Computational studies of the 3-Dimensional structure of cyclopenta polycyclic aromatic hydrocarbons containing a gulf region

Recently, some cyclopenta-fused polyaromatic hydrocarbons, an environmentally relevant subclass of chemicals, have been shown to have carcinogenic activity in animals. It has been suggested that benz[l] aceanthrylene ( I ), an active member of this subclass with a gulf region, has a trans dihydrodiol metabolite that is nonplanar and has two distinct spatial configurations. We have used MMP 2(85) and AM 1 to investigate the three-dimensional structure of this dihydrodiol and other similar derivatives of ( I ) and have found that although ( I ) is somewhat nonplanar the relevant derivatives are all nearly planar. Further, we have computed potential functions for the bending of the angular ring in the gulf region using MMP 2(85), AM 1, and ab initio computed energies for AM 1 spatial configurations and find that these molecules all have only a single potential minimum. We have performed the same calculations for benzo[c]phenanthren and its 1,12 dimethyl derivative, molecules with a similar gulf region for which crystallographic data exists. In agreement with that data, we find that two distinct spatial configurations exist separated by significant barries. The differences between the results generated by the three different methods of computation will be discussed.     

An approach to control the spurious currents in a multiphase lattice Boltzmann method and to improve the implementation of initial condition

Multiphase lattice Boltzmann methods are known to generate spurious or parasitic currents at the fluid–fluid interfaces. This nonphysical phenomenon has to be avoided, or at least controlled, in order to achieve reliable solutions. In this article, a method to control these fictitious velocities via lattice refinement is proposed, which is based on interface thickness control for which both the spurious currents and the physical fluid–fluid interface thickness vanishes as the spatial resolution increases. It has been found that a proper interface thickness adjustment is required as the lattice refinement is applied, or an increase in spurious currents, instead of a reduction, can occur. By combining the new method with an appropriate multiphase flow initialization, the overall stability for high density O(1000) and viscosity O(100) ratios is greatly improved. Although this research has been conducted with a Rothman and Keller type lattice Boltzmann model, it is believed that other types of multiphase lattice Boltzmann models could benefit from the basic ideas underlying this research. Copyright © 2015 John Wiley & Sons, Ltd.     

Parameterization of Org27569: An allosteric modulator of the cannabinoid CB1 G protein‐coupled receptor

The cannabinoid CB₁ receptor is a class A G protein‐coupled receptor (GPCR) that is the most widely expressed GPCR in the brain. Many GPCRs contain allosteric binding sites for endogenous and/or synthetic ligands, which are topographically distinct from the agonist‐binding site that is known as the orthosteric site. While both endogenous and synthetic ligands that act at the CB₁ orthosteric site have been known for some time, compounds that act at a CB₁ allosteric site have only recently been discovered. The most studied of these is 5‐chloro‐3‐ethyl‐1H‐indole‐2‐carboxylic acid [2‐(4‐piperidin‐1‐ylphenyl)ethyl]amide (Org27569). Because allosteric ligands are thought to act through conformational changes in the receptor that are transmitted from the allosteric to the orthosteric site, computational studies of the structural and dynamic interactions of Org27569 with the CB₁ receptor are crucial to achieve a molecular level understanding of the basis of action of this important new class of compounds. To date, such computational studies have not been possible due to the lack of a complete set of molecular mechanics force field parameters for Org27569. Here, we present the development of missing CHARMM force field parameters for Org27569 using previously published methods and the validation and application of these new parameters using normal mode analysis and molecular dynamics simulations combined with experimental infrared measurements. © 2011 Wiley Periodicals, Inc. J Comput Chem, 2011     

A search for properties which produce discrimination between cannabinoid psychoactivity and analgesic activity

One long-range goal of our work has been the design of cannabinoid analgesics with reduced psychopharmacological liability. We review here the progress we have made toward this goal. When we began our work on the cannabinoids, no cannabinoid analgesic had been reported that did not also possess significant psychoactivity. We approached the cannabinoid problem by calculating molecular reactivity characteristics (MRCS ) of template molecules for each activity: (?)-trans-delta-9-tetrahydrocannabinol (Δ⁹-THC) for psychoactivity, and (?)-9-nor-9-betahydroxyhexahydrocannabinol (9-nor-9β-OH? HHC) for analgesic activity. We then compared the MRC s of each template with the MRCS of a carefully chosen set of other cannabinoids (both active and inactive). Our focus in the calculation of MRCS was on accessible conformations of each subject molecule and on the molecular electrostatic potential generated in key planes by each accessible conformer. Our working hypothesis concerning the molecular basis of psychopharmacological activity in the cannabinoids was that activity is conferred by the set of molecular properties generated (1) by the orientation of the lone pairs of electrons of the phenyl group hydroxyl oxygen and (2) by the orientation of the carbocyclic ring and its C–9 substituent relative to this oxygen. Our working hypothesis concerning the molecular basis of cannabinoid analgesic activity was that activity is conferred by the set of molecular properties generated by the presence and relative location of two negative potential regions in the top half of the cannabinoid analgesic molecule. Our work thus far has revealed important steric and electronic features of the cannabinoids that may be used to enhance discrimination. We have shown that a simple structural feature, a C–9 substituent protruding into the α face of the molecule, can abolish or significantly diminish psychoactivity. We have also demonstrated that a free phenol group is not an absolute requirement for activity. Instead, we have found that compounds that do not possess free phenolic hydrogens, but that do maintain the orientation of the lone pairs of electrons of the “phenolic” oxygen toward the carbocyclic ring, exhibit selectivity toward analgesia.     

A staggered control volume scheme for unstructured triangular grids

The purpose of this work is to introduce and validate a new staggered control volume method for the simulation of 2D/axisymmetric incompressible flows. The present study introduces a numerical procedure for solving the Navier–Stokes equations using the primitive variable formulation. The proposed method is an extension of the staggered grid methodology to unstructured triangular meshes for a control volume approach which features ease of handling of irregularly shaped domains. Two alternative elements are studied: transported scalars are stored either at the sides of an element or at its vertices, while the pressure is always stored at the centre of an element. Two interpolation functions were investigated for the integration of the momentum equations: a skewed mass-weighted upwind function and a flow-oriented exponential shape function. The momentum equations are solved over the covolume of a side or of a vertex and the pressure–velocity coupling makes use of a localized linear reconstruction of the discontinuous pressure field surrounding an element in order to obtain the pressure gradient terms. The pressure equation is obtained through a discretization of the continuity equation which uses the triangular element itself as the control volume. The method is applied to the simulation of the following test cases: backward-facing step flow, flow over a two-dimensional obstacle and flow in a pipe with sudden contraction of cross-sectional area. All numerical investigations are compared with experimental data from the literature. A grid convergence and error analysis study is also carried out for flow in a driven cavity. Results compared favourably with experimental data and so the new control volume scheme is deemed well suited for the prediction of incompressible flows in complex geometries. © 1997 John Wiley & Sons, Ltd.     

Vibrational analysis for surge precursor definition in gas turbines

Compressor behaviour analysis in critical working conditions, such as incipient surge, represents a significant aspect in the turbomachinery research field. Turbines connected with large-size volumes present critical issues related to surge prevention especially during transient operations. Investigations based on acoustic and vibrational measurements appear to provide an interesting diagnostic and predictive solution by adopting suitable quantifiers calculated from microphone and accelerometer signals. For this scope a wide experimental activity has been conducted on a T100 microturbine connected with different volume sizes. A machine dynamical characterisation has been useful for better interpretation of signals during its transient to the surge. Hence, different possible methods of incipient surge identification have been developed through the use of different signal processing techniques in time, frequency and angle domain. These results will be useful for control system development to prevent compressor failures.

     

LTE computation of axisymmetric arc-flow interaction incircuit-breakers

A numerical procedure for the computation of arc-flow interaction in gas-blast circuit breakers is presented. In the proposed approach the flow is obtained via the solution of the Euler equations and the coupling with the arc by a source term in the energy equation. This source term is composed of an ohmic energy production part and a radiative transport part. The equations are solved by a time-marching procedure using a finite-volume discretization. The model is applied to the computation of an axisymmetric arc in a model breaker. The results reproduce qualitatively the major features of arc-flow interaction and show the presence of a localized form of choking of the flow around the arc boundary     

Numerical solution of axisymmetric multi-species compressible gas flow: towards improved circuit breaker simulation

Nozzle wall ablation caused by high-temperature electrical arcs is studied in the context of high voltage SF₆ circuit breakers. The gases generated by the ablation mix with insulating gas, thereby modifying the thermodynamics and chemistry of the problem. To simulate these phenomena, an axisymmetric Euler equations model for multi-species flow at local thermodynamic equilibrium has been developed. The governing equations are solved using a finite-volume method based on Roe's flux-splitting scheme and a new procedure is proposed to obtain the mean values used in Roe's matrix involving multi-species. The change in the gas composition due to dissociation, ionisation and recombinations are taken into account by a dynamic coupling to a thermodynamic database. The formulation is appropriate for general equations of state. The scheme has been verified by comparisons with the analytical solution of a classic shock-tube problem. An experimental validation is presented involving the simulation of shock interactions with helium cylinders and bubbles in air. The scheme is also compared to experimental ablation results, as well as a previous version of the code. The model is then applied to a well controlled experimental arrangement with an arc inside a small Teflon^® tube. Finally, a simulation with a model circuit breaker completes the study.     

Cannabinoid CB1 receptor recognition of endocannabinoids via the lipid bilayer: molecular dynamics simulations of CB1 transmembrane helix 6 and anandamide in a phospholipid bilayer

The phospholipid bilayer plays a central role in the lifecycle of the endogenous cannabinoid, N-arachidonoylethanolamine (anandamide, AEA). Therefore, the orientation and location of AEA in the phospholipid bilayer with respect to key membrane associated proteins, is a central issue in understanding the mechanism of endocannabinoid signaling. In this paper, we report a test of the hypothesis that a βXXβ motif (formed by beta branching amino acids, V6.43 and I6.46) on the lipid face of the cannabinoid CB1 receptor in its inactive state may serve as an initial CB1 interaction site for AEA. Eight 6 ns NAMD2 molecular dynamics simulations of AEA were conducted in a model system composed of CB1 transmembrane helix 6 (TMH6) in a 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) bilayer. In addition, eight 6 ns NAMD2 molecular dynamics simulations of a low CB1 affinity (20:2, n−6) analog of AEA were conducted in the same model system. AEA was found to exhibit a higher incidence of V6.43/I6.46 groove insertion than did the (20:2, n−6) analog. In certain cases, AEA established a high energy of interaction with TMH6 by first associating with the V6.43/I6.46 groove and then molding itself to the lipid face of TMH6 to establish a hydrogen bonding interaction with the exposed backbone carbonyl of P6.50. Based upon these results, we propose that the formation of this hydrogen bonded AEA/TMH6 complex may be the initial step in CB1 recognition of AEA in the lipid bilayer.