Structural and NMR Studies of the Hexameric Copper(I) Complex with N‐n‐butyl‐N′‐ethoxycarbonyl‐thioureate

The copper sulfide mineral flotation collector, N‐n‐butyl‐N′‐ethoxycarbonyl‐thiourea (H₂bectu), and the 1:1 hexameric copper(I) thioureate complex, [Cu(Hbectu)]₆, have been characterized by single crystal X‐ray diffraction. H₂bectu crystallizes in the triclinic space group with a = 5.2754(4), b = 9.0042(7), c = 12.6030(9) Å, α = 80.528(6), β = 90.173(6), γ = 76.472(7)°. An intramolecular N‐H···O hydrogen bond between the thioamide proton and carbonyl oxygen forms a planar six‐membered ring in the central core of the molecule with C=O, C=S and C‐N bond lengths in accord with those reported for other N‐alkyl/aryl‐N′‐acyl‐thiourea compounds. [Cu(Hbectu)]₆ crystallizes in the monoclinic space group C2/c with a = 23.269(5), b = 13.243(4), c = 23.037(7) Å, β = 91.81(2)° as discrete hexameric clusters disposed about a crystallographic centre of symmetry with a Cu₆S₆ core consisting of two Cu₃S₃ chair‐shaped rings linked by coordination of the deprotonated amide nitrogen atom to a copper atom in the adjacent ring. The six ligands assemble as a paddlewheel structure with the ethoxy and n‐butyl substituents packing in an alternating head to tail arrangement. Temperature dependent solution ¹H NMR spectroscopic studies show that the hexameric structure of the complex is maintained in solution.     

On achieving experimental accuracy from molecular dynamics simulations of flexible molecules: aqueous glycerol

The rotational isomeric states (RIS) of glycerol at infinite dilution have been characterized in the aqueous phase via a 1 micros conventional molecular dynamics (MD) simulation, a 40 ns enhanced sampling replica exchange molecular dynamics (REMD) simulation, and a reevaluation of the experimental NMR data. The MD and REMD simulations employed the GLYCAM06/AMBER force field with explicit treatment of solvation. The shorter time scale of the REMD sampling method gave rise to RIS and theoretical scalar 3J(HH) coupling constants that were comparable to those from the much longer traditional MD simulation. The 3J(HH) coupling constants computed from the MD methods were in excellent agreement with those observed experimentally. Despite the agreement between the computed and the experimental J-values, there were variations between the rotamer populations computed directly from the MD data and those derived from the experimental NMR data. The experimentally derived populations were determined utilizing limiting J-values from an analysis of NMR data from substituted ethane molecules and may not be completely appropriate for application in more complex molecules, such as glycerol. Here, new limiting J-values have been derived via a combined MD and quantum mechanical approach and were used to decompose the experimental 3J(HH) coupling constants into population distributions for the glycerol RIS.     

Most efficient cocaine hydrolase designed by virtual screening of transition states

Cocaine is recognized as the most reinforcing of all drugs of abuse. There is no anticocaine medication available. The disastrous medical and social consequences of cocaine addiction have made the development of an anticocaine medication a high priority. It has been recognized that an ideal anticocaine medication is one that accelerates cocaine metabolism producing biologically inactive metabolites via a route similar to the primary cocaine-metabolizing pathway, i.e., cocaine hydrolysis catalyzed by plasma enzyme butyrylcholinesterase (BChE). However, wild-type BChE has a low catalytic efficiency against the abused cocaine. Design of a high-activity enzyme mutant is extremely challenging, particularly when the chemical reaction process is rate-determining for the enzymatic reaction. Here we report the design and discovery of a high-activity mutant of human BChE by using a novel, systematic computational design approach based on transition-state simulations and activation energy calculations. The novel computational design approach has led to discovery of the most efficient cocaine hydrolase, i.e., a human BChE mutant with an approximately 2000-fold improved catalytic efficiency, promising for therapeutic treatment of cocaine overdose and addiction as an exogenous enzyme in human. The encouraging discovery resulted from the computational design not only provides a promising anticocaine medication but also demonstrates that the novel, generally applicable computational design approach is promising for rational enzyme redesign and drug discovery.     

Polymeric PARACEST agents for enhancing MRI contrast sensitivity

Linear polymers of PARACEST agents were prepared by using classical free radical chain polymerization conditions. The Eu3+-polymers exhibited similar intermediate-to-slow water exchange and CEST characteristics as the Eu3+-monomers. This provided an avenue to lower the detection limit of these imaging agents substantially and makes them potentially useful as MRI sensors for molecular imaging.     

Modulation of water exchange in europium(III) DOTA-tetraamide complexes via electronic substituent effects

The chemical exchange saturation transfer (CEST) efficiency for a series Eu3+-based tetraamide complexes bearing p-substituents on a single coordinating pendant arm is highly sensitive to water exchange rates. The CEST effect increases in the order Me < MeO < F approximately CO2tBu < CN < H. These results show that CEST contrast can be modulated by changes in electron density at a single ligating atom, and this forms the basis of creating imaging agents that respond to chemical oxidation and reduction.     

Linear solvation energy parameters for model tropospheric aerosol surfaces

Excited-state absorption spectra for several coumarin derivatives adsorbed to aerosol particles provide linear solvation energy (LSE) relationships for the aerosol surfaces. This study focuses on NaCl and (NH4)2SO(4) particles as models for tropospheric aerosol. We investigate several others, including NH(4)Cl, NaBr, KI, Na(2)SO(4), NaNO(3), Al(2)O3, and CaCO(3), to establish trends and understand the factors that control polarity for surfaces. The Kamlet-Taft dipolarity/polarizability parameter, pi*, for these particles ranges from 0.73 to 1.69. The values are high compared to most homogeneous molecular solvents and are attributable to ion-dipole forces, especially at defect sites. We also find that the smaller values of pi* (1.01 for (NH4)2SO(4) and 0.73 for NH(4)Cl) correlate with appreciable hydrogen bond donor acidity in the surface (alpha = 0.23 and 1.06, respectively). Strong hydrogen bonds with the surface lead to a drop in overall polarity either by making interaction with very polar defect sites less likely or orienting the probe molecule away from the surface. Adsorbed water layers mainly alter the alpha value of the surface, but can have indirect effects on pi* by changing the interaction of the adsorbed molecule with the surface.     

Modeling the gas flow upstream and in the sampling nozzle of the inductively coupled plasma mass spectrometer via the Direct Simulation Monte Carlo algorithm

The Direct Simulation Monte Carlo algorithm has been applied to the flow of neutral argon gas through the first vacuum stage of the Inductively Coupled Plasma Mass Spectrometer. Good agreement is found between the simulation results and the equations of fluid dynamics, including the approximate hemispherical sink model of Douglas and French. The simulation reveals details of boundary layer formation in the nozzle, including a reduction in the total flow through the nozzle of about 15% from the ideal value calculated by Douglas and French.