Unraveling the Structure and Function of G Protein-Coupled Receptors Through NMR Spectroscopy

G protein-coupled receptors (GPCRs) are a large superfamily of signaling proteins expressed on the plasma membrane. They are involved in a wide range of physiological processes and, therefore, are exploited as drug targets in a multitude of therapeutic areas. In this extent, knowledge of structural and functional properties of GPCRs may greatly facilitate rational design of modulator compounds. Solution and solid-state nuclear magnetic resonance (NMR) spectroscopy represents a powerful method to gather atomistic insights into protein structure and dynamics. In spite of the difficulties inherent the solution of the structure of membrane proteins through NMR, these methods have been successfully applied, sometimes in combination with molecular modeling, to the determination of the structure of GPCR fragments, the mapping of receptor-ligand interactions, and the study of the conformational changes associated with the activation of the receptors. In this review, we provide a summary of the NMR contributions to the study of the structure and function of GPCRs, also in light of the published crystal structures.

Modeled structure of a G-protein-coupled receptor:The cholecystokinin-1 receptor

The Cholecystokinin-1 receptor (CCK1R) mediates actions of CCK in areas of the central nervous system and of the gut. It is a potential target to treat a number of diseases. As for all G-protein-coupled receptors, docking of ligands into modeled CCK1R binding site should greatly help to understand intrinsic mechanisms of activation. Here, we describe the procedure we used to progressively build a structural model for the CCK1R, to integrated, and on the basis of site-directed mutagenesis data on its binding site. Reliability of the CCK1R model was confirmed by interaction networks that involved conserved and functionally crucial motifs in G-protein-coupled receptors, such as Glu/Asp-Arg-Tyr and Asn-Pro-Xaa-Xaa-Tyr motifs. In addition, the 3-D structure of CCK1R-bound CCK resembled that determined by NMR in a lipid environment. The derived computational model was also used for revealing binding modes of several nonpeptide ligands and for rationalizing ligand structure-activity relationships known from experiments. Our findings indeed support that our "validated CCK1R model" could be used to study the intrinsic mechanism of CCK1R activation and design new ligands.

Dynamical scattering models in optomechanics: Going beyond the 'coupled cavities' model

Recently [A. Xuereb, et al., Phys. Rev. Lett. 105, 013602 (2010)], we calculated the radiation field and the optical forces acting on a moving object inside a general one-dimensional configuration of immobile optical elements. In this article we analyse the forces acting on a semi-transparent mirror in the 'membrane-in-the-middle' configuration and compare the results obtained from solving scattering model to those from the coupled cavities model that is often used in cavity optomechanical system. We highlight the departure of this model from the more exact scattering theory when the reflectivity of the moving element drops below about 50%.

Modulational instability in asymmetric coupled wave functions

The evolution of the amplitude of two nonlinearly interacting waves is considered, via a set of coupled nonlinear Schrödinger-type equations. The dynamical profile is determined by the wave dispersion laws (i.e. the group velocities and the group velocity dispersion terms) and the nonlinearity and coupling coefficients, on which no assumption is made. A generalized dispersion relation is obtained, relating the frequency and wave-number of a small perturbation around a coupled monochromatic (Stokes') wave solution. Explicitly stability criteria are obtained. The analysis reveals a number of possibilities. Two (individually) stable systems may be destabilized due to coupling. Unstable systems may, when coupled, present an enhanced instability growth rate, for an extended wave number range of values. Distinct unstable wavenumber windows may arise simultaneously.

Microscopic theory for random processes in weakly-coupled open systems

In order to relate macroscopic random motion (described e.g. by Langevin-type theories) to microscopic dynamics, we have undertaken the derivation of a Fokker-Planck-type equation from first microscopic principles. Both subsystems are subject to an external force field. Explicit expressions for the diffusion and drift coefficients are obtained, in terms of the field.

Physical Models of Wind Instruments : A Generalized Excitation Coupled with a Modular Tube Simulation Platform

To develop real-time simulations of wind instruments, digital waveguides filters can be used as an efficient representation of the air column. Many aerophones are shaped as horns which can be approximated using conical sections. Therefore the derivation of conical waveguide filters is of special interest. When these filters are used in combination with a generalized reed excitation, several classes of wind instruments can be simulated. In this paper we present the methods for transforming a continuous description of conical tube segments to a discrete filter representation. The coupling of the reed model with the conical waveguide and a simplified model of the termination at the open end are described in the same way. It turns out that the complete lossless conical waveguide requires only one type of filter.Furthermore, we developed a digital reed excitation model, which is purely based on numerical integration methods, i.e., without the use of a look-up table.

Nonlinear dust-acoustic solitary waves in strongly coupled dusty plasmas

Dust-acoustic waves are investigated in a three-component plasma consisting of strongly coupled dust particles and Maxwellian electrons and ions. A fluid model approach is used, with the effects of strong coupling being accounted for by an effective electrostatic "pressure" which is a function of the dust number density and the electrostatic potential. Both linear and weakly nonlinear cases are considered by derivation and analysis of the linear dispersion relation and the Korteweg-de Vries equation, respectively. In contrast to previous studies using this model, this paper presents the results arising from an expansion of the dynamical form of the electrostatic pressure, accounting for the variations in its value in the vicinity of the wave. DOI: 10.1103/PhysRevE.86.066404

Small aperture evanescent-mode waveguide antenna matched using distributed coupled resonators

Presented is a design methodology which permits the application of distributed coupled resonator bandpass filter principles to form wideband small-aperture evanescent-mode waveguide antenna designs. This approach permits matching of the complex antenna aperture admittance of an evanescent-mode open-ended waveguide to a real impedance generator, and thereby to a coaxial feed probe. A simulated reflection coefficient of < - 10 dB was obtained over a bandwidth of 20%, from 2.0-2.45 GHz, in a 2.58 GHz cutoff waveguide. Dielectric-filled propagating waveguide and air-filled evanescent-mode waveguide sections are used to form the resonators/coupling elements of the antenna's coupled resonator matching sections. Simulated realised gain variation from 3.4-5.0 dBi is observed across the bandwidth. The antenna's maximum aperture dimension is < 0.47 wavelength at the upper operating frequency and so it is suitable for use in a wide angle scanning phased array.

ESTIMATION OF PURITY FOR A QUANTUM HARMONIC OSCILLATOR INITIALLY PREPARED IN A DISPLACED THERMAL STATE

We address the estimation of purity for a quantum oscillator initially prepared in a displaced thermal state and probed by a suitably prepared qubit interacting with the oscillator via Jaynes-Cummings Hamiltonian without the rotating-wave approximation. We evaluate the quantum Fisher information (QFI) and show that optimal estimation of purity can be achieved by measuring the population of the qubit after a properly chosen interaction time. We also address the estimation of purity at fixed total energy and show that the corresponding precision is independent of the presence of a coherent amplitude.

Qubit-assisted thermometry of a quantum harmonic oscillator

We use the theory of quantum estimation in two different qubit-boson coupling models to demonstrate that the temperature of a quantum harmonic oscillator can be estimated with high precision by quantum-limited measurements on the qubit. The two models that we address embody situations of current physical interest due to their connection with ongoing experimental efforts on the control of mesoscopic dynamics. We show that population measurements performed over the qubit probe are near optimal for a broad range of temperatures of the harmonic oscillator.

Discharge kinetics of inductively coupled oxygen plasmas:Experiment and model

In this paper, neutral and charged particle dynamics in both the capacitive and inductive modes of an inductively coupled oxygen discharge are presented. Langmuir probes, laser-assisted photodetachment and two-photon laser-induced fluorescence are employed to measure plasma parameters in the 13.56MHz system for a range of plasma powers and gas pressures. It is found that the capacitive mode is more electronegative with lower molecular dissociation compared with the inductive mode. However, the negative ion density in each mode is comparable. A maximum is observed in the negative ion density and fraction with pressure for both modes. The experimental measurements are supplemented by a global model, which includes capacitive and inductive coupling effects. The model and experiments demonstrate that negative ion loss is dominated by ion-ion recombination and electron detachment at low pressures (

Nonlinearly coupled localized plasmon resonances: Resonant second-harmonic generation

The efficient resonant nonlinear coupling between localized surface plasmon modes is demonstrated in a simple and intuitive way using boundary integral formulation and utilizing second-order optical nonlinearity. The nonlinearity is derived from the hydrodynamic description of electron plasma and originates from the presence of material interfaces in the case of small metal particles. The coupling between fundamental and second-harmonic modes is shown to be symmetry selective and proportional to the spatial overlap between polarization dipole density of the second-harmonic mode and the square of the polarization charge density of the fundamental mode. Particles with high geometrical symmetry will convert a far-field illumination into dark nonradiating second-harmonic modes, such as quadrupoles. Effective second-harmonic susceptibilities are proportional to the surface-to-volume ratio of a particle, emphasizing the nanoscale enhancement of the effect.

3D coupled thermomechanical finite element analysis of ultrasonic consolidation

A 3-D coupled temperature-displacement finite element analysis is performed to study an ultrasonic consolidation process. Results show that ultrasonic wave is effective in causing deformation in aluminum foils. Ultrasonic vibration leads to an oscillating stress field. The oscillation of stress in substrate lags behind the ultrasonic vibration by about 0.1 cycle of ultrasonic wave. The upper foil, which is in contact with the substrate, has the most severe deformation. The substrate undergoes little deformation. Apparent material softening by ultrasonic wave, which is of great concern for decades, is successfully simulated. The higher the friction coefficient, the more obvious the apparent material softening effect.