Contributions of 3'-overhang to the dissociation of small interfering RNAs from the PAZ domain: molecular dynamics simulation study

RNA interference (RNAi) is a ‘knock-down’ reaction to reduce expression of a specific gene through highly regulated, enzyme-mediated processes. Small interfering RNAs (siRNAs) are RNA molecules that play an effector role in RNAi and can bind the PAZ domains present in Dicer and RISC. We investigated the interaction between the PAZ domain and the siRNA-like duplexes through dissociation molecular dynamics (DMD) simulations. Specifically, we focused on the response of the PAZ domain to various 3′-overhang structures of the siRNA-like duplexes. We found that the siRNA-like duplex with the 3′ UU-overhang made relatively more stable complex with the PAZ domain compared to those with 3′ CC-, AA-, and GG-overhangs. The siRNA-like duplex with UU-overhang was easily dissociated from the PAZ domain once the structural stability of the complex is impaired. Interestingly, the 3′ UU-overhang spent the least time at the periphery region of the binding pocket during the dissociation process, which can be mainly attributable to UU-overhang's smallest number of hydrogen bonds.     

基于TDR的多孔介质中含水/水合物饱和度测量方法仿真研究

为了优化设计时域反射技术（TDR）中的探针结构,建立基于TDR响应的含水/水合物测量模型,利用有限元数值模拟方法建立了TDR测量过程数值仿真模型。分别以空气、不同浓度氯化钠溶液以及不同水合物含量的石英砂为被测介质验证了模型的正确性、研究了被测介质电导率和介电常数对反射波形的影响规律。通过改变被测介质的介电常数来模拟含水/水合物饱和度不同的石英砂,随着石英砂中水合物含量的增加,含水量逐渐降低,表观介电常数随之减小,电磁波传播速度随之以非线性形式增加;与理论值相比较,仿真计算所得到的传播速度最大误差处于5%以内。下一步需要在数值模型中的被测区域中填充各相异性材料来更加真实地模拟含水合物沉积物被测介质。     

Functionalized graphene as a nanostructured membrane for removal of copper and mercury from aqueous solution: A molecular dynamics simulation study

The purpose of the present study was to investigate the removal of copper and mercury using functionalized graphene as a nanostructured membrane. The molecular dynamics simulation method was used to investigate the removal ability of these ions from aqueous solution using functionalized graphene membrane. The studied systems included a functionalized graphene membrane which was placed in the aqueous ionic solution of CuCl₂ and HgCl₂. An external electrical field was applied along the z axis of the system. The results indicated that the application of electrical field on the system caused the desired ions to pass through the functionalized graphene membrane. The Fluorinated pore (F-pore) terminated graphene selectively conducted Cu²⁺ and Hg²⁺ ions. The calculation of the potential of mean force of ions revealed that Cu²⁺ and Hg²⁺ ions face a relatively small energy barrier and could not pass through the F-pore graphene unless an external electrical field was applied upon them. In contrast, the energy barrier for the Cl⁻ ion was large and it could not pass through the F-pore graphene. The findings of the study indicate that the permeation of ions across the graphene was a function of applied electrical fields. The findings of the present study are based on the detailed analysis and consideration of potential of mean force and radial distribution function curves.     

Effect of graphene oxide on the conformational transitions of amyloid beta peptide: A molecular dynamics simulation study

The interactions between nanomaterials (NMs) and amyloid proteins are central to the nanotechnology-based diagnostics and therapy in neurodegenerative disorders such as Alzheimer's and Parkinson's. Graphene oxide (GO) and its derivatives have shown to modulate the aggregation pattern of disease causing amyloid beta (Aβ) peptide. However, the mechanism is still not well understood. Using molecular dynamics simulations, the effect of graphene oxide (GO) and reduced graphene oxide (rGO) having carbon:oxygen ratio of 4:1 and 10:1, respectively, on the conformational transitions (alpha-helix to beta-sheet) and the dynamics of the peptide was investigated. GO and rGO decreased the beta-strand propensity of amino acid residues in Aβ. The peptide displayed different modes of adsorption on GO and rGO. The adsorption on GO was dominated by electrostatic interactions, whereas on rGO, both van der Waals and electrostatic interactions contributed in the adsorption of the peptide. Our study revealed that the slight increase in the hydrophobic patches on rGO made it more effective inhibitor of conformational transitions in the peptide. Alpha helix-beta sheet transition in Aβ peptide could be one of the plausible mechanism by which graphene oxide may inhibit amyloid fibrillation.     

典型矿区煤层气与煤炭协调开发动态模拟研究

针对传统方法难以展现煤层气与煤炭协调开发流程的问题,提出了一种新的三维动态模拟思路,采用三维可视化和动画推演的方法展示煤层气与煤炭协调开发模式。以"晋城模式"为背景,基于数字矿山三维平台MineSystem,采用井上下三维一体化快速建模、协调开发三维可视化动态编辑、三区联动立体抽采动画推演等关键技术,完成了三区联动井上下整体抽采煤层气开发模式的动态模拟,实现了生产规划区、开拓准备区、煤炭生产区三维一体化整体展示,为促进煤层气与煤炭协调开发利用工艺的推广应用提供了技术支撑。     

Factors responsible for the aggregation behavior of hydrophobic polyelectrolyte PEA in aqueous solution studied by molecular dynamics simulations

Self-association (i.e. interchain aggregation) behavior of atactic poly(ethacrylic acid) PEA in dilute aqueous solution as function of degree-of-neutralization by Na⁺ counter-ions (i.e. charge fraction f) was investigated by molecular dynamics simulations. Aggregation is found to occur in the range 0 ≤ f ≤0.7 in agreement with experimental results compared at specified polymer concentration C_p = 0.36 mol/l in dilute solution. The macromolecular solution was characterized and analysed for radius-of-gyration, torsion angle distribution, inter and intra-molecular hydrogen bonds, radial distribution functions of intermolecular and inter-atomic pairs, inter-chain contacts and solvation enthalpy. The PEA chains form aggregate through attractive inter-chain interaction via hydrogen bonding, in the range f < 0.7, in agreement with experimental observation. The numbers of inter-chain contacts decreases with f. A critical structural transition occurs at f = 0.7, observed via simulations for the first time, in R_g as well as inter-chain H-bonds. The inter-chain distance increases with f due to repulsive interactions between COO− groups on the chains. PEA-PEA electrostatic interactions dominant solvation enthalpy. The PEA solvation enthalpy becomes increasingly favorable with increase in f. The transition enthalpy change, in going from uncharged (acid) state to fully charged state (f = 1) is unfavorable towards aggregate formation.     

Deconstruction of the human connexin 26 hemichannel due to an applied electric field; A molecular dynamics simulation study

Connexins are a 21-member membrane protein family constituting channels evolved in direct communication between adjacent cells by passaging cytoplasmic molecules and ions. Hexametrical assembly of connexin proteins in plasma membrane forms a wide aqueous pore known as connexin hemichannel. These hemichannels mediate cytoplasm and extracellular milieu communication both in many external tissues and in the central nervous system. In this study, a series of molecular dynamics simulations has been performed to investigate the effect of applied static and alternating electric fields on the stability and conformation of human connexin26 hemichannel. The root mean square deviations of C-alpha atoms, the dipole moment distribution, the number of inter-protein hydrogen bonds and the number of water-protein hydrogen bonds were used to assess connexin26 hemichannel stability. In the static field case, our results show that although the lowest field used in this study (0.1 V/nm) does not lead to the hemichannel deconstruction, stronger fields (>0.1 V/nm), however, disrupt the protein structure during the simulations time period. Furthermore, in the alternating case, compared to static field case, field effects on the connexin26 hemichannel conformation are reduced and consequently the protein maintains its native structure for longer times. Specifically, for the highest frequency used in this study (50 GHz), the hemichannel keeps its structure even under the effect of the strongest field (0.4 V/nm). According to our results, the protein secondary structure is preserved in the characteristic times determined for the protein deconstruction. Consequently, we suggest that the protein deconstruction is due to the tertiary and quaternary structure loss.     

Study of the mechanism of protonated histidine-induced conformational changes in the Zika virus dimeric envelope protein using accelerated molecular dynamic simulations

The Zika virus has drawn worldwide attention because of the epidemic diseases it causes. It is a flavivirus that has an icosahedral protein shell constituted by an envelope glycoprotein (E-protein) and membrane protein (M-protein) in the mature virion. The multistep process of membrane fusion to infect the host cell is pH-induced. To understand the mechanism of the conformational changes in the (E-M)₂ protein homodimer embedded in the membrane, two 200-ns accelerated dynamic simulations were performed under different pH conditions. The low pH condition weakens the interactions and correlations in both E-protein monomers and in the E-M heterodimer. The highly conserved residues, His249, His288, His323 and His446, are protonated under low pH conditions and play key roles in driving the fusion process. The analysis and discussion in this study may provide some insight into the molecular mechanism of Zika virus infection.     

Solvent effect on the crystal morphology of 2,6-diamino-3,5-dinitropyridine-1-oxide: A molecular dynamics simulation study

The attachment energy (AE) calculations were performed to predict the growth morphology of 2,6-diamino-3,5-dinitropyridine-1-oxide (ANPyO) in vacuum. The molecular dynamics (MD) method was applied to simulate the interaction of trifluoroacetic acid solvent with the habit faces and the corrected AE model was adopted to predict the growth habit of ANPyO in the solvent. The results indicate that the growth morphology of ANPyO in vacuum is dominated by (1 1 0), (1 0 0), (1 0 −1) and (1 1 −2) faces. The corrected AE energies change in the order of (1 1 0) > (1 0 −1) > (1 1 −2) > (1 0 0), which causes the crystal morphology to become very close to a flake in trifluoroacetic acid solvent and accords well with the results obtained from experiments. The radial distribution function analysis shows that the solvent molecules adsorb on the ANPyO faces mainly via the solvent–crystal face interactions of hydrogen bonds, Coulomb and Van der Waals forces. In addition to the above results, the analysis of diffusion coefficient of trifluoroacetic acid molecules on the crystal growth faces shows that the growth habit is also affected by the diffusion capacity of trifluoroacetic acid molecules. These suggestions may be useful for the formulation design of ANPyO.     

Studying the adsorption of DNA nanostructures on graphene in the aqueous phase using molecular dynamic simulations

DNA nanostructures can undergo large structural fluctuations and deviate from their intended configurations. In this work, two model DNA nanostructures (i.e., Nan and Kai) were designed based on the shape of the two Chinese characters of the name of Nankai University, and additional single-stranded DNA fragments were added to interact with graphene. During four 50-ns molecular dynamic simulations in aqueous solution, the DNA nanostructures adsorbed onto graphene demonstrated more stable conformations with lower root mean square deviations and smaller coordinate changes in the z-axis direction than the DNA nanostructures that were not adsorbed onto graphene. The interaction analyses and energetic calculations show that π-π interactions between single-stranded DNA and graphene are necessary for adsorption of the DNA nanostructures. Overall, this work examined the interactions between DNA and graphene at a large spatial scale with the hope that it provides a new strategy to stabilize DNA nanostructures.     

A method for determining the mutual diffusion coefficient of molecular solutes based on surface plasmon resonance sensing

An experimental method, combining surface plasmon resonance sensing and microfluidics, to determine the mutual diffusion coefficient of molecular solutes, as ethanol and bovine serum albumin, is presented. Representative refractive index variations of analyte samples over time, and associated dynamic solute concentration profiles, respectively, have been employed to access molecular transport parameters. From both, Fick’s diffusion length and Taylor’s pulse dispersion methods, solute and solvent mutual diffusion coefficients for diluted ethanol and concentrated protein aqueous solutions have been obtained. Additionally, the dynamic behavior and geometry effects of molecular transport have been exploited using finite element simulations for the 3-dimensional case and confirmed experimentally. The numerical simulation also addresses the influence of temperature effects.     

Effect of temperature on the structure and hydration layer of TATA-box DNA: A molecular dynamics simulation study

DNA within the living cells experiences a diverse range of temperature, ranging from freezing condition to hot spring water. How the structure, the mechanical properties of DNA, and the solvation dynamics around DNA changes with the temperature is important to understand the functionality of DNA under those acute temperature conditions. In that notion, we have carried out molecular dynamics simulations of a DNA oligomer, containing TATA-box sequence for three different temperatures (250 K, 300 K and 350 K). We observed that the structure of the DNA, in terms of backbone torsion angles, sugar pucker, base pair parameters, and base pair step parameters, did not show any unusual properties within the studied range of temperatures, but significant structural alteration was noticed between B_I and B_II forms at higher temperature. As expected, the flexibility of the DNA, in terms of the torsional rigidity and the bending rigidity is highly temperature dependent, confirming that flexibility increases with increase in temperature. Additionally, the groove widths of the studied DNA showed temperature sensitivity, specifically, the major groove width decreases and the minor groove width increases, respectively, with the increase in temperature. We observed that at higher temperature, water around both the major and the minor groove of the DNA is less structured. However, the water dynamics around the minor groove of the DNA is more restricted as compared to the water around the major groove throughout the studied range of temperatures, without any anomalous behavior.     

A study on performance of dynamic file replication algorithms for real-time file access in Data Grids

Real-time Grid applications are emerging in many disciplines of science and engineering. In order to run these applications while meeting the associated real-time constraints with them, the Grid infrastructure should be designed to respect these constraints and allocate its computing, networking, storage, and the other resources accordingly. Furthermore, these applications involve a large number of data intensive jobs and require to access terabytes of data in real-time. On the other hand, a variety of dynamic file replication algorithms were proposed for the best-effort Data Grid environments in an attempt to decrease job completion times and save network bandwidth. Until now, there is no study in the literature which tries to elaborate on the real-time performance of these dynamic file replication algorithms. Based on this motivation, in this study, the performance of eight dynamic replication algorithms are evaluated under various Data Grid settings. For this evaluation, a process oriented and discrete-event driven simulator called DGridSim is developed. A detailed set of simulation studies are conducted using DGridSim and the results obtained are presented to reveal the real-time performance of the dynamic file replication algorithms.     

Understanding the molecular mechanism and regioselectivity in the synthesis of celecoxib via a domino reaction: A DFT study

The molecular mechanism and energetic of the domino reaction involved in the synthesis of celecoxib, a well-known anti-inflammatory drug, were theoretically studied at the DFT-B3LYP/6-31G^* level. The first reaction in this domino process, which is also the rate-determining step, is a complete regioselective [3 + 2] cycloaddition (32CA) reaction associated with the nucleophilic attack of C5 carbon atom of enamine 7 on the C3 carbon atom of nitrile imine 6, leading to cycloadduct 8. The second reaction is a rapid acid/base catalysed stepwise elimination reaction of the morpholine 9 from cycloadduct 8 affording celecoxibe 3. The results also show that neither molecular mechanism of reaction nor activation barriers are considerably affected by the inclusion of solvent. The calculated relative Gibbs free energies as well as local reactivity indices obtained using the calculated Parr functions explain the complete regioselective fashion provided by the 32CA reaction under consideration in excellent agreement with the experimental findings.     

Understanding the molecular basis of stability in Kunitz (STI) family of inhibitors in terms of a conserved core tryptophan residue: A theoretical investigation

β-trefoil is one of the superfolds among proteins. Important classes of proteins like Interleukins (ILs), FibroblastGrowth Factors (FGFs), Kunitz (STI) family of inhibitors etc. belong to this fold. Kunitz (STI) family of inhibitors of proteins possess a highly conserved and structurally important Trytophan 91 (W91) residue, which stitches the top layer of the barrel with the lid. In this article we have investigated the molecular insights of the involvement of this W91 residue in the stability and folding pathway of Kunitz (STI) family. Winged bean Chymotrypsin inhibitor (WCI), a member of Kunitz (STI) family was chosen as a model system for carrying out the work. Molecular dynamics (MD) simulations were run with a set of total six proteins, including wild type WCI (WT) & five mutants namely W91F, W91M, W91A, W91H and W91I. Among all of them the coordinates of four proteins were taken from their crystal structures deposited in the Protein Data Bank (PDB), where as the coordinates for the rest two was generated using in-silico modelling. Our results suggest that truly this W91 residue plays a determining role in stability and folding pathway of Kunitz (STI) family. The mutants are less stable and more susceptible to quicker unfolding at higher temperatures compared to the wild type WCI. These effects are most pronounced for the smallest mutants namely W91H and W91A, indicating more is the cavity created by mutation at W91 position more the proteins becomes unstable.     

阿霉素纳米粒的制备与模拟体外释放行为

制备以聚乙烯吡咯烷酮为载体的阿霉素纳米粒,研究纳米粒在生理盐水中的释放行为,并采用不同数学模型模拟。结果表明,制备的阿霉素纳米粒粒径小,球形度好;体外释放结果表明阿霉素纳米粒具有缓释特性,且双相动力学方程能模拟阿霉素纳米粒在生理盐水中的释放行为。     

Molecular modeling study on the effect of residues distant from the nucleotide-binding portion on RNA binding in Staphylococcus aureus Hfq

Hfq is an abundant RNA-binding bacterial protein that was first identified in E. coli as a required host factor for phage Qβ RNA replication. The pleiotrophic phenotype resulting from the deletion of Hfq predicates the importance of this protein. Two RNA-binding sites have been characterized: the proximal site which binds sRNA and mRNA and the distal site which binds poly(A) tails. Previous studies mainly focused on the key residues in the proximal site of the protein. A recent mutation study in E. coli Hfq showed that a distal residue Val43 is important for the protein function. Interestingly, when we analyzed the sequence and structure of Staphylococcus aureus Hfq using the CONSEQ server, the results elicited that more functional residues were located far from the nucleotide-binding portion (NBP). From the analysis seven individual residues Asp9, Leu12, Glu13, Lys16, Gln31, Gly34 and Asp40 were selected to investigate the conformational changes in Hfq–RNA complex due to point mutation effect of those residues using molecular dynamics simulations. Results showed a significant effect on Asn28 which is an already known highly conserved functionally important residue. Mutants D9A, E13A and K16A depicted effects on base stacking along with increase in RNA pore diameter, which is required for the threading of RNA through the pore for the post-translational modification. Further, the result of protein stability analysis by the CUPSAT server showed destabilizing effect in the most mutants. From this study we characterized a series of important residues located far from the NBP and provide some clues that those residues may affect sRNA binding in Hfq.     

Traffic aware dynamic load distribution in the Data Plane of SDN using Genetic Algorithm: A case study on NSF network

For a particular topology, with the best controller and switch positions SDN occasionally exhibits subpar performance, resulting in annoyance-inducing delays and unsatisfied users. Increased traffic volume can lead to congestion, which raises the burden on specific switches and controllers and lengthens the delay of data transmission. Additionally, the failure of specific nodes or links might result in an anomalous rise in the traffic load on specific switches and controllers. The conventional switch migration and congestion control techniques might not be sufficient to deliver the best throughput and capacity for frequent and unpredictable network traffic variations. Also, certain switches/controllers may experience heavy traffic load as compared to other switches/controllers. Under such adverse situations, the performance of the network becomes extremely poor. In light of these factors, this paper suggests an effective approach based on Genetic Algorithm for traffic load distribution in the Data Plane of SDN, which effectively reroutes packet flows (when such an adverse situation arises) in order to avoid abnormal load on switches/links and maintain acceptable network performance with the available resources. The proposed approach was applied to the NSF network and a case study was performed. The proposed approach was evaluated and found to be quite effective in reducing abnormal loads on switches/links as it is found that there can be a decrease in the average load by 396 units at the cost of increasing the average latency by 1.29 ms only.