Enhanced Pre-Strain Application for Goodman Data Generated with Vibration-Based Testing

Experimental Mechanics - Imparting residual stress is an essential step in the generation of Goodman data via Air Force Research Laboratory’s vibration-based fatigue test. Conventional...     

Halogen–Aromatic π Interactions Modulate Inhibitor Residence Times

Prolonged drug residence times may result in longer‐lasting drug efficacy, improved pharmacodynamic properties, and “kinetic selectivity” over off‐targets with high drug dissociation rates. However, few strategies have been elaborated to rationally modulate drug residence time and thereby to integrate this key property into the drug development process. Herein, we show that the interaction between a halogen moiety on an inhibitor and an aromatic residue in the target protein can significantly increase inhibitor residence time. By using the interaction of the serine/threonine kinase haspin with 5‐iodotubercidin (5‐iTU) derivatives as a model for an archetypal active‐state (type I) kinase–inhibitor binding mode, we demonstrate that inhibitor residence times markedly increase with the size and polarizability of the halogen atom. The halogen–aromatic π interactions in the haspin–inhibitor complexes were characterized by means of kinetic, thermodynamic, and structural measurements along with binding‐energy calculations.     

Complexes formed by the reactions of fluorinated and non-fluorinated organonitriles with [Zn(SO2)2][AsF6]2: A structural study

[Zn(SO₂)₂][AsF₆]₂ (1) has been prepared from zinc metal and AsF₅ in liquid sulfur dioxide, and crystallized from sulfur dioxide giving crystals of [Zn(SO₂)₄(AsF₆)₂] (1a). The compound 1 forms the homoleptic complexes [Zn(NCR)₆](AsF₆)₂ (R: CH₃ (2a), C₆H₅ (3a), C₆F₅ (3b)) with the corresponding nitriles. In these complexes, the metal center is octahedrally surrounded by six ligands (average Zn–N 2.13 ?). Reaction of 1 with the weaker ligand F₃CCN results in dicoordination at the metal center complemented by a two-dimensional polymeric network (2b) containing bridging AsF₆ ⁻ anions. [Zn(SO₂)₄(AsF₆)₂] (1a): monoclinic, P2₁/c, a=8.5176(8) ?, b=13.5787(14) ?, c=14.7661(15) ?, β=99.296(2)°; [Zn(NCCH₃)₆][AsF₆]₂ (2a): rhombohedral, R-3, a=11.2225(8) ?, b=11.2225(8) ?, c=16.9393(14) ?; [Zn (NCCF₃)₂][μ-FAsF₅)₂( (2b): monoclinic, P2₁/c, a=11.226(3) ?, b=6.6147(19) ?, c=10.460(3) ?, β=104.028(5)°; [Zn(NCC₆H₅)₆][AsF₆]₂ (3a): monoclinic, P2₁/n, a=13.7968(10) ?, b=19.8861(15) ?, c=16.1692(12) ?, β=91.563(2)°; [Zn(NCC₆F₅)₆][AsF₆]₂·2SO₂ (3b): monoclinic, P2₁/n, a=10.8448(9) ?, b=154456(13) ?, c=17.5206(15) ?, β=104.158(1)°.     

[Ag{NCC(O)CN}<Subscript>2</Subscript>]<Subscript>n</Subscript> [SbF<Subscript>6</Subscript>]<Subscript>n</Subscript>, the first metal complex of carbonyl cyanide

The first metal complex of carbonyl cyanide [Ag{NCC(O)CN}₂]_n [SbF₆]_n was synthesized and characterized by X-ray crystallography. The silver(I) centers are bridged by the cyanide groups of the carbonyl cyanides giving a two-dimensional layer structure. The SbF₆⁻ anions are embedded in the cationic framework to neutralize the charge with only very weak contacts to the Ag⁺. The compound crystallizes in the monoclinic space group C2/c with a = 11.8737(13) Å, b = 10.2497(13) Å, c = 10.5883(13) Å, β = 90.183(3)^∘.     

A note on planar semimodular lattices

In an earlier paper, we constructed all finite, planar, semimodular lattices in three simple steps from the direct product of two finite chains. In this note we prove that one of the three steps can be eliminated. The research of the first author was supported by the NSERC of Canada.     

Auto-hydroxylation of FIH-1: an Fe(ii), alpha-ketoglutarate-dependent human hypoxia sensor

HIF-asparaginyl hydroxylase (FIH-1) normally couples O(2)-activation to hydroxylation of Asn(803) on the alpha-subunit of the hypoxia-inducible factor (HIFalpha), a key step in pO(2) sensing; in the absence of HIFalpha, O(2)-activation becomes uncoupled, leading to self-hydroxylation at Trp(296) and a purple Fe(iii)-O-Trp chromophore-this alternative reactivity may affect human hypoxia sensing.     

Turn-on fluorescence detection of H2O2 and TATP

Peroxide-based explosives, like triacetone triperoxide (TATP), are important targets for detection because of their broad use in improvised explosives but pose challenges. We report a highly sensitive turn-on fluorescence detection for H2O2 and organic peroxides, including TATP. The detection strategy relies on oxidative deboronation to unmask H2Salen, which subsequently binds Zn(2+) to form fluorescent Zn(Salen). Sensitivity is excellent, with detection limits below 10 nM for H2O2, TATP, and benzoyl peroxide. In addition, acid treatment is necessary to sense TATP, suggesting the potential to discriminate between H2O2 and TATP based upon minimal sample pretreatment.     

Tautomeric modification of GlcNAc-thiazoline

The potent O-GlcNAcase (OGA) inhibitor GlcNAc-thiazoline has been modified by buffer- or acylation-induced imine-to-enamine conversion and then electrophile or radical addition (Xn = D3, F, N3, OH, SMe, COCF3, CF3). Several functionalized GlcNAc-thiazolines show highly selective inhibition of OGA vs human hexosaminidase and thus have promise as tools for targeted investigations of OGA, an enzyme linked to diabetes and neurodegeneration. A new radical addition/fragmentation reaction of the N-(trifluoroacetyl)enamine has been discovered.     

Protonation states of ammonia/ammonium in the hydrophobic pore of ammonia transporter protein AmtB

The crystal structure of the ammonia transport (Amt) protein AmtB at 1.4 Angstrom resolution revealed four ammonia/ammonium (NH(3)/NH(4)(+)) binding sites along the approximately 20 Angstrom narrow pore. It is an open question whether the bound NH(3)/NH(4)(+) are neutral (NH(3)) or cationic (NH(4)(+)). On the basis of the AmtB crystal structure, we calculated the pK(a) of these four NH(3)/NH(4)(+) by solving the Poisson-Boltzmann equation. Except for one NH(3)/NH(4)(+) binding site (Am1) at the entry point of the Amt pore, binding sites are occupied by NH(3) due to lack of energy contributions from solvation, eliminating an existence of charged form NH(4)(+) and, inevitably, its potential cation-pi interaction. The only two titratable residues in the pore, His168 and His318, are in the neutral charge state. The NH(4)(+) charge state at the Am1 site is stabilized by Ser219 functioning as an H-bond acceptor. However, when involving explicit crystal water nearby, the NH(3) charge state is stabilized by the reorientation of Ser219-OH group. This H-bond donor Ser219 significantly decreases the pK(a) of NH(3)/ NH(4)(+) at the Am1 site to approximately 1. The flip/flop H-bond of Ser219 may play a dual role first in binding and subsequently in deprotonating NH(4)(+), which is a prerequisite to conduct NH(3) through the Amt pore across the membrane.     

Recognition and modulation of cytochrome c's redox properties using an amphiphilic homopolymer

An amphiphilic homopolymer scaffold has been used to bind to the protein, cytochrome c. This interaction is analyzed using cyclic voltammetry, native gel electrophoresis, UV-visible absorption, and circular dichroism spectroscopy. The polymer binds to cytochrome c with micromolar affinity and the association of polymer with cytochrome c leads to a structural change of the protein. This conformational change exposes the heme unit of the protein, which affords an opportunity to reversibly modulate its electron-transfer properties. We have also shown that the electrostatic binding of polymer to cytochrome c can be used to disrupt its interaction with its natural partner, cytochrome c peroxidase.