Multivariate PLS Modeling of Apicomplexan FabD-Ligand Interaction Space for Mapping Target-Specific Chemical Space and Pharmacophore Fingerprints

Biomolecular recognition underlying drug-target interactions is determined by both binding affinity and specificity. Whilst, quantification of binding efficacy is possible, determining specificity remains a challenge, as it requires affinity data for multiple targets with the same ligand dataset. Thus, understanding the interaction space by mapping the target space to model its complementary chemical space through computational techniques are desirable. In this study, active site architecture of FabD drug target in two apicomplexan parasites viz. Plasmodium falciparum (PfFabD) and Toxoplasma gondii (TgFabD) is explored, followed by consensus docking calculations and identification of fifteen best hit compounds, most of which are found to be derivatives of natural products. Subsequently, machine learning techniques were applied on molecular descriptors of six FabD homologs and sixty ligands to induce distinct multivariate partial-least square models. The biological space of FabD mapped by the various chemical entities explain their interaction space in general. It also highlights the selective variations in FabD of apicomplexan parasites with that of the host. Furthermore, chemometric models revealed the principal chemical scaffolds in PfFabD and TgFabD as pyrrolidines and imidazoles, respectively, which render target specificity and improve binding affinity in combination with other functional descriptors conducive for the design and optimization of the leads.

Probabilistic Modeling of Rosette Formation

英文摘要: Rosetting, or forming a cell aggregate between a single target nucleated cell and a number of red blood cells (RBCs), is a simple assay for cell adhesion-mediated by specific receptor-ligand interaction. For example, rosette formation between sheep RBC and human lymphocytes has been used to differentiate T cells from B cells. Rosetting assay is commonly used to determine the interaction of Fc gamma-receptors (Fc gamma R) expressed on inflammatory cells and IgG-coated on RBCs. Despite its wide use in measuring cell adhesion, the biophysical parameters of rosette formation have not been well characterized. Here we developed a probabilistic model to describe the distribution of rosette sizes, which is Poissonian. The average rosette size is predicted to be proportional to the apparent two-dimensional binding affinity of the interacting receptor-ligand pair and their site densities. The model has been supported by experiments of rosettes mediated by four molecular interactions: Fc gamma RIII interacting with IgG, T cell receptor and coreceptor CD8 interacting with antigen peptide presented by major histocompatibility molecule, P-selectin interacting with P-selectin glycoprotein ligand 1 (PSGL-1), and L-selectin interacting with PSGL-1. The latter two are structurally similar and are different from the former two. Fitting the model to data enabled us to evaluate the apparent effective two-dimensional binding affinity of the interacting molecular pairs: 7.19x10(-5) mu m(4) for Fc gamma RIII-IgG interaction, 4.66x10(-3) mu m(4) for P-selectin-PSGL-1 interaction, and 0.94x10(-3) mu m(4) for L-selectin-PSGL-1 interaction. These results elucidate the biophysical mechanism of rosette formation and enable it to become a semiquantitative assay that relates the rosette size to the effective affinity for receptor-ligand binding.

Nonlinear Mechanical Modeling Of Cell Adhesion

Cell adhesion, which is mediated by the receptor-ligand bonds, plays an essential role in various biological processes. Previous studies often described the force-extension relationship of receptor-ligand bond with linear assumption. However, the force-extension relationship of the bond is intrinsically nonlinear, which should have significant influence on the mechanical behavior of cell adhesion. In this work, a nonlinear mechanical model for cell adhesion is developed, and the adhesive strength was studied at various bond distributions. We find that the nonlinear mechanical behavior of the receptor-ligand bonds is crucial to the adhesive strength and stability. This nonlinear behavior allows more bonds to achieve large bond force simultaneously, and therefore the adhesive strength becomes less sensitive to the change of bond density at the outmost periphery of the adhesive area. In this way, the strength and stability of cell adhesion are soundly enhanced. The nonlinear model describes the cell detachment behavior better than the linear model. (C) 2007 Elsevier Ltd. All rights reserved.

Monte Carlo Modeling of Micro Scale Gas Flows

An information preservation (IP) method has been used to simulate many micro scale gas flows. It may efficiently reduce the statistical scatter inherent in conventional particle approaches such as the direct simulation Monte Carlo (DSMC) method. This paper reviews applications of IP to some benchmark problems. Comparison of the IP results with those given by experiment, DSMC, and the linearized Boltzmann equation, as well as the Navier-Stokes equations with a slip boundary condition, and the lattice Boltzmann equation, shows that the IP method is applicable to micro scale gas flows over the entire flow regime from continuum to free molecular.

Studies of molecular bonding, interactions and decomposition reactions on the (001) surface of ruthenium

The interactions of N₂, formic acid and acetone on the Ru(001) surface are studied using thermal desorption mass spectrometry (TDMS), electron energy loss spectroscopy (EELS), and computer modeling.

Low energy electron diffraction (LEED), EELS and TDMS were used to study chemisorption of N₂ on Ru(001). Adsorption at 75 K produces two desorption states. Adsorption at 95 K fills only the higher energy desorption state and produces a (√3 x √3)R30° LEED pattern. EEL spectra indicate both desorption states are populated by N₂ molecules bonded "on-top" of Ru atoms.

Monte Carlo simulation results are presented on Ru(001) using a kinetic lattice gas model with precursor mediated adsorption, desorption and migration. The model gives good agreement with experimental data. The island growth rate was computed using the same model and is well fit by R(t)^m - R(t₀)^m = At, with m approximately 8. The island size was determined from the width of the superlattice diffraction feature.

The techniques, algorithms and computer programs used for simulations are documented. Coordinate schemes for indexing sites on a 2-D hexagonal lattice, programs for simulation of adsorption and desorption, techniques for analysis of ordering, and computer graphics routines are discussed.

The adsorption of formic acid on Ru(001) has been studied by EELS and TDMS. Large exposures produce a molecular multilayer species. A monodentate formate, bidentate formate, and a hydroxyl species are stable intermediates in formic acid decomposition. The monodentate formate species is converted to the bidentate species by heating. Formic acid decomposition products are CO₂, CO, H₂, H₂O and oxygen adatoms. The ratio of desorbed CO with respect to CO₂ increases both with slower heating rates and with lower coverages.

The existence of two different forms of adsorbed acetone, side-on, bonded through the oxygen and acyl carbon, and end-on, bonded through the oxygen, have been verified by EELS. On Pt(111), only the end-on species is observed. On dean Ru(001) and p(2 x 2)O precovered Ru(001), both forms coexist. The side-on species is dominant on clean Ru(001), while O stabilizes the end-on form. The end-on form desorbs molecularly. Bonding geometry stability is explained by surface Lewis acidity and by comparison to organometallic coordination complexes.

First principles based multiparadigm modeling of electronic structures and dynamics

Electronic structures and dynamics are the key to linking the material composition and structure to functionality and performance.

An essential issue in developing semiconductor devices for photovoltaics is to design materials with optimal band gaps and relative positioning of band levels. Approximate DFT methods have been justified to predict band gaps from KS/GKS eigenvalues, but the accuracy is decisively dependent on the choice of XC functionals. We show here for CuInSe₂ and CuGaSe₂, the parent compounds of the promising CIGS solar cells, conventional LDA and GGA obtain gaps of 0.0-0.01 and 0.02-0.24 eV (versus experimental values of 1.04 and 1.67 eV), while the historically first global hybrid functional, B3PW91, is surprisingly the best, with band gaps of 1.07 and 1.58 eV. Furthermore, we show that for 27 related binary and ternary semiconductors, B3PW91 predicts gaps with a MAD of only 0.09 eV, which is substantially better than all modern hybrid functionals, including B3LYP (MAD of 0.19 eV) and screened hybrid functional HSE06 (MAD of 0.18 eV).

The laboratory performance of CIGS solar cells (> 20% efficiency) makes them promising candidate photovoltaic devices. However, there remains little understanding of how defects at the CIGS/CdS interface affect the band offsets and interfacial energies, and hence the performance of manufactured devices. To determine these relationships, we use the B3PW91 hybrid functional of DFT with the AEP method that we validate to provide very accurate descriptions of both band gaps and band offsets. This confirms the weak dependence of band offsets on surface orientation observed experimentally. We predict that the CBO of perfect CuInSe₂/CdS interface is large, 0.79 eV, which would dramatically degrade performance. Moreover we show that band gap widening induced by Ga adjusts only the VBO, and we find that Cd impurities do not significantly affect the CBO. Thus we show that Cu vacancies at the interface play the key role in enabling the tunability of CBO. We predict that Na further improves the CBO through electrostatically elevating the valence levels to decrease the CBO, explaining the observed essential role of Na for high performance. Moreover we find that K leads to a dramatic decrease in the CBO to 0.05 eV, much better than Na. We suggest that the efficiency of CIGS devices might be improved substantially by tuning the ratio of Na to K, with the improved phase stability of Na balancing phase instability from K. All these defects reduce interfacial stability slightly, but not significantly.

A number of exotic structures have been formed through high pressure chemistry, but applications have been hindered by difficulties in recovering the high pressure phase to ambient conditions (i.e., one atmosphere and room temperature). Here we use dispersion-corrected DFT (PBE-ulg flavor) to predict that above 60 GPa the most stable form of N₂O (the laughing gas in its molecular form) is a 1D polymer with an all-nitrogen backbone analogous to cis-polyacetylene in which alternate N are bonded (ionic covalent) to O. The analogous trans-polymer is only 0.03-0.10 eV/molecular unit less stable. Upon relaxation to ambient conditions both polymers relax below 14 GPa to the same stable non-planar trans-polymer, accompanied by possible electronic structure transitions. The predicted phonon spectrum and dissociation kinetics validate the stability of this trans-poly-NNO at ambient conditions, which has potential applications as a new type of conducting polymer with all-nitrogen chains and as a high-energy oxidizer for rocket propulsion. This work illustrates in silico materials discovery particularly in the realm of extreme conditions.

Modeling non-adiabatic electron dynamics has been a long-standing challenge for computational chemistry and materials science, and the eFF method presents a cost-efficient alternative. However, due to the deficiency of FSG representation, eFF is limited to low-Z elements with electrons of predominant s-character. To overcome this, we introduce a formal set of ECP extensions that enable accurate description of p-block elements. The extensions consist of a model representing the core electrons with the nucleus as a single pseudo particle represented by FSG, interacting with valence electrons through ECPs. We demonstrate and validate the ECP extensions for complex bonding structures, geometries, and energetics of systems with p-block character (C, O, Al, Si) and apply them to study materials under extreme mechanical loading conditions.

Despite its success, the eFF framework has some limitations, originated from both the design of Pauli potentials and the FSG representation. To overcome these, we develop a new framework of two-level hierarchy that is a more rigorous and accurate successor to the eFF method. The fundamental level, GHA-QM, is based on a new set of Pauli potentials that renders exact QM level of accuracy for any FSG represented electron systems. To achieve this, we start with using exactly derived energy expressions for the same spin electron pair, and fitting a simple functional form, inspired by DFT, against open singlet electron pair curves (H₂ systems). Symmetric and asymmetric scaling factors are then introduced at this level to recover the QM total energies of multiple electron pair systems from the sum of local interactions. To complement the imperfect FSG representation, the AMPERE extension is implemented, and aims at embedding the interactions associated with both the cusp condition and explicit nodal structures. The whole GHA-QM+AMPERE framework is tested on H element, and the preliminary results are promising.

Molecular ecology of european mustelids: Unraveling evolutionary and ecological patterns in Martes and Lutra genera

208 p.

A novel short neurotoxin, cobrotoxin c, from monocellate cobra (Naja kaouthia) venom: isolation and purification, primary and secondary structure determination, and tertiary structure modeling

A novel short neurotoxin, cobrotoxin c (CBT C) was isolated from the venom of monocellate cobra (Naja kaouthia) using a combination of ion-exchange chromatography and FPLC. Its primary structure was determined by Edman degradation. CBT C is composed of 61 amino acid residues. It differs from cobrotoxin b (CBT B) by only two amino acid substitutions, Thr/Ala11 and Arg/Thr56, which are not located on the functionally important regions by sequence similarity. However, the LD50 is 0.08 mg/g to mice, i.e. approximately five-fold higher than for CBT B. Strikingly, a structure-function relationship analysis suggests the existence of a functionally important domain on the outside of Loop III of CBT C. The functionally important basic residues on the outside of Loop III might have a pairwise interaction with alpha subunit, instead of gamma or delta subunits of the nicotinic acetylcholine receptor (nAChR). (C) 2002 Elsevier Science Inc. All rights reserved.

Reynolds number effects on scalar dissipation rate transport and its modeling in turbulent premixed combustion

The effects of turbulent Reynolds number, Ret, on the transport of scalar dissipation rate of reaction progress variable in the context of Reynolds averaged Navier-Stokes simulations have been analyzed using three-dimensional simplified chemistry-based direct numerical simulation (DNS) data of freely propagating turbulent premixed flames with different values of Ret. Scaling arguments have been used to explain the effects of Ret on the turbulent transport, scalar-turbulence interaction, and the combined reaction and molecular dissipation terms. Suitable modifications to the models for these terms have been proposed to account for Ret effects, and the model parameters include explicit Ret dependence. These expressions approach expected asymptotic limits for large values of Ret. However, turbulent Reynolds number Ret does not seem to have any major effects on the modeling of the term arising from density variation. Copyright © Taylor and Francis Group, LLC.

Optical constants of cubic GaN/GaAs(001): Experiment and modeling

The optical constants epsilon(E)=epsilon(1)(E)+iepsilon(2)(E) of unintentionally doped cubic GaN grown on GaAs(001) have been measured at 300 K using spectral ellipsometry in the range of 1.5-5.0 eV. The epsilon(E) spectra display a structure, associated with the critical point at E-0 (direct gap) and some contribution mainly coming from the E-1 critical point. The experimental data over the entire measured spectral range (after oxide removal) has been fit using the Holden-Munoz model dielectric function [M. Munoz et al., J. Appl. Phys. 92, 5878 (2002)]. This model is based on the electronic energy-band structure near critical points plus excitonic and band-to-band Coulomb-enhancement effects at E-0, E-0 + Delta(0) and the E-1, E-1 + Delta(1), doublet. In addition to evaluating the energy of the E-0 critical point, the binding energy (R-1) of the two-dimensional exciton related to the E-1 critical point was estimated using the effective mass/k.p theory. The line, shape of the imaginary part of the cubic-GaN dielectric function shows excitonic effects at room temperature not withstanding that the exciton was not resolved. (C) 2003 American Institute of Physics.

Modeling study to compare the flow and heat transfer characteristics of low-power hydrogen, nitrogen and argon arc-heated thrusters

A modelling study is performed to compare the plasma °ow and heat transfer char- acteristics of low-power arc-heated thrusters (arcjets) for three di®erent propellants: hydrogen, nitrogen and argon. The all-speed SIMPLE algorithm is employed to solve the governing equa- tions, which take into account the e®ects of compressibility, Lorentz force and Joule heating, as well as the temperature- and pressure-dependence of the gas properties. The temperature, veloc- ity and Mach number distributions calculated within the thruster nozzle obtained with di®erent propellant gases are compared for the same thruster structure, dimensions, inlet-gas stagnant pressure and arc currents. The temperature distributions in the solid region of the anode-nozzle wall are also given. It is found that the °ow and energy conversion processes in the thruster nozzle show many similar features for all three propellants. For example, the propellant is heated mainly in the near-cathode and constrictor region, with the highest plasma temperature appear- ing near the cathode tip; the °ow transition from the subsonic to supersonic regime occurs within the constrictor region; the highest axial velocity appears inside the nozzle; and most of the input propellant °ows towards the thruster exit through the cooler gas region near the anode-nozzle wall. However, since the properties of hydrogen, nitrogen and argon, especially their molecular weights, speci¯c enthalpies and thermal conductivities, are di®erent, there are appreciable di®er- ences in arcjet performance. For example, compared to the other two propellants, the hydrogen arcjet thruster shows a higher plasma temperature in the arc region, and higher axial velocity but lower temperature at the thruster exit. Correspondingly, the hydrogen arcjet thruster has the highest speci¯c impulse and arc voltage for the same inlet stagnant pressure and arc current. The predictions of the modelling are compared favourably with available experimental results.

Molecular dynamics simulation of sub-transition for polyethersulfone

Molecular dynamics (MD) simulations of a polyethersulfone (PES) chain are carried out in the amorphous state by using the Dreiding 2.21 force field at four temperatures. Two types of molecular motion, i.e, rotations of phenylene rings and torsions of large segments containing two oxygen atoms, two sulfur atoms, and five phenylene rings on the backbone, are simulated. The modeling results show that the successive phenylene rings should be in-phase cooperative rotations, whereas the successive large segments should be out-of-phase cooperative torsions. By calculating the diffusion coefficient for the phenylene ring rotations, it is found that this rotation contributes to the beta -transition of PES.

Accommodating curvature in a highly ordered functionalized metal oxide nanofiber: synthesis, characterization and multi-scale modeling of layered nanosheets

A key element in the rational design of hybrid organic-inorganic nanostructures, is control of surfactant packing and adsorption onto the inorganic phase in crystal growth and assembly. In layered single crystal nanofibers and bilayered 2D nanosheets of vanadium oxide, we show how the chemisorption of preferred densities of surfactant molecules can direct formation of ordered, curved layers. The atom-scale features of the structures are described using molecular dynamics simulations that quantify surfactant packing effects and confirm the preference for a density of 5 dodecanethiol molecules per 8 vanadium attachment sites in the synthesised structures. This assembly maintains a remarkably well ordered interlayer spacing, even when curved. The assemblies of interdigitated organic bilayers on V2O5 are shown to be sufficiently flexible to tolerate curvature while maintaining a constant interlayer distance without rupture, delamination or cleavage. The accommodation of curvature and invariant structural integrity points to a beneficial role for oxide-directed organic film packing effects in layered architectures such as stacked nanofibers and hybrid 2D nanosheet systems.

Modeling the evolution of regulatory elements by simultaneous detection and alignment with phylogenetic pair HMMs.

The computational detection of regulatory elements in DNA is a difficult but important problem impacting our progress in understanding the complex nature of eukaryotic gene regulation. Attempts to utilize cross-species conservation for this task have been hampered both by evolutionary changes of functional sites and poor performance of general-purpose alignment programs when applied to non-coding sequence. We describe a new and flexible framework for modeling binding site evolution in multiple related genomes, based on phylogenetic pair hidden Markov models which explicitly model the gain and loss of binding sites along a phylogeny. We demonstrate the value of this framework for both the alignment of regulatory regions and the inference of precise binding-site locations within those regions. As the underlying formalism is a stochastic, generative model, it can also be used to simulate the evolution of regulatory elements. Our implementation is scalable in terms of numbers of species and sequence lengths and can produce alignments and binding-site predictions with accuracy rivaling or exceeding current systems that specialize in only alignment or only binding-site prediction. We demonstrate the validity and power of various model components on extensive simulations of realistic sequence data and apply a specific model to study Drosophila enhancers in as many as ten related genomes and in the presence of gain and loss of binding sites. Different models and modeling assumptions can be easily specified, thus providing an invaluable tool for the exploration of biological hypotheses that can drive improvements in our understanding of the mechanisms and evolution of gene regulation.

Modeling non-harmonic behavior of materials from experimental inelastic neutron scattering and thermal expansion measurements

Based on thermodynamic principles, we derive expressions quantifying the non-harmonic vibrational behavior of materials, which are rigorous yet easily evaluated from experimentally available data for the thermal expansion coefficient and the phonon density of states. These experimentally- derived quantities are valuable to benchmark first-principles theoretical predictions of harmonic and non-harmonic thermal behaviors using perturbation theory, ab initio molecular-dynamics, or Monte-Carlo simulations. We illustrate this analysis by computing the harmonic, dilational, and anharmonic contributions to the entropy, internal energy, and free energy of elemental aluminum and the ordered compound FeSi over a wide range of temperature. Results agree well with previous data in the literature and provide an efficient approach to estimate anharmonic effects in materials.