Extending Halogen-based Medicinal Chemistry to Proteins: IODO-INSULIN AS A CASE STUDY

Insulin, a protein critical for metabolic homeostasis, provides a classical model for protein design with application to human health. Recent efforts to improve its pharmaceutical formulation demonstrated that iodination of a conserved tyrosine (Tyr(B26)) enhances key properties of a rapid-acting clinical analog. Moreover, the broad utility of halogens in medicinal chemistry has motivated the use of hybrid quantum- and molecular-mechanical methods to study proteins. Here, we (i) undertook quantitative atomistic simulations of 3-[iodo-Tyr(B26)]insulin to predict its structural features, and (ii) tested these predictions by X-ray crystallography. Using an electrostatic model of the modified aromatic ring based on quantum chemistry, the calculations suggested that the analog, as a dimer and hexamer, exhibits subtle differences in aromatic-aromatic interactions at the dimer interface. Aromatic rings (Tyr(B16), Phe(B24), Phe(B25), 3-I-Tyr(B26), and their symmetry-related mates) at this interface adjust to enable packing of the hydrophobic iodine atoms within the core of each monomer. Strikingly, these features were observed in the crystal structure of a 3-[iodo-Tyr(B26)]insulin analog (determined as an R6 zinc hexamer). Given that residues B24-B30 detach from the core on receptor binding, the environment of 3-I-Tyr(B26) in a receptor complex must differ from that in the free hormone. Based on the recent structure of a "micro-receptor" complex, we predict that 3-I-Tyr(B26) engages the receptor via directional halogen bonding and halogen-directed hydrogen bonding as follows: favorable electrostatic interactions exploiting, respectively, the halogen's electron-deficient σ-hole and electronegative equatorial band. Inspired by quantum chemistry and molecular dynamics, such "halogen engineering" promises to extend principles of medicinal chemistry to proteins

Orbit Approach to Separation of Variables in sl(4)-Related Integrable Systems

Separation of variables by means of the orbit method is implemented to integrable systems on coadjoint orbits in an $\mathfrak{sl}(4)$ loop algebra. This is a development and a kind of explanation for Sklyanin's procedure of separation of variables. It is shown that points on a spectral curve serve as variables of separation for two integrable systems living on two generic orbits embedded into a common manifold. These orbits are endowed with different nonsingular Lie-Poisson brackets. Explicit expressions for the case of $\mathfrak{sl}(4)$ loop algebra are given.Comment: 12 pages. arXiv admin note: substantial text overlap with arXiv:1312.197

Plane quartics: the universal matrix of bitangents

Aronhold's classical result states that a plane quartic can be recovered by the configuration of any Aronhold systems of bitangents, i.e. special $7$-tuples of bitangents such that the six points at which any sub-triple of bitangents touches the quartic do not lie on the same conic in the projective plane. Lehavi (cf. \cite{lh}) proved that a smooth plane quartic can be explicitly reconstructed from its $28$ bitangents; this result improved Aronhold's method of recovering the curve. In a 2011 paper \cite{PSV} Plaumann, Sturmfels and Vinzant introduced an $8 \times 8$ symmetric matrix that parametrizes the bitangents of a nonsingular plane quartic. The starting point of their construction is Hesse's result for which every smooth quartic curve has exactly $36$ equivalence classes of linear symmetric determinantal representations. In this paper we tackle the inverse problem, i.e. the construction of the bitangent matrix starting from the 28 bitangents of the plane quartic, and we provide a Sage script intended for computing the bitangent matrix of a given curve

Genomic analysis of Mycobacterium bovis and other members of the Mycobacterium tuberculosis complex by isoenzyme analysis and pulsed-field gel electrophoresis.

Initially, multilocus enzyme electrophoresis was used to examine genetic relationships among 63 isolates of Mycobacterium bovis and 13 other members of the M. tuberculosis complex. The isolates were divided into five electrophoretic types, with a mean genetic diversity of 0.1. The strains were genetically homogenous, indicating that members of the complex were closely related. This supported the suggestion that they should be considered as subspecies of a single species. Pulsed-field gel electrophoresis (PFGE) was then used to differentiate these isolates, as well as 59 additional isolates of M. bovis from different parts of the world. PFGE differentiated these strains into 63 patterns (53 patterns for M. bovis). Isolates of M. bovis from Western Australia (n = 46) were more homogenous than isolates from other regions. Eight strains were identified in that state, and one predominantly bovine strain was isolated from two human beings and a feral pig. Although M. bovis isolates from different parts of the world had distinct DNA patterns, some were very similar. PFGE is a highly discriminatory technique for epidemiological studies of bovine tuberculosis. For example, it allowed differentiation between isolates of M. bovis cultured from animals in separate outbreaks of tuberculosis, it suggested the transmission of infection between certain properties, and it demonstrated the existence of multiple infections with different strains at certain farms

Quadrupole Susceptibility of Gd-Based Filled Skutterudite Compounds

It is shown that quadrupole susceptibility can be detected in Gd compounds contrary to our textbook knowledge that Gd$^{3+}$ ion induces pure spin moment due to the Hund's rules in an $LS$ coupling scheme. The ground-state multiplet of Gd$^{3+}$ is always characterized by $J$=7/2, where $J$ denotes total angular momentum, but in a $j$-$j$ coupling scheme, one $f$ electron in $j$=7/2 octet carries quadrupole moment, while other six electrons fully occupy $j$=5/2 sextet, where $j$ denotes one-electron total angular momentum. For realistic values of Coulomb interaction and spin-orbit coupling, the ground-state wavefunction is found to contain significant amount of the $j$-$j$ coupling component. From the evaluation of quadrupole susceptibility in a simple mean-field approximation, we point out a possibility to detect the softening of elastic constant in Gd-based filled skutterudites.Comment: 8 pages, 4 figure

Effect of adsorbed water on the specific surface area of some standards cotton

It is well known that cotton fibers are sensitive to moisture. The interactions of cellulose chains and water molecules could therefore have an influence on the fiber properties. In this presentation, we will investigate the effect of adsorbed water on the specific surface area of standards cotton fibers. The amount of adsorbed water was determined by Thermogravimetric analysis. Adsorption of methylene blue in aqueous phase was used to measure the surface specific area. A numerical relationship of the form SBM =a +b X has been obtained, where SBM represents the specific surface area, X the percentage of adsorbed water, a and b are experimental constants. (Résumé d'auteur

Construction of a Lax Pair for the E6(1)E_6^{(1)} qq-Painlev\'e System

We construct a Lax pair for the $E^{(1)}_6$ $q$-Painlev\'e system from first principles by employing the general theory of semi-classical orthogonal polynomial systems characterised by divided-difference operators on discrete, quadratic lattices [arXiv:1204.2328]. Our study treats one special case of such lattices - the $q$-linear lattice - through a natural generalisation of the big $q$-Jacobi weight. As a by-product of our construction we derive the coupled first-order $q$-difference equations for the $E^{(1)}_6$ $q$-Painlev\'e system, thus verifying our identification. Finally we establish the correspondences of our result with the Lax pairs given earlier and separately by Sakai and Yamada, through explicit transformations