Quantifying intrinsic specificity: A potential complement to affinity in drug screening

We report here the investigation of a novel description of specificity in protein-ligand binding based on energy landscape theory. We define a new term, intrinsic specificity ratio (ISR), which describes the level of discrimination in binding free energies of the native basin for a protein-ligand complex from the weaker binding states of the same ligand. We discuss the relationship between the intrinsic specificity we defined here and the conventional definition of specificity. In a docking study of molecules with the enzyme COX-2, we demonstrate a statistical correspondence between ISR value and geometrical shapes of the small molecules binding to COX-2. We further observe that the known selective (nonselective) inhibitors of COX-2 have higher (lower) ISR values. We suggest that intrinsic specificity ratio may be a useful new criterion and a complement to affinity in drug screening and in searching for potential drug lead compounds.

Physical and spectral characterization of the human cyclin A gene and its interactions with anthracycline anticancer drugs

Over expression of cyclin A in human tumors has been linked to cancer by various experimental lines of evidence. However, physical and spectral characterization of the human cyclin A gene and its interactions with anticancer drugs have not been reported. Our gene sequence analysis, singular value decomposition method and melting studies in the presence of antitumor agents, daunomycin, doxorubicin and Hoechst 33258 showed that cyclin A gene had both AT-rich and GC-rich domains. For a ligand with unknown DNA binding specificity, this gene sequence can be used to differentiate its DNA binding preference.

Energy landscape theory, funnels, specificity, and optimal criterion of biomolecular binding

We study the nature of biomolecular binding. We found that in general there exists several thermodynamic phases: a native binding phase, a non-native phase, and a glass or local trapping phase. The quantitative optimal criterion for the binding specificity is found to be the maximization of the ratio of the binding transition temperature versus the trapping transition temperature, or equivalently the ratio of the energy gap of binding between the native state and the average non-native states versus the dispersion or variance of the non-native states. This leads to a funneled binding energy landscape.

Effect of Rock Mass Structure and Block Size on the Slope Stability-Physical Modeling and Discrete Element Simulation

This paper studies the stability of jointed rock slopes by using our improved three-dimensional discrete element methods (DEM) and physical modeling. Results show that the DEM can simulate all failure modes of rock slopes with different joint configurations. The stress in each rock block is not homogeneous and blocks rotate in failure development. Failure modes depend on the configuration of joints. Toppling failure is observed for the slope with straight joints and sliding failure is observed for the slope with staged joints. The DEM results are also compared with those of limit equilibrium method (LEM). Without considering the joints in rock masses, the LEM predicts much higher factor of safety than physical modeling and DEM. The failure mode and factor of safety predicted by the DEM are in good agreement with laboratory tests for any jointed rock slope.

Growth of Silicon Carbide Bulk Crystals by Physical Vapor Transport Method and Modeling Efforts in the Process Optimization

Silicon carbide bulk crystals were grown in an induction-heating furnace using the physical vapor transport method. Crystal growth modeling was performed to obtain the required inert gas pressure and temperatures for sufficiently large growth rates. The SiC crystals were expanded by designing a growth chamber having a positive temperature gradient along the growth interface. The obtained 6H-SiC crystals were cut into wafers and characterized by Raman scattering spectroscopy and X-ray diffraction, and the results showed that most parts of the crystals had good crystallographic structures.

Thermoelastic Stresses in SiC Single Crystals Grown by the Physical Vapor Transport Method

A finite element-based thermoelastic anisotropic stress model for hexagonal silicon carbide polytype is developed for the calculation of thermal stresses in SiC crystals grown by the physical vapor transport method. The composite structure of the growing SiC crystal and graphite lid is considered in the model. The thermal expansion match between the crucible lid and SiC crystal is studied for the first time. The influence of thermal stress on the dislocation density and crystal quality is discussed.

Sensitivity Analysis of Dimensionless Parameters for Physical Simulation of Water-Flooding Reservoir

A numerical approach to optimize dimensionless parameters of water-flooding porous media flows is proposed based on the analysis of the sensitivity factor defined as the variation ration of a target function with respect to the variation of dimensionless parameters. A complete set of scaling criteria for water-flooding reservoir of five-spot well pattern case is derived from the 3-D governing equations, involving the gravitational force, the capillary force and the compressibility of water, oil and rock. By using this approach, we have estimated the influences of each dimensionless parameter on experimental results and thus sorted out the dominant ones with larger sensitivity factors ranging from10-4to10-0 .

Large Eddy Simulation of Complex Turbulent Flows: Physical Aspects and Research Trends

In the current paper, we have primarily addressed one powerful simulation tool developed during the last decades-Large Eddy Simulation (LES), which is most suitable for unsteady three-dimensional complex turbulent flows in industry and natural environment. The main point in LES is that the large-scale motion is resolved while the small-scale motion is modeled or, in geophysical terminology, parameterized. With a view to devising a subgrid-scale(SGS) model of high quality, we have highlighted analyzing physical aspects in scale interaction and-energy transfer such as dissipation, backscatter, local and non-local interaction, anisotropy and resolution requirement. They are the factors responsible for where the advantages and disadvantages in existing SGS models come from. A case study on LES of turbulence in vegetative canopy is presented to illustrate that LES model is more based on physical arguments. Then, varieties of challenging complex turbulent flows in both industry and geophysical fields in the near future-are presented. In conclusion; we may say with confidence that new century shall see the flourish in the research of turbulence with the aid of LES combined with other approaches.

Weibull modulus for diverse strength due to sample-specificity

By sample specificity it is meant that specimens with the same nominal material parameters and tested under the same environmental conditions may exhibit different behavior with diversified strength. Such an effect has been widely observed in the testing of material failure and is usually attributed to the heterogeneity of material at the mesoscopic level. The degree with which mesoscopic heterogeneity affects macroscopic failure is still not clear. Recently, the problem has been examined by making use of statistical ensemble evolution of dynamical system and the mesoscopic stress re-distribution model (SRD). Sample specificity was observed for non-global mean stress field models, such as the duster mean field model, stress concentration at tip of microdamage, etc. Certain heterogeneity of microdamage could be sensitive to particular SRD leading to domino type of coalescence. Such an effect could start from the microdamage heterogeneity and then be magnified to other scale levels. This trans-scale sensitivity is the origin of sample specificity. The sample specificity leads to a failure probability Phi (N) with a transitional region 0 < (N) < 1, so that globally stable and catastrophic modes could co-exist. It is found that the scatter in strength can fit the Weibull distribution very well. Hence, the Weibull modulus is indicative of sample specificity. Numerical results obtained from the SRD for different non-global mean stress fields show that Weibull modulus increases with increasing sample span and influence region of microdamage.

Physical modeling of untrenched submarine pipeline instability

Wave-induced instability of untrenched pipeline on sandy seabed is a `wave-soil-pipeline' coupling dynamic problem. To explore the mechanism of the pipeline instability, the hydrodynamic loading with U-shaped oscillatory flow tunnel is adopted, which is quite different from the previous experiment system. Based on dimensional analysis, the critical conditions for pipeline instability are investigated by altering pipeline submerged weight, diameter, soil parameters, etc. Based on the experimental results, different linear relationships between Froude number (Fr) and non-dimensional pipeline weight (G) are obtained for two constraint conditions. Moreover, the effects of loading history on the pipeline stability are also studied. Unlike previous experiments, sand scouring during the process of pipe's losing stability is detected in the present experiments. In addition, the experiment results are compared with the previous experiments, based on Wake II model for the calculation of wave-induced forces upon pipeline. It shows that the results of two kinds of experiments are comparable, but the present experiments provide better physical insight of the wave-soil-pipeline coupling effects.

Immunosensor Interface Based on Physical and Chemical Immunogylobulin G Adsorption onto Mixed Self-Assembled Monolayers

An immunosensor interface based on mixed hydrophobic self-assembled monolayers (SAMs) of methyl and carboxylic acid terminated thiols with covalently attached human Immunoglobulin G (hIgG), is investigated. The densely packed and organised SAMs were characterised by contact angle measurements and cyclic voltammetry. The effect of the non-ionic surfactant, Tween 20, in preventing nonspecific adsorption is addressed by ellipsometry during physical and covalent hIgG immobilization on pure and mixed SAMs, respectively. It is clearly demonstrated that nonspecific adsorption due to hydrophobic interactions of hIgG on methyl ended groups is totally inhibited, whereas electrostatic/hydrogen bonding interactions with the exposed carboxylic groups prevail in the presence of surfactant. Results of ellipsometry and Atomic Force Microscopy, reveal that the surface concentration of covalently immobilized hIgG is determined by the ratio of COOH/CH3-terminated thiols in SAM forming solution. Moreover, the ellipsometric data demonstrates that the ratio of bound anti-hIgG/hIgG depends on the density of hIgG on the surface and that the highest ratio is close to three. We also report the selectivity and high sensitivity achieved by chronoamperometry in the detection of adsorbed hIgG and the reaction with its antibody.

Physical parameters affecting sonoluminescence: A self-consistent hydrodynamic study

We studied the dependence of thermodynamic variables in a sonoluminescing ~SL! bubble on various physical factors, which include viscosity, thermal conductivity, surface tension, the equation of state of the gas inside the bubble, as well as the compressibility of the surrounding liquid. The numerical solutions show that the existence of shock waves in the SL parameter regime is very sensitive to these factors. Furthermore, we show that even without shock waves, the reflection of continuous compressional waves at the bubble center can produce the high temperature and picosecond time scale light pulse of the SL bubble, which implies that SL may not necessarily be due to shock waves.

Thickness And Component Distributions Of Yttrium-Titanium Alloy Films In Electron-Beam Physical Vapor Deposition

Thickness and component distributions of large-area thin films are an issue of international concern in the field of material processing. The present work employs experiments and direct simulation Monte Carlo (DSMC) method to investigate three-dimensional low-density, non-equilibrium jets of yttrium and titanium vapor atoms in an electron-beams physical vapor deposition (EBPVD) system furnished with two or three electron-beams, and obtains their deposition thickness and component distributions onto 4-inch and 6-inch mono-crystal silicon wafers. The DSMC results are found in excellent agreement with our measurements, such as evaporation rates of yttrium and titanium measured in-situ by quartz crystal resonators, deposited film thickness distribution measured by Rutherford backscattering spectrometer (RBS) and surface profilometer and deposited film molar ratio distribution measured by RBS and inductively coupled plasma atomic emission spectrometer (ICP-AES). This can be taken as an indication that a combination of DSMC method with elaborate measurements may be satisfactory for predicting and designing accurately the transport process of EBPVD at the atomic level.

Effects of physical parameter range on dimensionless variable sensitivity in water flooding reservoirs

The similarity criterion for water flooding reservoir flows is concerned with in the present paper. When finding out all the dimensionless variables governing this kind of flow, their physical meanings are subsequently elucidated. Then, a numerical approach of sensitivity analysis is adopted to quantify their corresponding dominance degree among the similarity parameters. In this way, we may finally identify major scaling law in different parameter range and demonstrate the respective effects of viscosity, permeability and injection rate.

Effects of physical parameter range on dimensionless variable sensitivity in water flooding reservoirs

The similarity criterion for water flooding reservoir flows is concerned with in the present paper. When finding out all the dimensionless variables governing this kind of flow, their physical meanings are subsequently elucidated. Then, a numerical approach of sensitivity analysis is adopted to quantify their corresponding dominance degree among the similarity parameters. In this way, we may finally identify major scaling law in different parameter range and demonstrate the respective effects of viscosity, permeability and injection rate.