Four-site Model Research Articles

Abstract 737: Modeling of σ2 selective agonists for the development of new anticancer agents that utilize the celecoxib scaffold

Abstract Celecoxib has proved to be an enigma as a potential anticancer agent. COX-2 inhibition is not necessarily involved in its mechanism of cytotoxicity, and it induces a non-classical apoptotic pathway leading to cell death in some cell culture models. Because the classical pathways are not always induced by celecoxib, we hypothesized that celecoxib might be working as a σ2 receptor agonist as part of its cytotoxicity. In addition, published research has supported the therapeutic potential of σ2 receptor agonists in cancer chemotherapy. We have determined that celecoxib will inhibit the CRL-1620 cell line with an IC50 of 32 μM, and the 9L rat glioma model with an IC50 of 60 μM. Using a group of 41 high affinity σ2 receptor selective agonists and following a ligand-based drug design approach, we have developed a four-site pharmacophore model for σ2 receptor agonists. Upon aligning celecoxib to this model, it matched three of the four sites, further supporting our hypothesis that celecoxib might be working as a σ2 receptor agonist as part of its cytotoxicity. Additional compounds have been developed utilizing the celecoxib scaffold as σ2 receptor agonist anticancer agents. From the pharmacophore model we also developed an in silico model for the σ2 receptor binding pocket as it has not been cloned nor has its three dimensional structure been determined. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 737.

Groundwater Level Prediction Using SOM-RBFN Multisite Model

In this paper, a groundwater level forecasting model is proposed by combining the theory of self-organizing map (SOM) and radial basis function network (RBFN). The proposed model is referred to as SOM-RBFN model. Recently, RBFN has been applied in time series forecasting. Traditionally, the number of hidden units and the positioning of the radial basis centers are crucial problems for establishing RBFN. The proposed model can decide the number of RBFN’s hidden units with using the two-dimensional feature map which is constructed by SOM, and then it can determine the positioning of the radial basis centers easily. The proposed model is applied to actual groundwater level data in southern Taiwan from 1997 to 2003. It is found that the multisite model can predict the 1 month ahead groundwater level more precisely than the single-site model. Moreover, it is also found that the four-site model is more competent in predicting groundwater level as compared to the single-site model and six-site model. Therefore, ...

Role of the Range in the Fluid−Crystal Coexistence for a Patchy Particle Model

We evaluate the phase diagram of the four-site Kern-Frenkel patchy particle model [Kern, N.; Frenkel, D. J. Chem. Phys. 2003, 118, 9882.], a model representative of particles interacting via short-range orientational interactions, for several values of the interaction range. Similar to what has been found for isotropic potentials, the liquid phase disappears as an equilibrium phase for values of the range on the order of 15% of the particle diameter. For smaller ranges, the gas-liquid phase separation becomes metastable with respect to crystallization into a diamond-like structure. Interestingly, and differently from the isotropic case, the supersaturation of the fluid at the critical point does not significantly increase upon going toward the adhesive (vanishing interaction range) limit.

Fast Isotopic Exchange between Mitochondria and Cytosol in Brain Revealed by Relayed 13C Magnetization Transfer Spectroscopy

In vivo 13C magnetic resonance spectroscopy has been applied to studying brain metabolic processes by measuring 13C label incorporation into cytosolic pools such as glutamate and aspartate. However, the rate of exchange between mitochondrial alpha-ketoglutarate/oxaloacetate and cytosolic glutamate/aspartate (Vx) extracted from metabolic modeling has been controversial. Because brain fumarase is exclusively located in the mitochondria, and mitochondrial fumarate is connected to cytosolic aspartate through a chain of fast exchange reactions, it is possible to directly measure Vx from the four-carbon side of the tricarboxylic acid cycle by magnetization transfer. In isoflurane-anesthetized adult rat brain, a relayed 13C magnetization transfer effect on cytosolic aspartate C2 at 53.2 ppm was detected after extensive signal averaging with fumarate C2 at 136.1 ppm irradiated using selective radiofrequency pulses. Quantitative analysis using Bloch-McConnell equations and a four-site exchange model found that Vx approximately 13-19 micromol per g per min (>>VTCA, the tricarboxylic acid cycle rate) when the longitudinal relaxation time of malate C2 was assumed to be within +/-33% of that of aspartate C2. If Vx approximately VTCA, the isotopic exchange between mitochondria and cytosol would be too slow on the time scale of 13C longitudinal relaxation to cause a detectable magnetization transfer effect.

One-loop corrections to theSparameter in the four-site model

We compute the leading chiral-logarithmic corrections to the $S$ parameter in the four-site Higgsless model. In addition to the usual electroweak gauge bosons of the standard model, this model contains two sets of heavy charged and neutral gauge bosons. In the continuum limit, the latter gauge bosons can be identified with the first excited Kaluza-Klein states of the ${W}^{\ifmmode\pm\else\textpm\fi{}}$ and $Z$ bosons of a warped extra-dimensional model with an $SU(2{)}_{L}\ifmmode\times\else\texttimes\fi{}SU(2{)}_{R}\ifmmode\times\else\texttimes\fi{}U(1{)}_{X}$ bulk gauge symmetry. We consider delocalized fermions and show that the delocalization parameter must be considerably tuned from its tree-level ideal value in order to reconcile experimental constraints with the one-loop results. Hence, the delocalization of fermions does not solve the problem of large contributions to the $S$ parameter in this class of theories and significant contributions to $S$ can potentially occur at one-loop.

Four-site Higgsless model with wave function mixing

Motivated by models of holographic technicolor, we discuss a four-site deconstructed Higgsless model with nontrivial wave function mixing. We compute the spectrum of the model, the electroweak triple gauge-boson vertices, and, for brane-localized fermions, the electroweak parameters to $\mathcal{O}({M}_{W}^{2}/{M}_{\ensuremath{\rho}}^{2})$. We discuss the conditions under which $\ensuremath{\alpha}S$ vanishes (even for brane-localized fermions) and the (distinct but overlapping) conditions under which the phenomenologically interesting decay ${a}_{1}\ensuremath{\rightarrow}W\ensuremath{\gamma}$ is nonzero and suppressed by only one power of (${M}_{W}/{M}_{\ensuremath{\rho}}$).

Thermodynamic properties of Holstein polarons and the effects of disorder

The ground state and finite-temperature properties of polarons are studied considering atwo-site and a four-site Holstein model by exact diagonalization of the Hamiltonian. Thekinetic energy, Drude weight, correlation functions involving charge and latticedeformations, and the specific heat have been evaluated as a function of electron–phonon(e–ph) coupling strength and temperature. The effects of site diagonal disorder on theabove properties have been investigated. The disorder is found to suppress thekinetic energy and the Drude weight, and reduces the spatial extension of thepolaron. Increasing temperature also reduces the kinetic energy, Drude weight andthe polaron size when the e–ph interaction is weak or intermediate. For strongcoupling the effect of temperature is small but opposite. For sufficiently strongcoupling the kinetic energy arises mainly from the incoherent hopping processesowing to the motion of electrons within the polaron and is almost independent ofthe disorder strength. The specific heat shows a peak in the intermediate rangeof coupling, and the peak is suppressed in the presence of disorder. From thecoherent and incoherent contributions to the kinetic energy, the temperature abovewhich the incoherent part dominates is determined as a function of e–ph couplingstrength.

Cluster mechanism of the anti-greenhouse effect

The Earth’s atmosphere is a complex dynamic system, which protects the biosphere. One of the significant factors impacting Earth’s radiation balance is the greenhouse effect. Its enhancement is not only due to an increase in solar activity but also due to an increase in the content of gases with pronounced radiation properties in the atmosphere. Water vapor and atmospheric gases, such as CO 2 , CH 4 , N 2 O, and others, have a decisive influence on the formation of thermal radiation fields. However, according to the Le Chatelier principle, there are opposite compensating processes in the atmosphere. Clustering of greenhouse gases can be considered as one of these processes. The autoregulation of the atmosphere composition due to the formation of water clusters and their subsequent capture of greenhouse gas molecules is, as a rule, ignored in estimates of Earth’s radiation balance. The characteristics of infrared (IR) radiation absorption by water clusters incorporating molecules of the most abundant atmospheric gases—nitrogen, oxygen, and argon—were studied in [1‐4]. This work deals with the molecular dynamics study of the influence of clustering of H 2 O vapor and atmospheric gases CO 2 , N 2 O, CH 4 , C 2 H 2 , and C 2 H 6 on the greenhouse effect. The IR absorption spectra were calculated for systems formed by water clusters and molecules of the above greenhouse gases at 233 K. Due to clustering, a homogeneous single-phase system represented by a mixture of gases transforms into a “twophase” or even “three-phase” state since, depending on the ambient conditions, clusters constituting a fine “phase” can be in both the liquid and solid states. Water clusters were simulated using the improved interaction potential TIP4P for water and the rigid foursite model of H 2 O molecules [5]. To determine the influence of absorbed polyatomic molecules on the greenhouse effect, we considered different types of ultradisperse systems: (H 2 O) n (I), (CO 2 ) i (H 2 O) 10 (II), (CH 4 ) i (H 2 O) 10 (III), (N 2 O) i (H 2 O) 10 (IV), (C 2 H 2 ) m (H 2 O) 20 (V), and (C 2 H 6 ) m (H 2 O) 20 (VI), where n = 10–20 , i = 1–10 , and m = 1‐6. The calculation of the autocorrelation function of the total dipole moment M of the clusters makes it possible to determine their IR spectra, which characterize absorption coefficients [6]. The IR radiation absorption cross section was specified by the equation [7]

Polymer-induced phase separation and crystallization in immunoglobulin G solutions

We study the effects of the size of polymer additives and ionic strength on the phase behavior of a nonglobular protein-immunoglobulin G (IgG)-by using a simple four-site model to mimic the shape of IgG. The interaction potential between the protein molecules consists of a Derjaguin-Landau-Verwey-Overbeek-type colloidal potential and an Asakura-Oosawa depletion potential arising from the addition of polymer. Liquid-liquid equilibria and fluid-solid equilibria are calculated by using the Gibbs ensemble Monte Carlo technique and the Gibbs-Duhem integration (GDI) method, respectively. Absolute Helmholtz energy is also calculated to get an initial coexisting point as required by GDI. The results reveal a nonmonotonic dependence of the critical polymer concentration rho(PEG) (*) (i.e., the minimum polymer concentration needed to induce liquid-liquid phase separation) on the polymer-to-protein size ratio q (equivalently, the range of the polymer-induced depletion interaction potential). We have developed a simple equation for estimating the minimum amount of polymer needed to induce the liquid-liquid phase separation and show that rho(PEG) (*) approximately [q(1+q)(3)]. The results also show that the liquid-liquid phase separation is metastable for low-molecular weight polymers (q=0.2) but stable at large molecular weights (q=1.0), thereby indicating that small sizes of polymer are required for protein crystallization. The simulation results provide practical guidelines for the selection of polymer size and ionic strength for protein phase separation and crystallization.

Syn, anti, and finally both conformations of cyclic AMP are involved in the CRP‐dependent transcription initiation mechanism in E. coli lac operon

The cyclic AMP receptor protein (CRP) of Escherichia coli regulates the activity of more than 150 genes. Allosteric changes in CRP structure accompanied by cAMP binding, initiate transcription through protein binding to specific DNA sequences. Initially, researchers proposed a two-site cAMP-binding model for CRP-dependent transcription activation since biophysical methods showed two transitions during titration experiments. Three conformational states were considered; apo-CRP, CRP:(cAMP)(1) and CRP:(cAMP)(2), and CRP:(cAMP)(1) was proposed as the active form in this initial model. X-ray data indicated an anti conformation and in contrast NMR experiments suggested a syn conformation for bound cAMPs. For years this paradigm about ligand conformation has been ambiguous. When CRP was crystallized with four bound cAMP in the last decade, two cAMPs were assigned to syn and the other two to anti conformations. Again three conformational states were suggested; apo-CRP, CRP:(cAMP)(2), and CRP:(cAMP)(4). This new structure changed the view of CRP allosteric activation from a two-site model to a four-site model in the literature and the new model has been supported by biochemical and genetic data so far. According to the accepted model, binding of the first two cAMP molecules displays positive cooperativity, however, binding of the last two cAMP molecules shows negative cooperativity. This resolved the conflict between dynamic and static experimental observations. However, this new model cannot explain the initiation mechanism as previously proposed because functionally active CRP has only one cAMP equivalent. Gene regulation and transcription factors are involved in regulating both prokaryotic and eukaryotic metabolism. Although gene regulation and expression are much more complex in eukaryotes, CRP-mediated transcription initiation is a model of general interest to life sciences and medicine. Therefore, the aim of this review is to summarize recent works and developments on the cAMP-dependent CRP activation mechanism in E. coli.

Lattice dynamics study of low energy guest–host coupling in clathrate hydrate

Our lattice dynamics simulation of Xe-hydrate with four-site TIP4P oxygen-shell model can accurately reproduce each peak position in the inelastic incoherent neutron scattering spectrum at the acoustic band (below 15meV) and yield correct relative intensity. Based on the results, the uncertain profile at ∼6 meV is assigned to anharmonic guest modes coupled strongly to small cages. Blue shift is proposed in phonon dispersion sheet in the case of anticrossing and found to be an evident signal for guest-host coupling that explains the anomalous thermal conductivity of clathrate hydrate.

Cavitation Free Energy for Organic Molecules Having Various Sizes and Shapes

Cavitation free energy DeltaG(cav), corresponding to the formation of an excluded volume cavity in water, is calculated for a large set of organic molecules employing the thermodynamic integration procedure, which is realized as the original two-step algorithm for growing the interaction potential between the hard cavity wall and the water molecules. A large variety of solute systems is considered. Their characteristic radii change in the range 3-7 A; spherical cavities with radii 3-6 A are also studied. The interaction between water molecules is described by the four-site nonpolarizable TIP4P model. The diversity of the trial molecular set is provided by using a specially formulated nonspherical criterion classifying the cavity shapes according to their deviation from a sphere. Molecular objects were partly taken from the data base NCI Diversity with the aid of this criterion. The so-computed free energies are approximated by the linear volume dependence DeltaG(cav)V = XiV, where V is the cavity volume. This relation works fairly well until the cavity size becomes very large (the effective radius larger than 7 A). The volume dependence valid for solutes of arbitrary shapes can be included in a calculation of the nonpolar free energy component as required in the implicit water model.

Molecular Dynamics Simulation of Hydration Structure of KNO3 Electrolyte Solution

Molecular dynamics simulations were carried out to study the structure of ion clusters and hydration properties of KNO3 solution. The water molecule was treated as a simple-point-charge (SPC) model, and a four-site model for the nitrate ion was adopted. Both the Coulomb and Lennard-Jones interactions between all the charged sites were considered, and the long-range Coulomb electrostatic interaction was treated using Ewald summation techniques. The configuration of ionic pairs, the radial distribution function of the solution, and the effect of solution concentration on ionic hydration were studied in detail. It was found that there are ionic association phenomena in KNO3 solution and that the dimeric, triplet, solvent-separated ion pairs, and other complex clusters can be observed at high ionic concentration condition. As the concentration of solution decreases, the ionic hydration number increases, 5-7 for cation K+ and 3.5-4.7 for anion NO3, which is in good agreement with former Monte Carlo and time-of-flight neutron diffraction results.

Molecular dynamics study of methane in water: diffusion and structure

We present molecular dynamics simulation results for the diffusion coefficients and structure of water–methane mixtures in constant NPT ensembles, at T = 270, 300 K and P = 8.104 × 107 Pa. The systems we have studied consist of one, four and eight CH4 molecules and varying H2O molecules per unit cell, which correspond to methane concentration of 0.081, 0.324 and 0.643 mol/l, respectively. The intermolecular potentials used in all the simulations were the four-site TIP4P model of water [1] and the fitted Lennard-Jones 12-6 potential for CH4–H2O [2]. Our results show that the methane concentration has little impact on the structure of water and the formation of hydrogen bonds (H-bonds) between water molecules. The H-bond numbers, H-bond length and the H-bond angle are independent of the methane concentration at the temperatures and densities examined in this study. We also find that the number of H-bonds and angles are sensitive to the temperature. The rise of temperature produces a decrease in the number and an increase in the angle of the H-bonds. Enhanced structuring of the hydration-shell water molecules is indicated by an increase of the first and second peak in the water oxygen–oxygen radial distribution function as temperature is decreased. The self-diffusion coefficient of water is sensitive to the methane concentration and temperature.

Best Predictors for Postfire Mortality of Ponderosa Pine Trees in the Intermountain West

Abstract Numerous wildfires in recent years have highlighted managers' needs for reliable tools to predict postfire mortality of ponderosa pine (Pinus ponderosa Dougl. ex Laws.) trees. General applicability of existing mortality models is uncertain, as researchers have used different sets of variables. We quantified tree attributes, crown and bole fire damage, ground fire severity, and insect presence from a total of 5,083 trees in four 2000 wildfires in four Intermountain states. Crown scorch (percentage) and consumption (percentage) volume collectively accounted for the majority of predictive capacity in all four individual models and in the pooled four-site model. The addition of tree diameter and presence of Ips beetles in the pooled model slightly improved predictive power. Four other statistically significant variables added little to the pooled model's predictive ability. The pooled model correctly classified 3-year postfire mortality of 89.9% of the trees and had a receiver operating characteristic (ROC) score of 0.96. In the external validation step, the model correctly classified 3-year postfire mortality of 96% of 1,361 trees in a 2001 wildfire. Our results and a number of previous studies suggest that a two-variable model using percentage crown scorch volume and crown consumed volume will have applicability beyond the Intermountain West.

Developing optimal Wertheim-like models of water for use in Statistical Associating Fluid Theory (SAFT) and related approaches

The statistical associating fluid theory (SAFT) is now well established as an approach for the description of the thermodynamics and phase equilibria of a wide variety of fluid systems. Numerous SAFT studies of the fluid phase equilibria of pure water and aqueous mixtures have been made with the various incarnations of the theory, yet there is no consensus on what the ‘optimal’ values of the intermolecular parameters are for water, or what the association scheme should be (two-, three-, or four-site models). We show that the conventional use of vapour-pressure and saturated-liquid-density data on their own leads to a degeneracy in the values of the parameters, particularly in the relative values of the dispersion and hydrogen-bonding energies. A discretized energy-parameter space is examined and a long valley of ‘optimal’ parameter sets for the vapour–liquid equilibria is found for the various models, ranging from low dispersion (high hydrogen-bonding) to high dispersion (low hydrogen-bonding) energies. Other thermodynamic information such as the heat of vaporization does not allow one to discriminate between the values of the parameters or the association scheme. An examination of the degree of association (hydrogen bonding) allows such a discrimination to be made: the four-site model is found to provide the best overall description of the thermodynamics, fluid phase equilibria, and degree of association. The set of parameters obtained in this way also provides the best description of the fluid-phase equilibria for a mixture of water and methanol. This degeneracy of parameters could also be important when models of water are refined to vapour–liquid equilibria in simulation studies of aqueous systems, and for other systems of associating molecules.

The interface response function and melting point of the prism interface of ice Ih using a fluctuating charge model (TIP4P-FQ)

Molecular Dynamics simulations have been used to follow the rate of growth and recession of the prismatic surface of a hexagonal ice–water interface. The fluctuating charge, four-site transferable intermolecular potential model, TIP4P-FQ, was used at temperatures between 265 and 310 K in a series of isobaric isothermal (NPT) Molecular Dynamics simulations. Using appropriate order parameters, an interface response function (IRF) that captures the speed of the moving interface as a function of temperature was constructed that covers the melting and growth of hexagonal ice. From the IRF ( T v=0), the melting temperature was found to be 303±8 K and the maximum crystallization velocity was estimated to be 1 m/s at 260 K (a 14% undercooling, similar to that of other systems such as Si). Changing the Lennard–Jones σ parameter from 3.159 to 3.173 Å, in line with a previous parameterization by Rick, reduces the melting temperature to 276 K. These values correspond well with experimental estimates given the relative simplicity of the model.

High Affinity Binding between Copper and Full-length Prion Protein Identified by Two Different Techniques

The cellular prion protein is known to be a copper-binding protein. Despite the wide range of studies on the copper binding of PrP, there have been no studies to determine the affinity of the protein on both full-length prion protein and under physiological conditions. We have used two techniques, isothermal titration calorimetry and competitive metal capture analysis, to determine the affinity of copper for wild type mouse PrP and a series of mutants. High affinity copper binding by wild type PrP has been confirmed by the independent techniques indicating the presence of specific tight copper binding sites up to femtomolar affinity. Altogether, four high affinity binding sites of between femto- and nanomolar affinities are located within the octameric repeat region of the protein at physiological pH. A fifth copper binding site of lower affinity than those of the octameric repeat region has been detected in full-length protein. Binding to this site is modulated by the histidine at residue 111. Removal of the octameric repeats leads to the enhancement of affinity of this fifth site and a second binding site outside of the repeat region undetected in the wild type protein. High affinity copper binding allows PrP to compete effectively for copper in the extracellular milieu. The copper binding affinities of PrP have been compared with those of proteins of known function and are of magnitudes compatible with an extracellular copper buffer or an enzymatic function such as superoxide dismutase like activity.

The Application of Diffuse Reflectance Infrared Spectroscopy and Temperature-Programmed Desorption To Investigate the Interaction of Methanol on η-Alumina

The adsorption of methanol and its subsequent transformation to form dimethyl ether (DME) on a commercial grade eta-alumina catalyst has been investigated using a combination of mass selective temperature-programmed desorption (TPD) and diffuse reflectance infrared spectroscopy (DRIFTS). The infrared spectrum of a saturated overlayer of methanol on eta-alumina shows the surface to be comprised of associatively adsorbed methanol and chemisorbed methoxy species. TPD shows methanol and DME to desorb with respective maxima at 380 and 480 K, with desorption detectable for both molecules up to ca. 700 K. At 673 K, infrared spectroscopy reveals the formation of a formate species; the spectral line width of the antisymmetric C-O stretch indicates the adoption of a high symmetry adsorbed state. Conventional TPD using a tubular reactor, combined with mass spectrometric analysis of the gas stream exiting the IR cell, indicate hydrogen and methane evolution to be associated with formation of the surface formate group and CO evolution with its decomposition. A reaction scheme is proposed for the generation and decomposition of this important reaction intermediate. The overall processes involved in (i) the adsorption/desorption of methanol, (ii) the transformation of methanol to DME, and (iii) the formation and decomposition of formate species are discussed within the context of a recently developed four-site model for the Lewis acidity of eta-alumina.

Deconstructed Higgsless models with one-site delocalization

In this note we calculate the form of electroweak corrections in deconstructed Higgsless models for the case of a fermion whose weak properties arise from two adjacent SU(2) groups on the deconstructed lattice. We show that, as recently proposed in the continuum, it is possible for the value of the electroweak parameter alpha S to be small in such a model. In addition, by working in the deconstructed limit, we may directly evaluate the size of off-Z-pole electroweak corrections arising from the exchange of Kaluza-Klein modes; this has not been studied in the continuum. The size of these corrections is summarized by the electroweak parameter alpha delta. In one-site delocalized Higgsless models with small values of alpha S, we show that the amount of delocalization is bounded from above, and must be less than 25% at 95% CL. We discuss the relation of these calculations to our previous calculations in deconstructed Higgsless models, and to models of extended technicolor. We present numerical results for a four-site model, illustrating our analytic calculations.