Halogen Bonding Interactions of Haloaromatic Endocrine Disruptors and the Potential for Inhibition of Iodothyronine Deiodinases

Halogen bonding (XB) is a potential mechanism for the inhibition of the thyroid-activating/deactivating iodothyronine deiodinase family of selenoproteins through interactions with halogenated endocrine disrupting compounds (EDCs). Trends in XB interactions were examined using density functional theory for a series of polyhalogenated dibenzo-1,4-dioxins, biphenyls, and other EDCs with methylselenolate, a simple model of the Dio active site selenocysteine. The strengths of the interactions depend upon the halogen (Br\u3eCl), the degree of substitution, and the position of the acceptor. In terms of donor-acceptor energies, interactions at the meta position are often the strongest, suggesting a link to the topology of THs, especially for outer-ring deiodination of thyroxine, which occurs at a meta iodine, and produces the active TH. However, relationships between XB interaction strengths and potential for Dio inhibition should be made in the context of the binding to the active sites, the topology of which are not fully characterized

Theoretical Studies of 2,3 -Sigmatropic Rearrangements of Allylic Selenoxides and Selenimides

Density-functional theory is used to model the endo and exo transition states for [2,3]-sigmatropic rearrangement of allylic aryl-selenoxides and -selenimides. The endo transition state is generally preferred for selenoxides if there is no substitution at the 2 position of the allyl group. Based upon the relative energies of the endo and exo transition states, enantioselectivity of rearrangements is expected to be greatest for molecules with substitutions at the 1- or (E)-3- position of the allyl group. Ortho substitution of a nitro group on the ancillary selenoxide phenyl ring reduces the activation barriers, increases the difference between the endo and exo activation barriers and shifts the equilibrium toward products

The Effect of Metalation on Antimicrobial Piscidins Imbedded in Normal and Oxidized Lipid Bilayers

Metalation of the N-terminal Amino Terminal Cu(II)- and Ni(II)-binding (ATCUN) motif may enhance the antimicrobial properties of piscidins. Molecular dynamics simulations of free and nickelated piscidins 1 and 3 (P1 and P3) were performed in 3 : 1 POPC/POPG and 2.6 : 1 : 0.4 POPC/POPG/aldo-PC bilayers (POPC, 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine: POPG, 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol; aldo-PC, 1-palmitoyl-2-(9′-oxo-nonanoyl)-sn-glycero-3-phosphocholine) bilayer models. Nickel(II) binding decreases the conformation dynamics of the ATCUN motif and lowers the charge of the N-terminus to allow it to embed deeper in the bilayer without significantly changing the overall depth due to interactions of the charged half-helix of the peptide with the headgroups. Phe1⋯Ni2+ cation–π and Phe2–Phe1 CH–π interactions contribute to a small fraction of structures within the nickelated P1 simulations and may partially protect a bound metal from metal-centered chemical activity. The substitution of Phe2 for Ile2 in P3 sterically blocks conformations with cation–π interactions offering less protection to the metal. This difference between metalated P1 and P3 may indicate a mechanism by which peptide sequence can influence antimicrobial properties. Any loss of bilayer integrity due to chain reversal of the oxidized phospholipid chains of aldo-PC may be enhanced in the presence of metalated piscidins

A Halogen Bonding Perspective on Iodothyronine Deiodinase Activity

Iodothyronine deiodinases (Dios) are involved in the regioselective removal of iodine from thyroid hormones (THs). Deiodination is essential to maintain TH homeostasis, and disruption can have detrimental effects. Halogen bonding (XB) to the selenium of the selenocysteine (Sec) residue in the Dio active site has been proposed to contribute to the mechanism for iodine removal. Polybrominated diphenyl ethers (PBDEs) and polychlorinated biphenyls (PCBs) are known disruptors of various pathways of the endocrine system. Experimental evidence shows PBDEs and their hydroxylated metabolites (OH-BDEs) can inhibit Dio, while data regarding PCB inhibition are limited. These xenobiotics could inhibit Dio activity by competitively binding to the active site Sec through XB to prevent deiodination. XB interactions calculated using density functional theory (DFT) of THs, PBDEs, and PCBs to a methyl selenolate (MeSe-) arrange XB strengths in the order THs \u3e PBDEs \u3e PCBs in agreement with known XB trends. THs have the lowest energy C–X*-type unoccupied orbitals and overlap with the Se lp donor leads to high donor-acceptor energies and the greatest activation of the C–X bond. The higher energy C–Br* and C–Cl* orbitals similarly result in weaker donor-acceptor complexes and less activation of the C–X bond. Comparison of the I...Se interactions for the TH group suggest that a threshold XB strength may be required for dehalogenation. Only highly brominated PBDEs have binding energies in the same range as THs, suggesting that these compounds may inhibit Dio and undergo debromination. While these small models provide insight on the I...Se XB interaction itself, interactions with other active site residues are governed by regioselective preferences observed in Dios

Effect of Methoxy Substituents on the Activation Barriers of the Glutathione Peroxidase-Like Mechanism of an Aromatic Cyclic Seleninate

Density functional theory (DFT) models including explicit water molecules have been used to model the redox scavenging mechanism of aromatic cyclic seleninates. Experimental studies have shown that methoxy substitutions affect the rate of scavenging of reactive oxygen species differently depending upon the position. Activities are enhanced in the para position, unaffected in the meta, and decreased in the ortho. DFT calculations show that the activation barrier for the oxidation of the selenenyl sulfide, a proposed key intermediate, is higher for the ortho methoxy derivative than for other positions, consistent with the low experimental conversion rate

Photoluminescence of 1-D Copper(I) Cyanide Chains: A Theoretical Description

Solid copper(I) cyanide occurs as extended one-dimensional chains with interesting photophysical properties. To explain the observed luminescence spectroscopy of CuCN, we report a series of computational studies using short bare and potassium-capped [Cun(CN)n+1] − (n = 1, 2, 3, 4, 5, and 7) chains as CuCN models. On the basis of TD-DFT calculations of these model chains, the excitation transitions in the UV spectrum are assigned as Laporte-allowed π−π transitions from MOs with Cu 3dπ and CN π character to empty MOs with Cu 4p and CN π* character. Transitions between the HOMO (3dz) and LUMO (Cu 4p and CN π*) are symmetry forbidden and are not assigned to the bands in the excitation spectrum. The emission spectrum is assumed to arise from transitions between the lowest triplet excited state and the ground-state singlet. The lowest energy triplet for the model networks has a bent structure due to distortions to remove the degeneracies in the partially occupied MOs of the linear triplet. The S0−T gap for the bent triplet chains is consistent with the emission wavelength for bulk CuCN

Meso-1, 2-Bis (Methylazo)-1, 2-Diphenylethane

The title compound, meso-1,2-bis(methyldiazenyl)-1,2-diphenylethane, C16H18N4, is arranged in a disordered manner around an inversion point. The N—N atom distances in the azo group of 1.192 (8) and 1.195 (8) Å, and the C—C atom distances in the ethylene moiety at 1.512 (8) and 1.503 (8) Å in the two models [refined to 51.7 (6) and 48.3 (6)% occupancies] were not significantly different

Thyroxine Binding to Type III Iodothyronine Deiodinase

Iodothyronine deiodinases (Dios) are important selenoproteins that control the concentration of the active thyroid hormone (TH) triiodothyronine through regioselective deiodination. The X-ray structure of a truncated monomer of Type III Dio (Dio3), which deiodinates TH inner rings through a selenocysteine (Sec) residue, revealed a thioredoxin-fold catalytic domain supplemented with an unstructured Ω-loop. Loop dynamics are driven by interactions of the conserved Trp207 with solvent in multi-microsecond molecular dynamics simulations of the Dio3 thioredoxin(Trx)-fold domain. Hydrogen bonding interactions of Glu200 with residues conserved across the Dio family anchor the loop\u27s N-terminus to the active site Ser-Cys-Thr-Sec sequence. A key long-lived loop conformation coincides with the opening of a cryptic pocket that accommodates thyroxine (T4) through an I…Se halogen bond to Sec170 and the amino acid group with a polar cleft. The Dio3-T4 complex is stabilized by an I…O halogen bond between an outer ring iodine and Asp211, consistent with Dio3 selectivity for inner ring deiodination. Non-conservation of residues, such as Asp211, in other Dio types in the flexible portion of the loop sequence suggests a mechanism for regioselectivity through Dio type-specific loop conformations. Cys168 is proposed to attack the selenenyl iodide intermediate to regenerate Dio3 based upon structural comparison with related Trx-fold proteins

Redox Active Motifs in Selenoproteins

Selenoproteins use the rare amino acid selenocysteine (Sec) to act as the first line of defense against oxidants, which are linked to aging, cancer, and neurodegenerative diseases. Many selenoproteins are oxidoreductases in which the reactive Sec is connected to a neighboring Cys and able to form a ring. These Sec-containing redox motifs govern much of the reactivity of selenoproteins. To study their fundamental properties, we have used Se-77 NMR spectroscopy in concert with theoretical calculations to determine the conformational preferences and mobility of representative motifs. This use of Se-77 as a probe enables the direct recording of the properties of Sec as its environment is systematically changed. We find that all motifs have several ring conformations in their oxidized state. These ring structures are most likely stabilized by weak, nonbonding interactions between the selenium and the amide carbon. To examine how the presence of selenium and ring geometric strain governs the motifs\u27 reactivity, we measured the redox potentials of Sec-containing motifs and their corresponding Cys-only variants. The comparisons reveal that for C-terminal motifs the redox potentials increased between 20-25 mV when the selenenylsulfide bond was changed to a disulfide bond. Changes of similar magnitude arose when we varied ring size or the motifs\u27 flanking residues. This suggests that the presence of Sec is not tied to unusually low redox potentials. The unique roles of selenoproteins in human health and their chemical reactivities may therefore not necessarily be explained by lower redox potentials, as has often been claimed

Interaction of dihydrogen with gold (I) hydride: Prospects for matrix-isolation studies

Most discussions have described the AuH3 molecule as a T-shaped complex. A recent study showed that a nonclassical Au(η2-H2)H complex was more stable than the classical AuH3 aurane complex by roughly 30 kcal/mol. The present study shows that the nonclassical isomer is only loosely bound (ΔEdis = 13.44 kcal/mol) vs AuH and dihydrogen, and that the dimerization of AuH3 units to a Au2H6 diaurane molecule is exothermic by roughly 20 kcal/mol. Additional data is provided which may prove useful for matrix-isolation experiments