Molecular insight into the specific binding of ADP-ribose to the nsP3 macro domains of chikungunya and Venezuelan equine encephalitis viruses: molecular dynamics simulations and free energy calculations

The outbreaks of chikungunya (CHIKV) and venezuelan equine encephalitis (VEEV) viral infections in humans have emerged or re-emerged in various countries of "Africa and southeast Asia", and "central and south America", respectively. At present, no drug or vaccine is available for the treatment and therapy of both viral infections, but the non-structural protein, nsP3, is a potential target for the design of potent inhibitors that fit at the adenosine-binding site of its macro domain. Here, so as to understand the fundamental basis of the particular interactions between the ADP-ribose bound to the nsP3 amino acid residues at the binding site, molecular dynamics simulations were applied. The results show that these two nsP3 domains share a similar binding pattern for accommodating the ADP-ribose. The ADP-ribose phosphate unit showed the highest degree of stabilization through hydrogen bond interactions with the nsP3 V33 residue and the consequent amino acid residues 110-114. The adenine base of ADP-ribose was specifically recognized by the conserved nsP3 residue D10. Additionally, the ribose and the diphosphate units were found to play more important roles in the CHIKV nsP3-ADP-ribose complex, while the ter-ribose was more important in the VEEV complex. The slightly higher binding affinity of ADP-ribose toward the nsP3 macro domain of VEEV, as predicted by the simulation results, is in good agreement with previous experimental data. These simulation results provide useful information to further assist in drug design and development for these two important viruses.     

Network Performance Improvement of All-Optical Networks Through an Algorithmic Based Dispersion Management Technique

Network blocking performance due to wavelength continuity constraint in a well-connected all-optical network can be efficiently reduced by utilizing wavelength converters. Nevertheless, the introduction of high bit rate optical services with strict tolerance to signal quality would have a serious impact on the overall network performance since in this circumstance, a request can be blocked due to unacceptable signal quality of potential routes. Chromatic dispersion tolerance, for example, is reduced by the square of the bit rate. By extending the typical application of parametric wavelength converter in solving a wavelength continuity problem, this paper aims to enhance chromatic dispersion management through an improved wavelength conversion algorithm. Consequently, significant improvement in network performance has been demonstrated through reduction in the dispersion effect when the proposed engineering rule is included in the conversion process.     

The study of hydrophobic hydration in supercritical water-methanol mixtures

We investigated hydrophobic hydration and heat capacity (CV) of diluted aqueous solutions of methanol at supercritical region using molecular dynamics method. We performed simulations for several concentrations of methanol and densities of mixtures. Similar to that observed for ambient conditions, the 600 K solution containing 0.12 mole fraction of methanol at the density of 0.98 gm.cm-3 yields the highest CV. The intermolecular structure between water and methanol molecules at this concentration was also found to be enhanced. Hydrophobic hydration, relative to ambient conditions, is diminished slightly at the concentration of Cv maximum and diminishes drastically for the other concentrations.     

Simple method for the layer-by-layer surface modification of multiwall carbon nanotubes

A simplified method for the surface modification of multiwall carbon nanotubes (MWCNTs) using the layer-by-layer (LbL) technique is proposed. In this approach, the minimum polyelectrolyte content was added to the solution in order to eliminate the tedious centrifugation step. The one pot LbL deposition of poly (diallyldimethylammonium chloride) (PDADMAC), and poly (sodium 4-styrenesulfonate), (PSS) is presented. UV–Vis spectroscopy and zeta potential measurements were used to determine the minimum PDADMAC and PSS concentration needed for the deposition of each polyelectrolyte layer. The deposition cycle was repeated until six layers of PDADMAC/PSS were deposited. The film growth was confirmed by transmission electron microcopy and was found to increase as a function of the number of deposited layers with a final thickness of 18 nm. Evidence of the alternate deposition of oppositely charged polyelectrolytes was further investigated by measurement of the zeta potential values which were found to reverse from positive to negative as a function of the number of deposited layers thus confirming the overcompensation of the surface charge at each adsorption step. This simple method could be useful for the fast preparation of large volumes of MWCNTs solutions in a single batch without the need for centrifugation step.     

How do carbon nanotubes serve as carriers for gemcitabine transport in a drug delivery system?

Aiming at understanding the molecular properties of the encapsulation of the anticancer drug gemcitabine in the single-walled carbon nanotube (SWCNT), molecular dynamics (MD) simulations were applied to the two scenarios; that of gemcitabine filling inside the SWCNT, and that of the drug in the free state. Inside the SWCNT, the cytosine ring of gemcitabine was found to form a π-π stacking conformation with the SWCNT surface, and this movement is not along the centerline of the tube from one end to the other of the tube where the distance from the center of gravity of the molecule to the surface is 4.7 ?. A tilted angle of 19° was detected between the cytosine ring of gemcitabine and the inner surface of SWCNT. In comparison to its conformation in the free form, no significant difference was observed on the torsion angle between the five- (ribose) and the six- (cytosine) membered rings. However, gemcitabine inside the SWCNT was found to have a lower number of solvating water molecules but with a stronger net solvation than the drug in the free state. This is due to the collaborative interactions between gemcitabine and the surface of the SWCNT. In addition, the steered molecular dynamics simulation (SMD) approach was employed to investigate the binding free energy for gemcitabine moving from one end to another end throughout the SWCNT. In excellent agreement with that yielded from the classical MD, the SMD energy profile confirms that the drug molecule prefers to locate inside the SWCNT.     

Structural and dynamical properties of different protonated states of mutant HIV-1 protease complexed with the saquinavir inhibitor studied by molecular dynamics simulations

To understand the basis of drug resistance, particularly of the HIV-1 PR, three molecular dynamics (MD) simulations of HIV-1 PR mutant species, G48V, complexed with saquinavir (SQV) in explicit aqueous solution with three protonation states, diprotonation on Asp25 and Asp25' (Di-pro) and monoprotonation on each Asp residue (Mono-25 and Mono-25'). For all three states, H-bonds between saquinavir and HIV-1 PR were formed only in the two regions, flap and active site. It was found that conformation of P2 subsite of SQV in the Mono-25 state differs substantially from the other two states. The rotation about 177 degrees from the optimal structure of the wild type was observed, the hydrogen bond between P2 and the flap residue (Val48) was broken and indirect hydrogen bonds with the three residues (Asp29, Gly27, and Asp30) were found instead. In terms of complexation energies, interaction energy of -37.3 kcal/mol for the Mono-25 state is significantly lower than those of -30.7 and -10.7kcal/mol for the Mono-25' and Di-pro states, respectively. It was found also that protonation at the Asp25 leads to a better arrangement in the catalytic dyad, i.e., the Asp25-Asp25' interaction energy of -8.8 kcal/mol of the Mono-25 is significantly lower than that of -2.6kcal/mol for the Mono-25' state. The above data suggest us to conclude that interaction in the catalytic area should be used as criteria to enhance capability in drug designing and drug screening instead of using the total inhibitor/enzyme interaction.     

SAC-CI theoretical investigation on electronic structure of fluorene-thiophene oligomers

The excited states of the fluorene-thiophene compounds whose polymers are useful as a light-emitting diode were studied by SAC-CI method. The effect of the torsional angle on the excited state was examined for the FT and FMT monomers in details. The first three excited states were calculated for the conformers of several torsional angles. These three excited states were found to change their characters by varying the torsional angle from 0 to 90°. The accurate absorption spectra were simulated by taking the thermal average for the conformers of torsional angle from 0 to 90°. The absorption spectra of dimer and trimer were also calculated at the equilibrium structure. It was found that the oscillator strength of S1 states of the dimer and trimer was very high and the red shift occurs due to the π-conjugation. The equilibrium structures are planar for both FT and FMT, and the calculated emission energies are in consistent agreement with the experiment. The effect of applying the electric fields to these molecules was examined.