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     

Extending the GGobi pipeline from R

This paper describes progress towards developing a platform for rapid prototyping of interactive data visualizations, using R, GGobi, rggobi and RGtk2. GGobi is a software tool for multivariate interactive graphics. At the core of GGobi is a data pipeline that incrementally transforms data through a series of stages into a plot and maps user interaction with the plot back to the data. The GGobi pipeline is extensible and mutable at runtime. The rggobi package, an interface from the R language to GGobi, has been augmented with a low-level interface that supports the customization of interactive data visualizations through the extension and manipulation of the GGobi pipeline. The large size of the GGobi API has motivated the use of the RGtk2 code generation system to create the low-level interface between R and GGobi. The software is demonstrated through an application to interactive network visualization.     

An image system and surface singularity solutions for potential flow past an elliptical cylinder

The Milne-Thomson circle theorem is extended to give a simplegeneral expression for the image system in an elliptical cylinderintroduced into an otherwise specified unbounded potential flowwhich contains no singularities in the region to be occupiedby the ellipse. This image system is used to obtain an expressionfor the corresponding source-sink surface singularity distributionon the ellipse, thus providing new benchmark test cases forsource-sink solutions as obtained numerically by a panel method.Several typical examples are given to illustrate the generaltheoretical approach.     

The microscopic investigation of structures of moving flux lines by neutron and muon techniques

We have used a variety of microscopic techniques to reveal the structure and motion of flux line arrangements, when the flux lines in low T _c type II superconductors are caused to move by a transport current. Using small-angle neutron scattering by the flux line lattice (FLL), we are able to demonstrate directly the alignment by motion of the nearest-neighbor FLL direction. This tends to be parallel to the direction of flux line motion, as had been suspected from two-dimensional simulations. We also see the destruction of the ordered FLL by plastic flow and the bending of flux lines. Another technique that our collaboration has employed is the direct measurement of flux line motion, using the ultra-high-resolution spectroscopy of the neutron spin-echo technique to observe the energy change of neutrons diffracted by moving flux lines. The muon spin rotation (μSR) technique gives the distribution of values of magnetic field within the FLL. We have recently succeeded in performing μSR measurements while the FLL is moving. Such measurements give complementary information about the local speed and orientation of the FLL motion. We conclude by discussing the possible application of this technique to thin film superconductors.     

The d'--d--d' vertical triad is less discriminating than the a'--a--a' vertical triad in the antiparallel coiled-coil dimer motif

Elucidating relationships between the amino-acid sequences of proteins and their three-dimensional structures, and uncovering non-covalent interactions that underlie polypeptide folding, are major goals in protein science. One approach toward these goals is to study interactions between selected residues, or among constellations of residues, in small folding motifs. The α-helical coiled coil has served as a platform for such studies because this folding unit is relatively simple in terms of both sequence and structure. Amino acid side chains at the helix-helix interface of a coiled coil participate in so-called "knobs-into-holes" (KIH) packing whereby a side chain (the knob) on one helix inserts into a space (the hole) generated by four side chains on a partner helix. The vast majority of sequence-stability studies on coiled-coil dimers have focused on lateral interactions within these KIH arrangements, for example, between an a position on one helix and an a' position of the partner in a parallel coiled-coil dimer, or between a--d' pairs in an antiparallel dimer. More recently, it has been shown that vertical triads (specifically, a'--a--a' triads) in antiparallel dimers exert a significant impact on pairing preferences. This observation provides impetus for analysis of other complex networks of side-chain interactions at the helix-helix interface. Here, we describe a combination of experimental and bioinformatics studies that show that d'--d--d' triads have much less impact on pairing preference than do a'--a--a' triads in a small, designed antiparallel coiled-coil dimer. However, the influence of the d'--d--d' triad depends on the lateral a'--d interaction. Taken together, these results strengthen the emerging understanding that simple pairwise interactions are not sufficient to describe side-chain interactions and overall stability in antiparallel coiled-coil dimers; higher-order interactions must be considered as well.     

Graphical Criticism: Some Historical Notes

This article proposes a bootstrap local bandwidth selector for estimating nonparametric additive models. The selector is derived from a bootstrap approximation of the conditional mean squared error, based on a wild bootstrap resampling scheme applied to the estimated residuals. The selector is computed exactly (without involving Monte Carlo approximations) and in practice can be evaluated for many additive estimation methods, including backfitting (bivariate), marginal integration, and mixed methods. We study the consistency of the bootstrap approximation and also carry out an empirical simulation study to explore the performance of the proposed selector in comparison with others. The graphical tool SiZer Map enables us to make meaningful comparisons between local and global selectors.