DNA Compaction by a Dendrimer

At physiological pH, a PAMAM dendrimer is positively charged and can effectively bind negatively charged DNA. Currently, there has been great interest in understanding this complexation reaction both for fundamental (as a model for complex biological reactions) as well as for practical (as a gene delivery material and probe for sensing DNA sequence) reasons. Here, we have studied the complexation between double-stranded DNA (dsDNA) and various generations of PAMAM dendrimers (G3-05) through atomistic molecular dynamics simulations in the presence of water and ions. We report the compaction of DNA on a nanosecond time scale. This is remarkable, given the fact that such a short DNA duplex with a length close to 13 nm is otherwise thought to be a rigid rod. Using several nanoseconds long MD simulations, we have observed various binding modes of dsDNA and dendrimers for various generations of PAMAM dendrimers at varying charge ratios, and it confirms some of the binding modes proposed earlier. The binding is driven by the electrostatic interaction, and the larger the dendrimer charge, the stronger the binding affinity. As DNA wraps/binds to the dendrimer, counterions originally condensed onto DNA (Na+) and the dendrimer (Cl-) get released. We calculate the entropy of counterions and show that there is gain in entropy due to counterion release during the complexation. MD simulations demonstrate that, when the charge ratio is greater than 1 (as in the case of the G5 dendrimer), the optimal wrapping of DNA is observed. Calculated binding energies of the complexation follow the trend G5 > 04 > 03, in accordance with the experimental data. For a lower-generation dendrimer, such as G3, and, to some extent, for G4 also, we see considerable deformation in the dendrimer structure due to their flexible nature. We have also calculated the various helicoidal parameters of DNA to study the effect of dendrimer binding on the structure of DNA. The B form of the DNA is well preserved in the complex, as is evident from various helical parameters, justifying the use of the PAMAM dendrimer as a suitable delivery vehicle.

Antiulcerogenic activity of Terminalia chebula fruit in experimentally induced ulcer in rats

Objective: The present study is to evaluate the antiulcer effect of hydroalcoholic (70%) extract of Terminalia chebula fruit. Materials and methods: Aspirin, ethanol and cold restraint stress-induced ulcer methods in rats were used for the study. The effects of the extract on gastric secretions, pH, total and free acidity using pylorus ligated methods were also evaluated. Results: Animals pretreated with doses of 200 and 500 mg/kg hydroalcoholic extract showed significant reduction in lesion index, total affected area and percentage of lesion in comparison with control group (P < 0.05 and P < 0.01) in the aspirin, ethanol and cold restraint stress-induced ulcer models. Similarly extracts increased mucus production in aspirin and ethanol-induced ulcer models. At doses of 200 and 500 mg/kg of T. chebula extract showed antisecretory activity in pylorus ligated model, which lead to a reduction in the gastric juice volume, free acidity, total acidity, and significantly increased gastric pH. Discussion and conclusion: These findings indicate that hydroalcoholic extract of the fruit T. chebula displays potential antiulcerogenic activity. This activity thus lends pharmacological credence to the suggested use of the plant as a natural remedy in the treatment or management of ulcer.

Microtensile testing of a free-standing Pt-aluminide bond coat

A finite element method (FEM)-based study has been carried out for the design of flat microtensile samples to evaluate tensile properties of Pt-aluminide (PtAl) bond coats. The critical dimensions of the sample have been determined using a two-dimensional elastic stress analysis. In the present testing scheme, the ratio of the dimensions of the holding length to the fillet radius of the sample was found important to achieve failure within the gage length. The effect of gage length and grip head length also has been examined. The simulation predictions have been experimentally verified by conducting microtensile test of an actual PtAl bond coat at room temperature. The sample design and testing scheme suggested in this study have also been found suitable for evaluation of tensile properties at high temperature. (C) 2010 Elsevier Ltd. All rights reserved.

Physics-Based Thermal Conductivity Model for Metallic Single-Walled Carbon Nanotube Interconnects

In this letter, a closed-form analytical model for temperature-dependent longitudinal diffusive lattice thermal conductivity (kappa) of a metallic single-walled carbon nanotube (SWCNT) has been addressed. Based on the Debye theory, the second-order three-phonon Umklapp, mass difference (MD), and boundary scatterings have been incorporated to formulate. in both low-and high-temperature regimes. It is proposed that. at low temperature (T) follows the T-3 law and is independent of the second-order three-phonon Umklapp and MD scatterings. The form factor due to MD scattering also plays a key role in the significant variation of. in addition to the SWCNT length. The present diameter-independent model of. agrees well with the available experimental data on suspended intrinsic metallic SWCNTs over a wide range of temperature and can be carried forward for electrothermal analyses of CNT-based interconnects.

Analysis of Hydrogen Bonding and Stability of Protein Secondary Structures in Molecular Dynamics Simulation

Molecular Dynamics (MD) simulations provide an atomic level account of the molecular motions and have proven to be immensely useful in the investigation of the dynamical structure of proteins. Once an MD trajectory is obtained, specific interactions at the molecular level can be directly studied by setting up appropriate combinations of distance and angle monitors. However, if a study of the dynamical behavior of secondary structures in proteins becomes important, this approach can become unwieldy. We present herein a method to study the dynamical stability of secondary structures in proteins, based on a relatively simple analysis of backbone hydrogen bonds. The method was developed for studying the thermal unfolding of beta-lactamases, but can be extended to other systems and adapted to study relevant properties.

Composition Driven Monolayer to Bilayer Transformation in a Surfactant Intercalated Mg-Al Layered Double Hydroxide

The structure and organization of dodecyl sulfate (DDS) surfactant chains intercalated in an Mg-Al layered double hydroxide (LDH), Mg(1-x)Alx(OH)(2), with differing Al/Mg ratios has been investigated. The Mg-Al LDHs can be prepared over a range of compositions with x varying from 0.167 to 0.37 and therefore provides a simple system to study how the organization of the alkyl chains of the intercalated DDS anions change with packing density; the Al/Mg ratio or x providing a convenient handle to do so. Powder X-ray diffraction measurements showed that at high packing densities (x >= 0.3) the alkyl chains of the intercalated dodecyl sulfate ions are anchored on opposing LDH sheets and arranged as bilayers with an interlayer spacing of similar to 27 angstrom. At lower packing densities (x < 0.2) the surfactant chains form a monolayer with the alkyl chains oriented flat in the galleries with an interlayer spacing of similar to 8 angstrom. For the in between compositions, 0.2 <= x < 0.3, the material is biphasic. MD simulations were performed to understand how the anchoring density of the intercalated surfactant chains in the Mg-Al LDH-DDS affects the organization of the chains and the interlayer spacing. The simulations are able to reproduce the composition driven monolayer to bilayer transformation in the arrangement of the intercalated surfactant chains and in addition provide insights into the factors that decide the arrangement of the surfactant chains in the two situations. In the bilayer arrangement, it is the dispersive van der Waals interactions between chains in opposing layers of the anchored bilayer that is responsible for the cohesive energy of the solid whereas at lower packing densities, where a monolayer arrangement is favored, Coulomb interactions between the positively charged Mg-Al LDH sheets and the negatively charged headgroup of the DDS anion dominate.

Coalition Formation With Communication Ranges and Moving Targets

A team of unmanned aerial vehicles (UAVs) with limited communication ranges and limited resources are deployed in a region to search and destroy stationary and moving targets. When a UAV detects a target, depending on the target resource requirement, it is tasked to form a coalition over the dynamic network formed by the UAVs. In this paper, we develop a mechanism to find potential coalition members over the network using principles from internet protocol and introduce an algorithm using Particle Swarm Optimization to generate a coalition that destroys the target is minimum time. Monte-Carlo simulations are carried out to study how coalition are formed and the effects of coalition process delays.

Variable Sparsity Kernel Learning

This paper(1) presents novel algorithms and applications for a particular class of mixed-norm regularization based Multiple Kernel Learning (MKL) formulations. The formulations assume that the given kernels are grouped and employ l(1) norm regularization for promoting sparsity within RKHS norms of each group and l(s), s >= 2 norm regularization for promoting non-sparse combinations across groups. Various sparsity levels in combining the kernels can be achieved by varying the grouping of kernels-hence we name the formulations as Variable Sparsity Kernel Learning (VSKL) formulations. While previous attempts have a non-convex formulation, here we present a convex formulation which admits efficient Mirror-Descent (MD) based solving techniques. The proposed MD based algorithm optimizes over product of simplices and has a computational complexity of O (m(2)n(tot) log n(max)/epsilon(2)) where m is no. training data points, n(max), n(tot) are the maximum no. kernels in any group, total no. kernels respectively and epsilon is the error in approximating the objective. A detailed proof of convergence of the algorithm is also presented. Experimental results show that the VSKL formulations are well-suited for multi-modal learning tasks like object categorization. Results also show that the MD based algorithm outperforms state-of-the-art MKL solvers in terms of computational efficiency.

Chain folding and A:T pairing in human telomeric DNA: a model-building and molecular dynamics study

The various types of chain folding and possible intraloop as well as interloop base pairing in human telomeric DNA containing d(TTAG(3)) repeats have been investigated by model-building, molecular mechanics, and molecular dynamics techniques. Model-building and molecular mechanics studies indicate that it is possible to build a variety of energetically favorable folded-back structures with the two TTA loops on same side and the 5' end thymines in the two loops forming TATA tetrads involving a number of different intraloop as well as interloop A:T pairing schemes. In these folded-back structures, although both intraloop and interloop Watson-Crick pairing is feasible, no structure is possible with interloop Hoogsteen pairing. MD studies of representative structures indicate that the guanine-tetraplex stem is very rigid and, while the loop regions are relatively much more flexible, most of the hydrogen bonds remain intact throughout the 350-ps in vacuo simulation. The various possible TTA loop structures, although they are energetically similar, have characteristic inter proton distances, which could give rise to unique cross-peaks in two-dimensional nuclear Overhauser effect spectroscopy (NOESY) experiments. These folded-back structures with A:T pairings in the loop region help in rationalizing the data from chemical probing and other biochemical studies on human telomeric DNA.

Molecular dynamics studies on nucleoside 2',3'-cyclic phosphates

2',3'-cyclic nucleotides are intermediates and substrates of Ribonuclease (RNase)-catalysed reactions. The characterization of the equilibrium conformation as well as the flexibility inherent in these molecules helps in understanding the enzymatic action of RNases. The present study explores parameters like phase angle, glycosydic torsion angle and hydrogen bond to find possible interrelationship between them through Molecular Dynamics (MD) simulations on 3'-GMP, 3'-UMP, A>p, G>p, U>p, C>p, GpA>p and UpA>p. Interesting results of the effect of cyclisation and other constraints such as hydrogen bond between certain groups on the equilibrium ribose conformation have emerged from this study.

Diffusion Anomaly in Silicalite and VPI-5 from Molecular Dynamics Simulations

Molecular dynamics (MD) simulations on rigid and flexible framework models of silicalite and a rigid framework model of the aluminophosphate VPI-5 for different sorbate diameters are reported. The sorbate-host interactions are modeled in terms of simple atom-atom Lennard-Jones interactions. The results suggest that the diffusion coefficient exhibits an anomaly as gamma approaches unity. The MD results confirm the existence of a linear regime for sorbate diameters significantly smaller than the channel diameter and an anomalous regime observed for sorbate diameters comparable to the channel diameter. The power spectra obtained by Fourier transformation of the velocity autocorrelation function indicate that there is an increase in the intensity of the low-frequency component for the velocity component parallel to the direction of motion for the sorbate diameter in the anomalous regime. The present results suggest that the diffusion anomaly is observed irrespective of (1) the geometry and topology of the pore structure and (2) the nature of the host material. The results are compared with the work of Derouane and co-workers, who have suggested the existence of ''floating molecules'' on the basis of earlier theoretical and computational approaches.

Effect of Strain Rate on Ductile-to-Brittle Transition Temperature of a Free-Standing Pt-Aluminide Bond Coat

The ductile-to-brittle transition temperature (DBTT) of a free-standing Pt-aluminide (PtAl) bondcoat was determined using the microtensile testing method and the effect of strain rate variation, in the range 10(-5) to 10(-1) s(-1), on the DBTT studied. The DBTT increased appreciably with the increase in strain rate. The activation energy determined for brittle-to-ductile transition, suggested that such transition is most likely associated with vacancy diffusion. Climb of aOE (c) 100 > dislocations observed in analysis of dislocation structure using a transmission electron microscope (TEM) supported the preceding mechanism.

Modeling of angiogenin-3 '-NMP complex

Angiogenin belongs to the Ribonuclease superfamily and has a weak enzymatic activity that is crucial for its biological function of stimulating blood vessel growth. Structural studies on ligand bound Angiogenin will go a long way in understanding the mechanism of the protein as well as help in designing drugs against it. In this study we present the first available structure of nucleotide ligand bound Angiogenin obtained by computer modeling. The importance of this study in itself notwithstanding, is a precursor to modeling a full dinucleotide substrate onto Angiogenin. Bovine Angiogenin, the structure of which has been solved at a high resolution, was earlier subjected to Molecular Dynamics simulations for a nanosecond. The MD structures offer better starting points for docking as they offer lesser obstruction than the crystal structure to ligand binding. The MD structure with the least serious short contacts was modeled to obtain a steric free Angiogenin - 3' mononucleotide complex structure. The structures were energetically minimized and subjected to a brief spell of Molecular Dynamics. The results of the simulation show that all the li,ligand-Angiogenin interactions and hydrogen bonds are retained, redeeming the structure and docking procedure. Further, following ligand - protein interactions in the case of the ligands 3'-CMP and 3'-UMP we were able to speculate on how Angiogenin, a predominantly prymidine specific ribonuclease prefers Cytosine to Uracil in the first base position.

Absolute Entropy and Energy of Carbon Dioxide Using the Two-Phase Thermodynamic Model

The two-phase thermodynamic (2PT) model is used to determine the absolute entropy and energy of carbon dioxide over a wide range of conditions from molecular dynamics trajectories. The 2PT method determines the thermodynamic properties by applying the proper statistical mechanical partition function to the normal modes of a fluid. The vibrational density of state (DoS), obtained from the Fourier transform of the velocity autocorrelation function, converges quickly, allowing the free energy, entropy, and other thermodynamic properties to be determined from short 20-ps MD trajectories. The anharmonic effects in the vibrations are accounted for by the broadening of the normal modes into bands from sampling the velocities over the trajectory. The low frequency diffusive modes, which lead to finite DoS at zero frequency, are accounted for by considering the DoS as a superposition of gas-phase and solid-phase components (two phases). The analytical decomposition of the DoS allows for an evaluation of properties contributed by different types of molecular motions. We show that this 2PT analysis leads to accurate predictions of entropy and energy of CO2 over a wide range of conditions (from the triple point to the critical point of both the vapor and the liquid phases along the saturation line). This allows the equation of state of CO2 to be determined, which is limited only by the accuracy of the force field. We also validated that the 2PT entropy agrees with that determined from thermodynamic integration, but 2PT requires only a fraction of the time. A complication for CO2 is that its equilibrium configuration is linear, which would have only two rotational modes, but during the dynamics it is never exactly linear, so that there is a third mode from rotational about the axis. In this work, we show how to treat such linear molecules in the 2PT framework.