How amantadine and rimantadine inhibit proton transport in the M2 protein channel

To understand how antiviral drugs inhibit the replication of influenza A virus via the M2 ion channel, molecular dynamics simulations have been applied to the six possible protonation states of the M2 ion channel in free form and its complexes with two commercial drugs in a fully hydrated lipid bilayer. Among the six different states of free M2 tetramer, water density was present in the pore of the systems with mono-protonated, di-protonated at adjacent position, tri-protonated and tetra-protonated systems. In the presence of inhibitor, water density in the channel was considerably better reduced by rimantadine than amantadine, agreed well with the experimental IC(50) values. With the preferential position and orientation of the two drugs in all states, two mechanisms of action, where the drug binds to the opening pore and the histidine gate, were clearly explained, i.e., (i) inhibitor was detected to localize slightly closer to the histidine gate and can facilitate the orientation of His37 imidazole rings to lie in the close conformation and (ii) inhibitor acts as a blocker, binding at almost above the opening pore and interacts slightly with the three pore-lining residues, Leu26, Ala30 and Ser31. Here, the inhibitors were found to bind very weakly to the channel due to their allosteric hindrance while theirs side chains were strongly solvated.     

The hydration structure of 18-crown-6/K+ complex as studied by Monte Carlo simulation using ab initio fitted potential

The intermolecular potential between a 18-crown-6/K+ complex and a water molecule is derived from 1200 energy points obtained from quantum chemical calculations using the 6-31G** basis set. The ab initio fitted potential was then applied to study the structural properties of the complex in an aqueous solution using the Monte Carlo simulation method. The radial distribution function (RDF) centered at K+ to the oxygen atom of water shows a sharp first peak at 2.88 A. The corresponding coordination number, integrated up to the first minimum at 3.76 A, is 2 water molecules. The results indicate clearly that the 18-crown-6/K+ complex was solvated by the two nearest neighbors, one above and other below the ligand's plane. Evaluation was focused on the precise position and orientation of the two water molecules. It was found that the oxygen atoms of the two nearest neighbors bind to the K+ while their hydrogen atoms rotate freely around the vector perpendicular to the ligand's molecular plane.     

Stress Induced and Inherent Anisotropy on Elastic Stiffness of Soft Clays

The influence of anisotropy on the elastic shear modulus of clays was addressed using test results obtained from a series of laboratory tests; i.e., triaxial test and Square oedometer. Under various stress stages imposing under triaxial condition, the deviator stress had an indiscernible influence on the elastic shear modulus. The path of vertically logged elastic shear modulus of clay could reasonably be expressed in terms of mean effective stress. Two pairs of bender elements were installed in the square oedometer so that shear wave velocities of samples which were trimmed parallel or perpendicular to their bedding direction can be measured in the vertical and horizontal directions. For sample trimmed parallel to the bedding direction (conventional one), the horizontal shear wave velocity was larger than the vertical one. The opposite observation, however, was observed for sample trimmed 90 degrees apart. The extents of different in vertically and horizontally logged shear wave velocities from both types of samples were almost similar. This clearly indicated the influence of inherent anisotropy rather than the stress induced. The mean effective stress can well represent the stage variable of elastic shear modulus.     

Insight into analysis of interactions of saquinavir with HIV-1 protease in comparison between the wild-type and G48V and G48V/L90M mutants based on QM and QM/MM calculations

Saquinavir (SQV) was the first HIV-1 PR inhibitor licensed for clinical use and widely used for acquired immunodeficiency syndrome (AIDS) therapy. Its effectiveness, however, has been hindered by the emergence of resistant mutations. The two most important HIV-1 PR mutants are G48V and G48V/L90M. Inhibition studies of SQV on these mutants demonstrated 13.5- and 419-fold reductions of susceptibility, respectively. In this study, an analysis of energetic binding affinity between saquinavir and the HIV-1 PR wild-type and these two mutants has been performed in detail based on density functional theory and the hybrid quantum mechanical/molecular mechanical (QM/MM) calculations. We have found that the interaction of SQV with flap residue 48 of the mutants is significantly perturbed, as shown by the reduced stability of binding between SQV and residue 48 for the G48V and G48V/L90M mutants over the wild-type. This was associated with conformational changes of the inhibitor and the enzyme, leading to the loss of hydrogen bonding between the binding subsite P2 and the backbone carbonyl of residue 48. Moreover, the G48V/L90M mutations cause the repositioning of the residues close to residues 48 and 90, at important locations as a part of the flap and catalytic regions, respectively. The repositioning of these residues consequently perturbed the binding affinity of SQV in the pocket as indicated by the decreasing interaction energies. In addition to the loss of inhibitor/enzyme binding, it is interesting to observe that the mutation leads significantly to an increase of the stability of the enzyme.     

Structural analysis of lead fullerene-based inhibitor bound to human immunodeficiency virus type 1 protease in solution from molecular dynamics simulations

Molecular dynamics (MD) simulations of the HIV-1 protease (HIVP) complexed with lead fullerene-based inhibitor (diphenyl C60 alcohol) in the three protonated states, unprotonated (Un-), monoprotonated (Mono-), and diprotonated (Di-) states at Asp25 and Asp25' were performed. As the X-ray structure of the investigated complex is not available, it was built up starting with the X-ray crystallographic structure of the HIVP complexed with non-peptide inhibitor (PDB code: 1AID) and that of the diphenyl C60 alcohol optimized using the integrated ONIOM molecular orbital calculations. The inhibitor was, then, introduced into the enzyme pocket using a molecular docking method. Change of the HIVP binding cavity for all three states were evaluated in terms of distance between the two catalytic residues, Asp25 and Asp25' as well as those between the catalytic residues and the flap regions. The torsional angles formed by the O-C-C-O of the two carboxyl groups of the catalytic dyad show the non-planar configuration with the most frequency at about -45 degrees for the Un-, 35 degrees and -95 degrees for the Mono- and 60 degrees for the Di-systems. At equilibrium, different orientations of the fullerene-based inhibitor in the three protonation states were observed. For the Di-state, the OH group of the inhibitor stably forms hydrogen bonds with the two aspartic residues. It turns to the flap region to form hydrogen bonding to the backbone N of Ile50' for the Un-state. In contrast, the OH group turns to locate between the catalytic and the flap region for the Mono-states. Beside the molecular orientation, the rotation of the OH group of the inhibitor in the Un-state was also detected. In terms of solvation, the carboxylate oxygens of the aspartic residues in the Un- and Mono-states were solvated by one to three water molecules while the OH group in these two states was coordinated by one water molecule. This is in contrast to the Di-state in which no water molecule is available in the radius of 5-6A around the oxygen atoms of the carboxylate groups of enzyme and of the OH group of the inhibitor. The simulated results lead to the conclusion that the active site of the HIVP complexed with the diphenyl C60 alcohol is the diprotonation states on Asp25 and Asp25'.     

Mobile Technology: Opportunity for Entrepreneurship

The recent extraordinary growth of smart phones and tablets gives rise to the mobile application market. It opens up opportunity for new type of entrepreneurs to tap into the fast-growing mobile application market, bypassing the incumbent operators and requiring minimal capitals. Therefore, focus should be given to promoting these mobile entrepreneurs in order to change Thailand from a ‘consumer’ to a ‘producer’ of ICT technologies. This paper reviews recent trends on mobile technology in the mobile ecosystem and mobile application market. It then identifies emerging opportunity for business entrepreneurs. Furthermore, the measures being implemented by Mobile Technology for Thailand ( $\text{ MT}^{2})$ , an alliance from government, business and education sectors for promotion of mobile application industry, are explained. Specifically, it consists of human resource development, entrepreneur incubation and marketing support. It is expected that by focusing on inspiring a new generation of mobile application developers into entrepreneurship, incubating them into successful business and promoting their mobile app to the world market, Thailand could become a regional hub for mobile application industry in the near future.     

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.     

Influence of segmental joints on tunnel lining

A simplified method for evaluating the moment carrying of a segmental tunnel liner was proposed using a result from a FEM analysis in which parameters were obtained by calibration against a true scale model test. Influence of segmental joint, number of segment and soil subgrade modulus on the bending moment carrying characteristics of a segmental tunnel was examined. Joint was represented by a series of springs called angular joint stiffness. Based on a set of model tests, practical range of angular joint stiffness was in range of 1000–3000 kN m/rad. It was found that jointed lining carried smaller value of maximum bending moment than the non-jointed one. The reduction in bending moment, represented by the parameter called moment reduction factor, can be simply expressed as a function of angular joint stiffness and number segment.