the typical tests, on 16 nodes the scalability of GDDI is 1.7 times better than that of the standard parallelization scheme DDI and on 128 nodes GDDI is 93 times faster than DDI (on a multihub Fast Ethernet network). FMO delivered scalability of 80-90% on 128 nodes, depending on the molecular system (water clusters and a protein). A numerical gradient calculation for a water cluster achieved a scalability of 70% on 128 nodes. It is expected that GDDI will become a preferred tool on massively parallel computers for appropriate computational tasks.     

Coated wire ion-selective electrode for palladium(II) and its application to catalyst analysis

The construction, performance and application of polymeric membrane (PME) and coated wire (CWE) palladium(II)-selective electrodes based on the ion pair between tetra bromopalladate(II) and hexadecylpyridinium cation (HDP⁺) in a poly(vinyl chloride) matrix, plasticized with o-NPOE are described. The influence of membrane composition, bromide ion concentration and pH on the potentiometric responses of electrodes were investigated. Nernstian responses were obtained for the two type of electrodes with low limits of detection (1.0×10⁻⁶ M for PME and 5.0×10⁻⁸ M for CWE). The potentiometric responses are independent of the pH of test solution in the range 3–8. The response time of electrodes are fast (30 s for PME and 10 s for CWE), and they can be used for at least 3 months without any considerable divergence in potentials. The proposed electrodes revealed good selectivity for palladium(II) respect to different cations and anions. They were used to the direct potentiometric determination of palladium(II) in silicon-alumina catalysts.     

New parallel optimal‐parameter fast multipole method (OPFMM)

The three key translation equations of the fast multipole method (FMM) are deduced from the general polypolar expansions given earlier. Simplifications are introduced for the rotation‐based FMM that lead to a very compact FMM formalism. The optimum‐parameter searching procedure, a stable and efficient way of obtaining the optimum set of FMM parameters, is established with complete control over the tolerable error (ε). This new procedure optimizes the linear scaling with respect to the number of particles for a given ε. In addition, a new parallel FMM algorithm, which requires virtually no internode communication, is suggested that is suitable for the parallel construction of Fock matrices in electronic structure calculations. © 2001 John Wiley & Sons, Inc. J Comput Chem 22: 1484–1501, 2001     

Efficient lookup table using a linear function of inverse distance squared

The major bottleneck in molecular dynamics (MD) simulations of biomolecules exist in the calculation of pairwise nonbonded interactions like Lennard‐Jones and long‐range electrostatic interactions. Particle‐mesh Ewald (PME) method is able to evaluate long‐range electrostatic interactions accurately and quickly during MD simulation. However, the evaluation of energy and gradient includes time‐consuming inverse square roots and complementary error functions. To avoid such time‐consuming operations while keeping accuracy, we propose a new lookup table for short‐range interaction in PME by defining energy and gradient as a linear function of inverse distance squared. In our lookup table approach, densities of table points are inversely proportional to squared pair distances, enabling accurate evaluation of energy and gradient at small pair distances. Regardless of the inverse operation here, the new lookup table scheme allows fast pairwise nonbonded calculations owing to efficient usage of cache memory. © 2013 Wiley Periodicals, Inc.     

Effects of modifiers on the chromatographic behaviour of propafenone and its major metabolites

Summary Propafenone (PPF) is a new antiarrhythmic agent with structural features in common with the class of beta-blocking drugs (phenoxypropanolamines). Because of its high lipophilicity, the drug is strongly retained in reverse phase (RP) columns and simultaneous determination with the main polar metabolites 5-OH-PPF, N-depropyl-PPF and 5-OH-4-methoxy-PPF requires long run times (up to 50 min.) Oxidative metabolism in vivo often produces derivatives whose higher polarity results from the addition of a polar group and/or the subtraction of an apolar one. These metabolites show similar chromatographic behaviour in RP mode and the trade-off between their separation and the sensitivity of the parent compound must be investigated. In an effort to shorten the run time we examined the retention of these early eluting substances as a function of different amine additives, pH and organic content in mobile phase using C8 and C-18 columns from different sources, previously characterized for their free silanophilic and hydrophobic activities. Under optimal conditions the run time was reduced to 14 minutes and an application of the optimized method to the determination in plasma samples of the drug and its main metabolites after chronic therapy with PPF is presented. To investigate possible coelution of other yet undiscovered metabolites which could accumulate in some patients under chronic treatment, the analysis was carried out using an electrochemical detection in parallel with the UV. Agreement was found between the two detection procedures and suggest no interference.     

Human complement factor 3 polymorphism determination by capillary electrophoresis of serum

Variability of complement factor 3 (C3) mobility in serum protein electrophoresis was investigated. We found that the migration time of C3 can be reproducibly determined (beween‐run CV=0.76%) using clinical capillary electrophoresis (CE) equipment (the Capillarys? 2 system, Sebia). Moreover, we found a significant difference (p<0.001) in migration times of the major C3 phenotypes FF (fast‐fast), FS (fast‐slow) and SS (slow‐slow). Glycosylation did not significantly affect test results. This is the first report on the migration time of C3 phenotypes on a clinical CE instrument. The presented method allows faster data than agarose‐electrophoresis or genotyping. Moreover, reference ranges for serum C3 concentration depend on C3 phenotype, which allows a better tailored clinical interpretation of C3 concentrations.     

The influence of simulation conditions in molecular dynamics investigations of model β-sheet peptides

The influence of simulation methods, cutoff based and particle mesh Ewald (PME) on the accuracy by which experimentally derived nuclear Overhauser effect (NOE) data are reproduced, has been investigated using 500-ns-long molecular dynamics simulations on a model -sheet peptide in explicit solvent. The structural and conformational features under the different conditions were evaluated in terms of flexibility, secondary structure content, hydrogen-bonding pattern and percent of native contacts as a function of time. It was found that the different simulation methods strongly influence the dynamics of the peptide, confirming previous observations based on ideal peptide models simulated for much shorter times. Moreover, the results of our simulations prove once more that it is necessary to reach extremely long time scales to obtain enough statistics to accurately reproduce experimental NOE restraints even in the case of the PME method, despite its tendency to the stabilization of conformations which are structurally closely related to the ones derived through experiment. Possible implications regarding the stabilization and folding mechanisms, together with their relationship to the experimental study of peptide models, are discussed.     

Novel Ag ion-selective electrodes based on two new mixed azathioether crowns containing a 1,10-phenanthroline sub-unit

Novel polymeric membrane (PME) and coated graphite (CGE) silver-selective electrodes based on two recently synthesized mixed azathioether crowns containing a 1,10-phenanthroline sub-unit were prepared. The electrodes reveal a Nernstian behavior over quite wide Ag⁺ ion concentration ranges with a very low limits of detection (LOD) (i.e. down to 1.0×10⁻⁸ M for CGEs and 8.0×10⁻⁷ M for PMEs). The potentiometric responses are independent of the pH of the test solution in the pH range 3.0-7.0. The electrodes possess advantages of low resistance, very fast response time, relatively long lifetimes and, especially, good selectivities relative to a wide variety of other cations. The electrodes were used, as indicator electrodes, in the potentiometric titration of silver ion and in the determination of Ag⁺ in waste water, photographic emulsion and radiographic and photographic films.     

Micellar electrokinetic capillary chromatography of amoxycillin and related molecules.

A micellar electrokinetic capillary chromatographic method has been developed for the qualitative assay of amoxycillin and its degradation products and clavulanic acid. Together with amoxycillin the latter acid is an important constituent in the antibiotic Augmentin. The analytical procedure is fast and analytes can be identified both from their migration times and from changes in migration time observed either at different pH values or in electropherograms run in H2O and D2O based buffers of the same acidity.     

A fast gas chromatography/mass spectrometry method for the determination of stimulants and narcotics in urine

A fast method has been developed for the simultaneous determination of 52 stimulants and narcotics excreted unconjugated in urine by gas chromatography/mass spectrometry (GC/MS). The procedure involves the liquid/liquid extraction of the analytes from urine at strong alkaline pH and the injection of the extract into a GC/MS instrument with a fast GC column (10 m × 0.18 mm i.d.); the short column allows the complete separation of the 52 analytes in a chromatographic run of 8 min. The method has been fully validated giving lower limits of detection (LLODs) satisfactory for its application to antidoping analysis as well as to forensic toxicology. The repeatability of the concentrations and the retention times are good both for intra‐ and for inter‐day experiments (%CV of concentrations always lower than 15 and %CV of retention times lower than 0.6). In addition, the analytical bias is satisfactory (A% always >15%). The method proposed here would be particularly useful whenever there are time constraints and the analyses have to be completed in the shortest possible time. Copyright © 2010 John Wiley & Sons, Ltd.     

A comparison of protoporphyrin IX and protoporphyrin IX dimethyl ester as a photosensitizer in poorly differentiated human nasopharyngeal carcinoma cells

Protoporphyrin IX dimethyl ester (PME), a dimethyl esterification of protoporphyrin IX (PpIX), exhibits higher intracellular uptake into NPC/CNE2 cells, a poorly differentiated human nasopharyngeal carcinoma, than does PpIX. Phototoxicity studies reveal PME to be a more potent photosensitizer than is PpIX, at the early and late incubation time points. Correlating phototoxicity with subcellular localization indicates that PME is a more potent photosensitizer when its primary target of photodamage is mitochondria. Also, additional targeting of lysosome enhances phototoxicity.     

Salt-Assisted Graphene Oxide Dispersive Solid Phase Microextraction for Sensitive Detection of Malachite Green and Crystal Violet by HPLC

In this study, an efficient sample pretreatment method, salt-assisted graphene oxide dispersive solid phase microextraction (SA-GO-DSPME), was established for extraction of malachite green (MG) and crystal violet (CV). The dispersive graphene oxide was found to be easily aggregated and completely centrifuged in the presence of NaCl. The adsorption kinetic of SA-GO-DSPME was shown to be quite fast (equilibrium time = 5 min). Key parameters that influenced extraction efficiency including sample pH, the eluent type, GO amount, extraction time, NaCl concentration and centrifuging time were investigated. Coupled with SA-GO-DSPME, high-performance liquid chromatography (HPLC) could be used for sensitive detection of MG and CV with detection limits down to 1.7 and 0.3 ng mL^?1 for MG and CV, respectively. The relative standard deviations for extraction reproducibility (n = 5) were 1.8 % for MG and 3.8 % for CV. The proposed method has been successfully applied for detection of MG and CV in real water samples, and the recoveries ranged from 89.7 to 116.4 %. This simple and fast extraction method may provide a promising alternative for extraction of trace amount of MG and CV in complicated samples.     

Salt-Assisted Graphene Oxide Dispersive Solid Phase Microextraction for Sensitive Detection of Malachite Green and Crystal Violet by HPLC

In this study, an efficient sample pretreatment method, salt-assisted graphene oxide dispersive solid phase microextraction (SA-GO-DSPME), was established for extraction of malachite green (MG) and crystal violet (CV). The dispersive graphene oxide was found to be easily aggregated and completely centrifuged in the presence of NaCl. The adsorption kinetic of SA-GO-DSPME was shown to be quite fast (equilibrium time = 5 min). Key parameters that influenced extraction efficiency including sample pH, the eluent type, GO amount, extraction time, NaCl concentration and centrifuging time were investigated. Coupled with SA-GO-DSPME, high-performance liquid chromatography (HPLC) could be used for sensitive detection of MG and CV with detection limits down to 1.7 and 0.3 ng mL⁻¹ for MG and CV, respectively. The relative standard deviations for extraction reproducibility (n = 5) were 1.8 % for MG and 3.8 % for CV. The proposed method has been successfully applied for detection of MG and CV in real water samples, and the recoveries ranged from 89.7 to 116.4 %. This simple and fast extraction method may provide a promising alternative for extraction of trace amount of MG and CV in complicated samples.